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1.  Priorities in pediatric epilepsy research 
Neurology  2013;81(13):1166-1175.
The Priorities in Pediatric Epilepsy Research workshop was held in the spirit of patient-centered and patient-driven mandates for developing best practices in care, particularly for epilepsy beginning under age 3 years. The workshop brought together parents, representatives of voluntary advocacy organizations, physicians, allied health professionals, researchers, and administrators to identify priority areas for pediatric epilepsy care and research including implementation and testing of interventions designed to improve care processes and outcomes. Priorities highlighted were 1) patient outcomes, especially seizure control but also behavioral, academic, and social functioning; 2) early and accurate diagnosis and optimal treatment; 3) role and involvement of parents (communication and shared decision-making); and 4) integration of school and community organizations with epilepsy care delivery. Key factors influencing pediatric epilepsy care included the child's impairments and seizure presentation, parents, providers, the health care system, and community systems. Care was represented as a sequential process from initial onset of seizures to referral for comprehensive evaluation when needed. We considered an alternative model in which comprehensive care would be utilized from onset, proactively, rather than reactively after pharmacoresistance became obvious. Barriers, including limited levels of evidence about many aspects of diagnosis and management, access to care—particularly epilepsy specialty and behavioral health care—and implementation, were identified. Progress hinges on coordinated research efforts that systematically address gaps in knowledge and overcoming barriers to access and implementation. The stakes are considerable, and the potential benefits for reduced burden of refractory epilepsy and lifelong disabilities may be enormous.
doi:10.1212/WNL.0b013e3182a55fb9
PMCID: PMC3795602  PMID: 23966254
2.  Density Spectral Array for Seizure Identification in Critically Ill Children 
PURPOSE
We evaluated the validity and inter-rater reliability of encephalographer interpretation of color density spectral array (CDSA) EEG for seizure identification in critically ill children and explored predictors of accurate seizure identification.
METHODS
Conventional EEG tracings from 21 consecutive critically ill children were scored for electrographic seizures. Four two-hour long segments from each patient were converted to 8 channel CDSA displays, yielding 84 images. Eight encephalographers received CDSA training and circled elements thought to represent seizures. Images were reviewed in random order (Group A) or with information regarding seizure presence in the initial 30 minutes and with patient images in order (Group B). Sensitivity, specificity, and inter-rater reliability were calculated. Factors associated with CDSA seizure identification were assessed.
RESULTS
Seizure prevalence was 43% on conventional EEG. Specificity was significantly higher for Group A (92.3% versus 78.2%, p<0.00). Sensitivity was not significantly different between Groups A and B (64.8% versus 75%, p=0.22). Inter-rater reliability was moderate in both groups. Ten percent of images were falsely classified as containing a seizure. Seizure duration ≥2 minutes predicted identification (p<0.001).
CONCLUSIONS
CDSA may be a useful screening tool for seizure identification by encephalographers, but it does not identify all seizures and false positives occur.
doi:10.1097/WNP.0b013e31829de01c
PMCID: PMC3743420  PMID: 23912575
Critical Care; EEG; Pediatric; Seizure; EEG monitoring
3.  Electroencephalographic Monitoring in Critically Ill Children: Current Practice and Implications for Future Study Design 
Epilepsia  2013;54(8):1419-1427.
Purpose
Survey data indicate that continuous EEG (CEEG) monitoring is used with increasing frequency to identify electrographic seizures in critically ill children, but studies of current CEEG practice have not been conducted. We aimed to describe the clinical utilization of CEEG in critically ill children at tertiary care hospitals with a particular focus on variables essential for designing feasible prospective multi-center studies evaluating the impact of electrographic seizures on outcome.
Methods
Eleven North American centers retrospectively enrolled 550 consecutive critically ill children who underwent CEEG. We collected data regarding subject characteristics, CEEG indications, and CEEG findings.
Key Findings
CEEG indications were encephalopathy with possible seizures in 67% of subjects, event characterization in 38% of subjects, and management of refractory status epilepticus in 11% of subjects. CEEG was initiated outside routine work hours in 47% of subjects. CEEG duration was <12 hours in 16%, 12-24 hours in 34%, and >24 hours in 48%. Substantial variability existed among sites in CEEG indications and neurologic diagnoses, yet within each acute neurologic diagnosis category a similar proportion of subjects at each site had electrographic seizures. Electrographic seizure characteristics including distribution and duration varied across sites and neurologic diagnoses.
Significance
These data provide a systematic assessment of recent CEEG use in critically ill children and indicate variability in practice. The results suggest that multi-center studies are feasible if CEEG monitoring pathways can be standardized. However, the data also indicate that electrographic seizure variability must be considered when designing studies addressing the impact of electrographic seizures on outcome.
doi:10.1111/epi.12261
PMCID: PMC4062191  PMID: 23848569
EEG Monitoring; Seizure; Status Epilepticus; Pediatric; Non-Convulsive Seizure
4.  Pretreatment EEG in childhood absence epilepsy 
Neurology  2013;81(2):150-156.
Objective:
In children with newly diagnosed childhood absence epilepsy (CAE), determine pretreatment EEG features and their associations with baseline neuropsychological function and short-term treatment outcome.
Methods:
In a multicenter, randomized clinical trial, patients with CAE underwent a pretreatment, 1-hour video-EEG and neuropsychological testing with freedom-from-failure and seizure-freedom (SF) outcome assessed at the 16- to 20-week visit.
Results:
Detailed evaluation of the pretreatment EEG was possible for 99.8% of participants (445/446). Median time to first seizure was 6.0 minutes (range 0–59 minutes), median number of seizures was 5 (range 1–60), and median seizure duration was 10.8 seconds (range 3.3–77.6 seconds). Median duration of shortest seizure per EEG was 7.5 seconds (range 3.0–77.6 seconds). Seizure frequency was not associated with baseline measures of attention, executive function, or treatment outcome. Presence of a seizure lasting ≥20 seconds was noted in 29% of subjects (129/440); these children had higher median omissions T score on the Conners Continuous Performance Test (56.3 vs 51.6, p = 0.01). Patients with a shortest seizure of longer duration were more likely to demonstrate treatment success by both freedom-from-failure (p = 0.02) and SF (p = 0.005) criteria, even after controlling for age, treatment group, and number of seizures, with good predictive value (area under the curve 78% for SF).
Conclusions:
CAE is reliably and quickly confirmed by EEG. Occurrence of a seizure ≥20 seconds, but not overall seizure frequency, was associated with differential baseline measures of attention. Patients whose shortest pretreatment EEG seizure was longer in duration were more likely to achieve SF, regardless of treatment.
doi:10.1212/WNL.0b013e31829a3373
PMCID: PMC3770172  PMID: 23719147
5.  Nonconvulsive Electrographic Seizures are Common in Children With Abusive Head Trauma* 
Objective
To determine the prevalence of nonconvulsive seizures in children with abusive head trauma.
Design
Retrospective study of children with abusive head trauma undergoing clinically indicated continuous electroencephalographic monitoring.
Setting
PICU of a tertiary care hospital.
Subjects
Children less than or equal to 2 years old with evidence of abusive head trauma determined by neuroimaging, physical examination, and determination of abuse by the Child Protection Team.
Interventions
None.
Measurements and Main Results
Thirty-two children with abusive head trauma were identified with a median age of 4 months (interquartile range 3, 5.5 months). Twenty-one of 32 children (66%) underwent electroencephalographic monitoring. Those monitored were more likely to have a lower admission Glasgow Coma Scale (8 vs 15, p = 0.05) and be intubated (16 vs 2, p = 0.002). Electrographic seizures occurred in 12 of 21 children (57%) and constituted electrographic status epilepticus in 8 of 12 children (67%). Electrographic seizures were entirely nonconvulsive in 8 of 12 children (67%). Electroencephalographic background category (discontinuous and slow-disorganized) (p = 0.02) and neuroimaging evidence of ischemia were associated with the presence of electrographic seizures (p = 0.05). Subjects who had electrographic seizures were no more likely to have clinical seizures at admission (67% electrographic seizures vs 33% none, p = 0.6), parenchymal imaging abnormalities (61% electrographic seizures vs 39% none, p = 0.40), or extra-axial imaging abnormalities (56% electrographic seizures vs 44% none, p = 0.72). Four of 21 (19%) children died prior to discharge; none had electrographic seizures, but all had attenuated-featureless electroencephalographic backgrounds. Follow-up outcome data were available for 16 of 17 survivors at a median duration of 9.5 months following PICU admission, and the presence of electrographic seizures or electrographic status epilepticus was not associated with the Glasgow Outcome Scale score (p = 0.10).
Conclusions
Electrographic seizures and electrographic status epilepticus are common in children with abusive head trauma. Most seizures have no clinical correlate. Further study is needed to determine whether seizure identification and management improves outcome.
doi:10.1097/PCC.0b013e3182917b83
PMCID: PMC4082326  PMID: 23842589
abusive head trauma; electroencephalographic monitoring; electroencephalography; seizure; traumatic brain injury
6.  Current Treatment of Electrographic Seizures and Status Epilepticus in Critically Ill Children: a Single Center Experience 
Purpose
Electrographic seizures (ES) and electrographic status epilepticus (ESE) are common in encephalopathic children in the pediatric intensive care unit (PICU) and associated with worse short-term outcome. Survey data indicate most physicians treat ES and ESE with antiepileptic drugs (AEDs), but few data are available regarding AED usage patterns. We aimed to describe AED usage for ES and ESE in critically ill children.
Methods
We performed an observational study of patients who underwent continuous electroencephalographic (cEEG) monitoring in the PICU of a single quaternary care children’s hospital. We collected data regarding age, clinical diagnoses, ES and ESE occurrence, and AEDs utilized.
Results
200 subjects underwent cEEG. ES occurred in 21% (41/200) and ESE occurred in 22% (43/200). Of the 84 patients with ES or ESE, 80 received non-benzodiazepine AEDs including 48% (38 of 80) with ES and 52% (42 of 80) with ESE. The most commonly administered first AEDs were levetiracetam in 38% (30/80), phenobarbital in 31% (25/80), phenytoin-fosphenytoin in 28% (22/80), and valproate in 4% (3/80). Seizures terminated after administration of the first AED in 74% (28/38) with ES and 22% (9/41) with ESE.
Conclusions
Levetiracetam, phenobarbital, and phenytoin-fosphenytoin are commonly used to manage ES and ESE at our center. Over half of subjects received multiple AEDs.
doi:10.1016/j.seizure.2013.03.008
PMCID: PMC3681868  PMID: 23601851
Seizure; Status Epilepticus; Pediatric; Critically Ill; Electroencephalogram; Anticonvulsant; Phenytoin; Fosphenytoin; Phenobarbital; Levetiracetam
7.  Pediatric ICU EEG Monitoring: Current Resources and Practice in the United States and Canada 
PURPOSE
To describe current continuous EEG (cEEG) utilization in critically ill children.
METHODS
An online survey of pediatric neurologists from 50 United States (U.S.) and 11 Canadian institutions was conducted in August 2011.
RESULTS
Responses were received from 58 of 61 (95%) surveyed institutions. Common cEEG indications are altered mental status after a seizure or status epilepticus (97%), altered mental status of unknown etiology (88%), or altered mental status with an acute primary neurological condition (88%). The median number of patients undergoing cEEG per month per center increased from August 2010 to August 2011 (6 to 10 per month in U.S., 2 to 3 per month in Canada). Few institutions have clinical pathways addressing cEEG use (31%). Physicians most commonly review cEEG twice per day (37%). There is variability regarding which services can order cEEG, the degree of neurology involvement, technologist availability, and whether technologists perform cEEG screening.
CONCLUSIONS
Among the surveyed institutions, which included primarily large academic centers, cEEG use in pediatric intensive care units is increasing and is often considered indicated for children with altered mental status at risk for non-convulsive seizures. However, there remains substantial variability in cEEG access and utilization among institutions.
doi:10.1097/WNP.0b013e31827eda27
PMCID: PMC3616267  PMID: 23545766
Critical Care; EEG; Pediatric; Survey; EEG monitoring
8.  A review of long-term EEG monitoring in critically ill children with hypoxic-ischemic encephalopathy, congenital heart disease, ECMO, and stroke 
doi:10.1097/WNP.0b013e3182872af9
PMCID: PMC3616335  PMID: 23545764
EEG monitoring; seizure; pediatric; hypoxia-ischemia; stroke; ECMO; cardiac arrest; congenital heart disease; status epilepticus
9.  Electrographic seizures in pediatric ICU patients 
Neurology  2013;81(4):383-391.
Objectives:
We aimed to determine the incidence of electrographic seizures in children in the pediatric intensive care unit who underwent EEG monitoring, risk factors for electrographic seizures, and whether electrographic seizures were associated with increased odds of mortality.
Methods:
Eleven sites in North America retrospectively reviewed a total of 550 consecutive children in pediatric intensive care units who underwent EEG monitoring. We collected data on demographics, diagnoses, clinical seizures, mental status at EEG onset, EEG background, interictal epileptiform discharges, electrographic seizures, intensive care unit length of stay, and in-hospital mortality.
Results:
Electrographic seizures occurred in 162 of 550 subjects (30%), of which 61 subjects (38%) had electrographic status epilepticus. Electrographic seizures were exclusively subclinical in 59 of 162 subjects (36%). A multivariable logistic regression model showed that independent risk factors for electrographic seizures included younger age, clinical seizures prior to EEG monitoring, an abnormal initial EEG background, interictal epileptiform discharges, and a diagnosis of epilepsy. Subjects with electrographic status epilepticus had greater odds of in-hospital death, even after adjusting for EEG background and neurologic diagnosis category.
Conclusions:
Electrographic seizures are common among children in the pediatric intensive care unit, particularly those with specific risk factors. Electrographic status epilepticus occurs in more than one-third of children with electrographic seizures and is associated with higher in-hospital mortality.
doi:10.1212/WNL.0b013e31829c5cfe
PMCID: PMC3772834  PMID: 23794680
10.  Electrographic Status Epilepticus is Associated with Mortality and Worse Short-Term Outcome in Critically Ill Children 
Critical care medicine  2013;41(1):210-218.
Objectives
Electrographic seizures (ES) and electrographic status epilepticus (ESE) are common in critically ill children. We aimed to determine whether ES and ESE are associated with higher mortality or worse short-term neurologic outcome.
Design
Prospective observational study.
Setting
Pediatric intensive care unit of a tertiary children’s hospital.
Patients
Non-neonatal children admitted to a pediatric intensive care unit (PICU) with acute encephalopathy underwent continuous electroencephalographic (cEEG) monitoring. EEGs were scored as (1) no seizures, (2) ES, or (3) ESE. Covariates included age, acute neurologic disorder category, prior neurodevelopmental status, sex, and EEG background category. Outcomes were mortality and worsening of Pediatric Cerebral Performance Category (PCPC) from pre-admission to PICU discharge. Chi-squared analysis, Fisher’s exact test, and multivariable logistic regression were used to evaluate the associations between ES or ESE and mortality or short-term neurologic outcome, using odds ratios (OR) and 95% confidence intervals (95%CI).
Interventions
None
Main Results
Two hundred children underwent cEEG. Eighty-four (42%) had seizures which were categorized as ES in 41 (20.5%) and ESE in 43 (21.5%). Thirty-six subjects (18%) died and 88 subjects (44%) had PCPC worsening. In multivariable analysis ESE was associated with an increased risk of mortality (OR 5.1; 95%CI 1.4, 18, p=0.01) and PCPC worsening (OR 17.3; 95%CI 3.7, 80, p<0.001) while ES was not associated with an increased risk of mortality (OR 1.3; 95%CI 0.3, 5.1; p=0.74) or PCPC worsening (OR 1.2; 95%CI 0.4, 3.9; p=0.77).
Conclusions
ESE, but not ES, is associated with mortality and worse short-term neurologic outcome in critically ill children with acute encephalopathy.
doi:10.1097/CCM.0b013e3182668035
PMCID: PMC3531581  PMID: 23164815
EEG Monitoring; Seizure; Status Epilepticus; Pediatric; Outcome; Non-Convulsive Seizure
11.  Ethosuximide, Valproic Acid and Lamotrigine in Childhood Absence Epilepsy: Initial Monotherapy Outcomes at 12 months 
Epilepsia  2012;54(1):141-155.
Purpose
Determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy based on 12 months of double blind therapy.
Methods
A double-blind, randomized controlled clinical trial compared the efficacy, tolerability and neuropsychological effects of ethosuximide, valproic acid and lamotrigine in children with newly diagnosed childhood absence epilepsy. Study medications were titrated to clinical response and subjects remained in the trial unless they reached a treatment failure criterion. Maximal target doses were ethosuximide 60 mg/kg/day or 2000 mg/day, valproic acid 60 mg/kg/day or 3000 mg/day and lamotrigine 12 mg/kg/day or 600 mg/day. Original primary outcome was at 16–20 weeks and included a video EEG assessment. For this report, the main effectiveness outcome was the freedom from failure rate 12 months after randomization and included a video EEG assessment; differential drug effects were determined by pairwise comparisons. The main cognitive outcome was the percentage of subjects experiencing attentional dysfunction at the Month 12 visit.
Key Findings
A total of 453 children were enrolled and randomized; seven were deemed ineligible and 446 subjects comprised the overall efficacy cohort. There were no demographic differences between the three cohorts. By 12 months after starting therapy, only 37% of all enrolled subjects were free from treatment failure on their first medication. At the Month 12 visit, the freedom-from-failure rates for ethosuximide and valproic acid were similar (45% and 44%, respectively; odds ratio with valproic acid vs. ethosuximide, 0.94; 95% confidence interval [CI], 0.60 to 1.48; P = 0.82) and were higher than the rate for lamotrigine (21%; odds ratio with ethosuximide vs. lamotrigine, 3.09; 95% CI, 1.86 to 5.13; odds ratio with valproic acid vs. lamotrigine, 2.90; 95% CI, 1.74 to 4.83; P<0.001 for both comparisons). The frequency of treatment failures due to lack of seizure control (p < 0.001) and intolerable adverse events (p < 0.037) were significantly different among the treatment groups. Almost two thirds of the 125 subjects with treatment failure due to lack of seizure control were in the lamotrigine cohort. The largest subgroup (42%) of the 115 subjects discontinuing due to adverse events were in the valproic acid group. The previously reported higher rate of attentional dysfunction seen at 16–20 weeks in the valproic acid group compared with the ethosuximide or lamotrigine groups persisted at 12 months (p < 0.01).
Significance
As initial monotherapy, the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine in controlling seizures without intolerable adverse events noted at 16–20 weeks persisted at 12 months. The valproic acid cohort experienced a higher rate of adverse events leading to drug discontinuation as well as significant negative effects on attentional measures that were not seen in the ethosuximide cohort. These 12 month outcome data coupled with the study’s prespecified decision making algorithm indicates that ethosuximide is the optimal initial empirical monotherapy for childhood absence epilepsy. This is the first randomized controlled trial meeting ILAE criteria for Class I evidence for childhood absence epilepsy (or for any type of generalized seizure in adults or children). (NCT00088452.)
doi:10.1111/epi.12028
PMCID: PMC3538883  PMID: 23167925
Randomized Clinical Trial; Pediatric Epilepsy; Epilepsy Syndrome Treatment
12.  Mapping and mining interictal pathological gamma (30–100 Hz) oscillations with clinical intracranial EEG in patients with epilepsy 
Expert systems with applications  2012;39(8):7355-7370.
Localizing an epileptic network is essential for guiding neurosurgery and antiepileptic medical devices as well as elucidating mechanisms that may explain seizure-generation and epilepsy. There is increasing evidence that pathological oscillations may be specific to diseased networks in patients with epilepsy and that these oscillations may be a key biomarker for generating and indentifying epileptic networks. We present a semi-automated method that detects, maps, and mines pathological gamma (30–100 Hz) oscillations (PGOs) in human epileptic brain to possibly localize epileptic networks. We apply the method to standard clinical iEEG (<100 Hz) with interictal PGOs and seizures from six patients with medically refractory epilepsy. We demonstrate that electrodes with consistent PGO discharges do not always coincide with clinically determined seizure onset zone (SOZ) electrodes but at times PGO-dense electrodes include secondary seizure-areas (SS) or even areas without seizures (NS). In 4/5 patients with epilepsy surgery, we observe poor (Engel Class 4) post-surgical outcomes and identify more PGO-activity in SS or NS than in SOZ. Additional studies are needed to further clarify the role of PGOs in epileptic brain.
doi:10.1016/j.eswa.2012.01.071
PMCID: PMC3480232  PMID: 23105174
Epileptic network; Interictal epileptic discharge; Pathological gamma oscillation; Detection; Mapping; Data-mining
13.  EEG Monitoring in Critically Ill Children: Indications and Strategies 
Pediatric Neurology  2012;46(3):158-161.
Continuous electroencephalographic monitoring often detects non-convulsive seizures in critically ill children, but is resource intense and has not been shown to improve outcome. As institutions develop clinical pathways for monitoring, it is important to consider how seemingly minor variations may have a substantial impact on resource utilization and cost. We performed a one month prospective observational study in which each patient in a 45-bed pediatric intensive care unit was screened for potential monitoring indications. 247 patients were screened. Minor differences in monitoring indications would have a substantial impact on resource utilization. We then calculated the number of monitoring days that would be required each month based on two strategies that differed in monitoring duration. The prolonged-targeted and brief-targeted strategies would have required 106 and 33 monitoring days, respectively. Based on published non-convulsive seizure occurrence data, these strategies would detect 0.14, and 0.43 patients with seizures per monitoring day performed, respectively. A brief-targeted strategy provides a high yield for non-convulsive seizure identification, but would fail to diagnose some patients with seizures.
doi:10.1016/j.pediatrneurol.2011.12.009
PMCID: PMC3286021  PMID: 22353290
EEG Monitoring; Non-Convulsive Seizure; Pediatric
14.  Common Data Elements in Epilepsy Research: Development and Implementation of the NINDS Epilepsy CDE Project 
Epilepsia  2011;52(6):1186-1191.
Summary
The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection, decrease study start-up time, and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antepileptic Therapies (AETs), )2) Comorbidities, (3) Electrophysiology, (4) Imaging,(5) Neurological Exam, (6) Neuropsychology,(7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward “harmonization” of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during their further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.
doi:10.1111/j.1528-1167.2011.03018.x
PMCID: PMC3535455  PMID: 21426327
Research; Epilepsy; National Institute of Neurological Disorders and Stroke
15.  Outcome prediction by motor and pupillary responses in children treated with therapeutic hypothermia after cardiac arrest 
Objective
Clinical neurologic signs considered predictive of adverse outcome after pediatric cardiac arrest (CA) may have a different prognostic value in the setting of therapeutic hypothermia (TH). We aimed to determine the prognostic value of motor and pupillary responses in children treated with TH after CA.
Design
Prospective cohort study.
Setting
Pediatric ICU in tertiary care hospital.
Patients
Children treated with TH after CA.
Measurements and Main Results
Thirty-five children treated with TH after CA were prospectively enrolled. Examinations were performed by emergency medicine physicians and intensive care unit bedside nurses. Examinations were performed after resuscitation, 1 hour after achievement of hypothermia, during the last hour of hypothermia, 1 hour after achievement of normothermia, after 24 hours of normothermia, and after 72 hours of normothermia. The primary outcome was unfavorable outcome at ICU discharge, defined as a Pediatric Cerebral Performance Category (PCPC) score of 4–6 at hospital discharge. The secondary outcome was death (PCPC = 6). The associations between exam responses and unfavorable outcomes (as both PCPC 4,5,6 and PCPC 6) are presented as positive predictive values (PPV), for both all subjects and subjects not receiving paralytics. Statistical significance for these comparisons was determined using Fisher’s exact test. At all examination times and examination categories PPV is higher for the unfavorable outcome PCPC 4,5,6 than PCPC 6. By normothermia hour 24, absent motor and pupil responses were highly predictive of unfavorable outcome (PCPC 4,5,6) (PPV 100% and p<0.03 for all categories), while at earlier times the predictive value was lower.
Conclusions
Absent motor and pupil responses are more predictive of unfavorable outcome when defined more broadly than when defined as only death. Absent motor and pupil responses during hypothermia and soon after return of spontaneous circulation were not predictive of unfavorable outcome while absent motor and pupil responses once normothermic were predictive of unfavorable short-term outcome. Further study is needed using more robust short-term and long-term outcome measures.
doi:10.1097/PCC.0b013e3182196a7b
PMCID: PMC3264396  PMID: 21499174
Therapeutic Hypothermia; Neurological Examination; Pediatric; Hypoxic Ischemic Encephalopathy; Cardiac Arrest; Prognosis
16.  Impact of Continuous EEG Monitoring on Clinical Management in Critically Ill Children 
Neurocritical care  2011;15(1):70-75.
Background
Continuous EEG (cEEG) monitoring is being used with increasing frequency in critically ill patients, most often to detect non-convulsive seizures. While cEEG is non-invasive and feasible in the critical care setting, it is also expensive and labor intensive, and there has been little study of its impact on clinical care. We aimed to determine prospectively the impact of cEEG on clinical management in critically ill children.
Methods
Critically ill children (non-neonates) with acute encephalopathy underwent cEEG. Study enrollment and data collection were prospective.
Results
100 children were studied. EEG monitoring led to specific clinical management changes in 59 children. These included initiating or escalating anti-seizure medications in 43 due to seizure detection, demonstrating that a specific event (subtle movement or vital sign change) was not a seizure in 21, or obtaining urgent neuroimaging that led to a clinical change in 3. In the remaining 41 children, cEEG ruled out the presence of non-convulsive seizures but did not lead to a specific change in clinical management.
Conclusions
EEG monitoring led to changes in clinical management in the majority of patients, suggesting it may have an important role in management of critically ill children. Further study is needed to determine whether the management changes elicited by cEEG improve outcome.
doi:10.1007/s12028-010-9380-z
PMCID: PMC3134111  PMID: 20499208
Seizure; Status epilepticus; Pediatric; Critically Ill; Electroencephalogram; EEG monitoring
17.  Electrographic Seizures During Therapeutic Hypothermia for Neonatal Hypoxic-ischemic Encephalopathy 
Journal of child neurology  2011;26(6):724-728.
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.
doi:10.1177/0883073810390036
PMCID: PMC3102150  PMID: 21447810
hypothermia; induced; infant; seizures; electroencephalography; hypoxia-ischemia; brain
18.  Levetiracetam for Treatment of Neonatal Seizures 
Journal of child neurology  2011;26(4):465-470.
Neonatal seizures are often refractory to treatment with initial antiseizure medications. Consequently, clinicians turn to alternatives such as levetiracetam, despite the lack of published data regarding its safety, tolerability, or efficacy in the neonatal population. We report a retrospectively identified cohort of 23 neonates with electroencephalographically confirmed seizures who received levetiracetam. Levetiracetam was considered effective if administration was associated with a greater than 50% seizure reduction within 24 hours. Levetiracetam was initiated at a mean conceptional age of 41 weeks. The mean initial dose was 16 ± 6 mg/kg and the mean maximum dose was 45 ± 19 mg/kg/day. No respiratory or cardiovascular adverse effects were reported or detected. Levetiracetam was associated with a greater than 50% seizure reduction in 35% (8 of 23), including seizure termination in 7. Further study is warranted to determine optimal levetiracetam dosing in neonates and to compare efficacy with other antiseizure medications.
doi:10.1177/0883073810384263
PMCID: PMC3082578  PMID: 21233461
neonatal seizures; status epilepticus; levetiracetam; anticonvulsant
19.  Short-Term Outcome Prediction by Electroencephalographic Features in Children Treated with Therapeutic Hypothermia After Cardiac Arrest 
Neurocritical care  2011;14(1):37-43.
Background
Electroencephalographic (EEG) features may provide objective data regarding prognosis in children resuscitated from cardiac arrest (CA), but therapeutic hypothermia (TH) may impact its predictive value. We aimed to determine whether specific EEG features were predictive of short-term outcome in children treated with TH after CA, both during hypothermia and after return to normothermia.
Methods
Thirty-five children managed with a standard clinical TH algorithm after CA were prospectively enrolled. EEG recordings were scored in a standardized manner and categorized. EEG category 1 consisted of continuous and reactive tracings. EEG category 2 consisted of continuous but unreactive tracings. EEG category 3 included those with any degree of discontinuity, burst suppression, or lack of cerebral activity. The primary outcome was unfavorable short-term outcome defined as Pediatric Cerebral Performance Category score of 4–6 (severe disability, vegetative, death) at hospital discharge. Univariate analyses of the association between EEG category and outcome was performed using logistic regression.
Results
For tracings obtained during hypothermia, patients with EEGs in categories 2 or 3 were far more likely to have poor outcome than those in category 1 (OR 10.7, P = 0.023 and OR 35, P = 0.004, respectively). Similarly, for tracings obtained during normothermia, patients with EEGs in categories 2 or 3 were far more likely to have poor outcomes than those in category 1 (OR 27, P = 0.006 and OR 18, P = 0.02, respectively).
Conclusions
A simple EEG classification scheme has predictive value for short-term outcome in children undergoing TH after CA.
doi:10.1007/s12028-010-9450-2
PMCID: PMC3086560  PMID: 20890677
Therapeutic hypothermia; Outcome; Pediatric; Hypoxic ischemic encephalopathy; Heart arrest; Prognosis
20.  Interobserver reproducibility of electroencephalogram interpretation in critically ill children 
Purpose
Correct outcome prediction after cardiac arrest in children may improve clinical decision making and family counseling. Various investigators have used EEG to predict outcome with varying success, but one limiting issue is the potential lack of reproducibility of EEG interpretation. Therefore, we aimed to evaluate interobserver agreement using standardized terminology in the interpretation of EEG tracings obtained from critically ill children following cardiac arrest.
Methods
3 pediatric neurophysiologists scored 74 EEG samples using standardized categories, terminology, and interpretation rules. Interobserver agreement was evaluated using kappa and intra-class correlation coefficients.
Results
Agreement was substantial for the categories of continuity, burst suppression, sleep architecture, and overall rating. Agreement was moderate for seizure occurrence and inter-ictal epileptiform discharge type. Agreement was fair for inter-ictal epileptiform discharge presence, beta activity, predominant frequency, and fastest frequency. Agreement was slight for maximum voltage and focal slowing presence.
Conclusions
The variability of inter-rater agreement suggests that some EEG features are superior to others for use in a predictive algorithm. Using only reproducible EEG features is needed to ensure the most accurate and consistent predictions. Since even seizure identification had only moderate agreement, studies of non-convulsive seizures in critically ill patients must be conducted and interpreted cautiously.
doi:10.1097/WNP.0b013e3182051123
PMCID: PMC3107383  PMID: 21221016
Electroencephalogram; Interobserver variability; Seizure; Pediatric; Hypoxic Ischemic Encephalopathy; Cardiac Arrest
21.  Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures 
Objective
Intravenous (IV) levetiracetam (LEV) is approved for use in patients older than 16 years and may be useful in critically ill children, although there is little data available regarding pharmacokinetics. We aim to investigate the safety, an appropriate dosing, and efficacy of IV LEV in critically ill children.
Design
We describe a cohort of critically ill children who received IV LEV for status epilepticus, including refractory or nonconvulsive status, or acute repetitive seizures.
Results
There were no acute adverse effects noted. Children had temporary cessation of ongoing refractory status epilepticus, termination of ongoing nonconvulsive status epilepticus, cessation of acute repetitive seizures, or reduction in epileptiform discharges with clinical correlate.
Conclusions
IV LEV was effective in terminating status epilepticus or acute repetitive seizures and well tolerated in critically ill children. Further study is needed to elucidate the role of IV LEV in critically ill children.
doi:10.1097/PCC.0b013e3181a0e1cf
PMCID: PMC2946960  PMID: 19325512
levetiracetam; status epilepticus; seizure; pediatric
22.  Use of EEG Monitoring and Management of Non-Convulsive Seizures in Critically Ill Patients: A Survey of Neurologists 
Neurocritical care  2010;12(3):382-389.
Background
Continuous EEG monitoring (cEEG) of critically ill patients is frequently utilized to detect non-convulsive seizures (NCS) and status epilepticus (NCSE). The indications for cEEG, as well as when and how to treat NCS, remain unclear. We aimed to describe the current practice of cEEG in critically ill patients to define areas of uncertainty that could aid in designing future research.
Methods
We conducted an international survey of neurologists focused on cEEG utilization and NCS management.
Results
Three-hundred and thirty physicians completed the survey. 83% use cEEG at least once per month and 86% manage NCS at least five times per year. The use of cEEG in patients with altered mental status was common (69%), with higher use if the patient had a prior convulsion (89%) or abnormal eye movements (85%). Most respondents would continue cEEG for 24 h. If NCS or NCSE is identified, the most common anticonvulsants administered were phenytoin/fosphenytoin, lorazepam, or levetiracetam, with slightly more use of levetiracetam for NCS than NCSE.
Conclusions
Continuous EEG monitoring (cEEG) is commonly employed in critically ill patients to detect NCS and NCSE. However, there is substantial variability in current practice related to cEEG indications and duration and to management of NCS and NCSE. The fact that such variability exists in the management of this common clinical problem suggests that further prospective study is needed. Multiple points of uncertainty are identified that require investigation.
doi:10.1007/s12028-010-9337-2
PMCID: PMC2944658  PMID: 20198513
Continuous EEG; Non-convulsive seizure; Non-convulsive status epilepticus; Anticonvulsant; Monitoring
23.  Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy 
The New England journal of medicine  2010;362(9):790-799.
BACKGROUND
Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with ethosuximide, valproic acid, or lamotrigine. The most efficacious and tolerable initial empirical treatment has not been defined.
METHODS
In a double-blind, randomized, controlled clinical trial, we compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy. Drug doses were incrementally increased until the child was free of seizures, the maximal allowable or highest tolerable dose was reached, or a criterion indicating treatment failure was met. The primary outcome was freedom from treatment failure after 16 weeks of therapy; the secondary outcome was attentional dysfunction. Differential drug effects were determined by means of pairwise comparisons.
RESULTS
The 453 children who were randomly assigned to treatment with ethosuximide (156), lamotrigine (149), or valproic acid (148) were similar with respect to their demographic characteristics. After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar (53% and 58%, respectively; odds ratio with valproic acid vs. ethosuximide, 1.26; 95% confidence interval [CI], 0.80 to 1.98; P = 0.35) and were higher than the rate for lamotrigine (29%; odds ratio with ethosuximide vs. lamotrigine, 2.66; 95% CI, 1.65 to 4.28; odds ratio with valproic acid vs. lamotrigine, 3.34; 95% CI, 2.06 to 5.42; P<0.001 for both comparisons). There were no significant differences among the three drugs with regard to discontinuation because of adverse events. Attentional dysfunction was more common with valproic acid than with ethosuximide (in 49% of the children vs. 33%; odds ratio, 1.95; 95% CI, 1.12 to 3.41; P = 0.03).
CONCLUSIONS
Ethosuximide and valproic acid are more effective than lamotrigine in the treatment of childhood absence epilepsy. Ethosuximide is associated with fewer adverse attentional effects. (ClinicalTrials.gov number, NCT00088452.)
doi:10.1056/NEJMoa0902014
PMCID: PMC2924476  PMID: 20200383
24.  Human and Automated Detection of High-Frequency Oscillations in Clinical Intracranial EEG Recordings 
Objective
Recent studies indicate that pathologic high-frequency oscillations (HFOs) are signatures of epileptogenic brain. Automated tools are required to characterize these events. We present a new algorithm tuned to detect HFOs from 30 – 85 Hz, and validate it against human expert electroencephalographers.
Methods
We randomly selected 28 3-minute single-channel epochs of intracranial EEG (IEEG) from two patients. Three human reviewers and three automated detectors marked all records to identify candidate HFOs. Subsequently, human reviewers verified all markings.
Results
A total of 1,330 events were collectively identified. The new method presented here achieved 89.7% accuracy against a consensus set of human expert markings. A one-way ANOVA determined no difference between the mean F-measures of the human reviewers and automated algorithm. Human Kappa statistics (mean κ = 0.38) demonstrated marginal identification consistency, primarily due to false negative errors.
Conclusions
We present an HFO detector that improves upon existing algorithms, and performs as well as human experts on our test data set. Validation of detector performance must be compared to more than one expert because of interrater variability.
Significance
This algorithm will be useful for analyzing large EEG databases to determine the pathophysiological significance of HFO events in human epileptic networks.
doi:10.1016/j.clinph.2006.12.019
PMCID: PMC2020804  PMID: 17382583
high-frequency oscillation; HFO; intracranial EEG; epilepsy

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