Hearing Loss after Cardiac Surgery in Infancy: An Unintended Consequence of Life-Saving Care.

OBJECTIVES: To investigate the prevalence of hearing loss after cardiac surgery in infancy, patient and operative factors associated with hearing loss, and the relationship of hearing loss to neurodevelopmental outcomes. STUDY DESIGN: Audiologic and neurodevelopmental evaluations were conducted on 348 children who underwent repair of congenital heart disease at the Children's Hospital of Philadelphia as part of a prospective study evaluating neurodevelopmental outcomes at 4 years of age. A prevalence estimate was calculated based on presence and type of hearing loss. Potential risk factors and the impact of hearing loss on neurodevelopmental outcomes were evaluated. RESULTS: The prevalence of hearing loss was 21.6% (95% CI, 17.2-25.9). The prevalence of conductive hearing loss, sensorineural hearing loss, and indeterminate hearing loss were 12.4% (95% CI, 8.8-16.0), 6.9% (95% CI, 4.1-9.7), and 2.3% (95% CI, 0.6-4.0), respectively. Only 18 of 348 subjects (5.2%) had screened positive for hearing loss before this study and 10 used a hearing aid. After adjusting for patient and operative covariates, younger gestational age, longer postoperative duration of stay, and a confirmed genetic anomaly were associated with hearing loss (all P < .01). The presence of hearing loss was associated with worse language, cognition and attention (P <.01). CONCLUSIONS: These findings suggest that the prevalence of hearing loss in preschool children after heart surgery in infancy may be 20-fold higher than in the 1% prevalence seen in the general population. Younger gestational age, presence of a genetic anomaly, and longer postoperative duration of stay were associated with hearing loss. Hearing loss was associated with worse neurodevelopmental outcomes.

Plasma topiramate concentrations resulting from doses associated with neuroprotection against white matter injury and stroke in two strains of rat pups.

BACKGROUND: Cerebral white matter (WM) injury and stroke are common neuropathological injuries in newborns with congenital heart defects (CHDs) requiring surgery. Previous investigations in Long Evans rat pups subjected to hypoxia-ischemia found that intraperitoneal (i.p.) topiramate (TPM) at 30 mg/kg, but not 50 mg/kg, conferred neuroprotection. In Sprague-Dawley pups, a dose of 30 mg/kg protected against stroke. Concentrations associated with neuroprotective doses were not measured. The aims of this investigation were to determine concentrations associated with neuroprotective doses and to investigate the pharmacokinetics (PK) of i.p. TPM. METHODS: Concentration-time data following administration of 30 and 50 mg/kg doses were analyzed using nonlinear mixed-effect modeling. RESULTS: Mean predicted steady-state maximum and average concentrations following 30 mg/kg TPM were 31.3 and 16.8 µg/ml in Long Evans and 39.9 and 24.4 µg/ml in Sprague-Dawley pups. Mean predicted steady-state maximum and average concentrations following 50 mg/kg TPM were 52.1 and 28.1 µg/ml in Long Evans and 66.5 and 40.6 µg/ml in Sprague-Dawley pups. The apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.0470 ml/min and 22.2 ml, respectively, for Long Evans and 0.0325 ml/min and 19.7 ml, respectively, for Sprague-Dawley pups. CONCLUSION: TPM concentrations associated with neuroprotective doses were determined. Body size and strain were significant covariates on CL/F and V/F. Results provide targets for future neuroprotection studies.

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 may have a different prognostic value in the setting of therapeutic hypothermia. We aimed to determine the prognostic value of motor and pupillary responses in children treated with therapeutic hypothermia after cardiac arrest. DESIGN: Prospective cohort study. SETTING: Pediatric intensive care unit in tertiary care hospital. PATIENTS: Children treated with therapeutic hypothermia after cardiac arrest. MEASUREMENTS AND MAIN RESULTS: Thirty-five children treated with therapeutic hypothermia after cardiac arrest were prospectively enrolled. Examinations were performed by emergency medicine physicians and intensive care unit bedside nurses. Examinations were performed after resuscitation, 1 hr after achievement of hypothermia, during the last hour of hypothermia, 1 hr after achievement of normothermia, after 24 hrs of normothermia, and after 72 hrs of normothermia. The primary outcome was unfavorable outcome at intensive care unit discharge, defined as a pediatric cerebral performance category score of 4-6 at hospital discharge. The secondary outcome was death (pediatric cerebral performance category = 6). The associations between exam responses and unfavorable outcomes (as both pediatric cerebral performance category 4, 5, 6 and pediatric cerebral performance category 6) are presented as positive predictive values, 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, positive predictive values were higher for the unfavorable outcome pediatric cerebral performance category 4, 5, 6 than the pediatric cerebral performance category 6. By normothermia hour 24, absent motor and pupil responses were highly predictive of unfavorable outcome (pediatric cerebral performance category 4, 5, 6) (positive predictive value 100% and p < .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.

Impact of continuous EEG monitoring on clinical management in critically ill children.

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.

Short-term outcome prediction by electroencephalographic features in children treated with therapeutic hypothermia after cardiac arrest.

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.

Reliability and accuracy of EEG interpretation for estimating age in preterm infants.

OBJECTIVES: To determine the accuracy of, and agreement among, EEG and aEEG readers' estimation of maturity and a novel computational measure of functional brain age (FBA) in preterm infants. METHODS: Seven experts estimated the postmenstrual ages (PMA) in a cohort of recordings from preterm infants using cloud-based review software. The FBA was calculated using a machine learning-based algorithm. Error analysis was used to determine the accuracy of PMA assessments and intraclass correlation (ICC) was used to assess agreement between experts. RESULTS: EEG recordings from a PMA range 25 to 38 weeks were successfully interpreted. In 179 recordings from 62 infants interpreted by all human readers, there was moderate agreement between experts (aEEG ICC = 0.724; 95%CI:0.658-0.781 and EEG ICC = 0.517; 95%CI:0.311-0.664). In 149 recordings from 61 infants interpreted by all human readers and the FBA algorithm, random and systematic errors in visual interpretation of PMA were significantly higher than the computational FBA estimate. Tracking of maturation in individual infants showed stable FBA trajectories, but the trajectories of the experts' PMA estimate were more likely to be obscured by random errors. The accuracy of visual interpretation of PMA estimation was compromised by neurodevelopmental outcome for both aEEG and EEG review. INTERPRETATION: Visual assessment of infant maturity is possible from the EEG or aEEG, with an average of human experts providing the highest accuracy. Tracking PMA of individual infants was hampered by errors in experts' estimates. FBA provided the most accurate maturity assessment and has potential as a biomarker of early outcome.

Assessment of neonatal electroencephalography (EEG) background by conventional and two amplitude-integrated EEG classification systems.

OBJECTIVE: To determine the agreement among conventional electroencephalography (CEEG) terminology background classification and a simple and an advanced amplitude-integrated EEG (aEEG) system, and to evaluate whether aEEG interpreter experience or electrographic seizures affect this agreement. STUDY DESIGN: CEEG background was classified by traditional interpretive criteria for 144 neonatal recordings, from which a single channel was converted to aEEGs. These aEEGs were independently interpreted by neonatologists according to the simple and advanced classification systems. RESULTS: Interreader agreement was better with the simple aEEG system compared with the advanced aEEG system (multirater kappa, 0.66 vs 0.44). Fair-to-moderate agreement was found between both of the aEEG classification systems and CEEG (simple: kappa, 0.34 to 0.45; advanced: kappa, 0.36 to 0.45). Agreement did not vary significantly based on the aEEG interpreter experience or the presence of seizures. CONCLUSIONS: Neonatologists found better agreement using the simple aEEG system regardless of their expertise or the presence of seizures. This finding has implications for patient selection in future multicenter neonatal neuroprotection studies.

Characterization of neonatal seizures by conventional EEG and single-channel EEG.

OBJECTIVE: To perform a detailed, contemporary temporal-spatial characterization of neonatal seizures (NS) and to compare conventional EEG (CEEG) to single-channel EEG for NS detection. METHODS: Digitally recorded CEEGs were reviewed for NS characteristics (quantity, duration, location of onset, peak-to-peak amplitude). The presence and characteristics of each NS were simultaneously noted in a single, derived EEG channel (C3-->C4). RESULTS: Eight hundred fifty-one seizures from 125 CEEGs recorded were analyzed. Mean seizure rate was 7.0 NS/h (range: 0.5-21). Mean seizure burden (percent time CEEG showed NS at any location) was 24.8% (range: 0.7-86.9). Seizure rate was only moderately correlated with seizure burden (Spearman coefficient=0.58). Eighty-one percent of NS originated from central-temporal or midline vertex electrodes. Seventy-eight percent of NS appeared in the C3-->C4 channel. CONCLUSIONS: Accurate measurement of NS burden requires detailed temporal-spatial characterization. The theoretical ceiling of sensitivity for NS detection in the single EEG channel C3-->C4 is high. However, further processing the raw EEG in limited electrode arrays may reduce the sensitivity of NS detection. SIGNIFICANCE: CEEG is the gold standard for NS detection. However, reduced montage EEG techniques are increasingly available. This detailed contemporary temporal-spatial characterization of NS evaluates the potential limitations of reduced montage techniques.

Measuring the Severity of Neonatal Seizures: Temporal-Spatial Burden.

PURPOSE: The American Clinical Neurophysiology Society recommends measuring neonatal seizures' severity by their frequency (number of seizures-anywhere per hour), burden (percentage of time with seizures-anywhere), or on a region-by-region, temporal-spatial basis. This study compares two reduced-channel montages for temporal-spatial seizure burden analyses and examines the agreement of seizures' quantification among these three methodologies. METHODS: A convenience sample of 10 neonatal electroencephalograms was annotated for the beginnings and ends of seizures, which appeared anywhere in the full neonatal montage, then repeated on a more precise, region-by-region basis using 2 reduced-channel montages A and B. Seizure severity was measured by seizures-anywhere frequency, seizures-anywhere burden, and temporal-spatial seizure burdens using montages A and B. The results were compared by measuring their correlation and by linear regression modeling. RESULTS: Seizures-anywhere frequency was correlated with seizures-anywhere burden (ρ = 0.77). However, a narrow range of seizures-anywhere frequencies corresponded with a broad range of seizures-anywhere burdens. Although there was high correlation between seizures-anywhere burdens and temporal-spatial seizure burdens (ρ = 0.92 montage A, ρ = 0.90 montage B), seizures-anywhere burdens were insensitive to variations in the spatial aspects of seizures, which were highly prevalent even in this small sample set. After adjusting for intrareader variability, the temporal-spatial seizure burdens measured by montages A and B were not significantly different (P = 0.56). CONCLUSIONS: The severity of neonatal seizures is poorly represented by simple measures such as seizures-anywhere frequencies or burdens. The use of temporal-spatial seizure burden measurements is supported in work where great precision in quantifying neonatal seizures is required.

Rates of autism and potential risk factors in children with congenital heart defects.

OBJECTIVE: Atypical development, behavioral difficulties, and academic underachievement are common morbidities in children with a history of congenital heart defects and impact quality of life. Language and social-cognitive deficits have been described, which are associated with autism spectrum disorders. The current study aimed to assess the rates of autism spectrum disorders in a large sample of children with a history of congenital heart defects and to assess medical, behavioral, and individual factors that may be associated with the risk of autism spectrum disorders. DESIGN: Participants included 195 children with a history of congenital heart defects, who are followed in a large-scale longitudinal study. Measures included behavioral data from 4-year-old neurodevelopmental evaluations and parent-report data from a later annual follow-up. RESULTS: Using established cutoffs on an autism spectrum disorder screener, children with congenital heart defects showed higher rates of "possible" autism spectrum disorders than national rates, (Chi-square Test of Equal Proportions), all Ps < .05. A stepwise variable selection method was used to create a "best prediction model" and multivariable logistic regression was used to identify variables predicting diagnostic status. Factors associated with diagnostic risk included medical (delayed sternal closure, prematurity, positive genetic findings), behavioral (cognitive, language, attention issues), and individual (socioeconomic, cultural/racial) variables. ROC analyses identified a cutoff of 7 to maximize sensitivity/specificity based on parent-reported diagnosis. CONCLUSIONS: Risk of autism spectrum disorder screening status in children with congenital heart defects was higher than expected from population rates. Findings highlight the need for referral to a specialist to assess the presence and severity of social-communication issues and congenital heart defects population-specific screening thresholds for children with concern for autism spectrum disorders.

Effect of congenital heart disease on 4-year neurodevelopment within multiple-gestation births.

OBJECTIVES: We sought to assess the effect of congenital heart disease requiring infant surgery with cardiopulmonary bypass on neurodevelopmental outcomes and growth at 4 years of age, while matching for gestational age, socioeconomic status, maternal gestational conditions, home environment, and parental intelligence by studying multiple-gestation births. METHODS: We performed within-family comparison of 14 multiple-gestation births in which 1 child had congenital heart disease requiring surgery with cardiopulmonary bypass at ≤6 months of age. Between 4 and 5 years of age, a comprehensive neurodevelopmental assessment was performed. Paired comparisons were conducted between siblings with and without heart defects using a series of nonparametric tests. RESULTS: On average, the children qualified as late preterm (mean gestational age 35.4 ± 2.6 weeks). At an average age of 4.8 ± 0.1 years, children with congenital heart disease weighed less than their siblings (median weight for age z score -0.4 vs 0.1, P = .02) and had worse performance for cognition (median full-scale IQ 99 vs 109, P = .02) and fine motor skills (median Wide Range Assessment of Visual Motor Ability, Fine Motor score 94.5 vs 107.5, P < .01). CONCLUSIONS: After controlling for socioeconomic status, home environment, parental intelligence, and gestational factors by using multiple-gestation births, congenital heart disease requiring surgery with cardiopulmonary bypass at ≤6 months of age is associated with lower weight, cognitive abilities and fine motor skills at 4 years of age.

The newborn drug development initiative workshop: Summary proceedings from the neurology group on neonatal seizures.

BACKGROUND: The neonatal period eclipses all other epochs of the human life span for the highest incidence of seizures. Neonatal seizures are most commonly incited by serious acute illnesses such as hypoxic-ischemic encephalopathy, birth trauma, or infection. OBJECTIVE: The goal of this article was to summarize some of the Neurology Group's discussion on neonatal seizures and their treatment with phenobarbital (PB). METHODS: Information for this article was gathered from a workshop held March 29 and 30, 2004, in Baltimore, Maryland, as part of the Newborn Drug Development Initiative. A group of national experts was invited to form the Neurology Group to review certain aspects of neonatal seizures. Literature reviews were conducted using MEDLINE searches for original research studies, commentaries, and review articles between 1980 and 2004 using the key words neonatal seizures, treatment, and phenobarbital. RESULTS: It has been empirically established that infants who experience seizures face substantially higher mortality and morbidity rates than those who do not. Basic research indicates that neonatal seizures themselves are not innocuous and actively contribute to adverse neurodevelopmental outcomes. Current worldwide clinical practice most often includes empiric treatment with PB for definite or suspected seizures in the newborn. Unfortunately, this common practice has never been proven by even a single, rigorous, randomized controlled trial. The Neurology Group identified the treatment of neonatal seizures with PB as an important topic in the practice of neonatal neurology for further investigation. Three possible frameworks for ethically acceptable, clinical treatment trials were explored. From these, a suitable scenario was selected-an electroencephalographer-blinded study of PB versus placebo in a homogeneous group of newborns who are at high risk of developing early subclinical electroencephalographic neonatal seizures (ENSs). Prospective video-electroencephalogram monitoring performed immediately after an insult (such as major cardiac surgery for a serious congenital heart defect) would establish the presence and number of subclinical ENSs. For a brief period of time, neonates with subclinical ENSs would be randomized to PB (dosed to match the PB-binding characteristics of the individual) or placebo. Clear criteria for escape from the study to active treatment are defined. CONCLUSION: The investigation proposed here could refute or confirm the contemporary practice of PB administration as the first-line treatment of neonatal seizures.

Prolonged electroencephalogram monitoring for seizures and their treatment.

This article reviews the diagnosis of neonatal seizures using routine electroencephalogram (EEG) examinations and long-term EEG monitoring. EEG is considered the gold standard for identifying the presence and quantifying the burden of neonatal seizures. The most common medication used to treat neonatal seizures is phenobarbital, although its efficacy has never been demonstrated by a formal, randomized, placebo-controlled drug trial.

Increasing cumulative exposure to volatile anesthetic agents is associated with poorer neurodevelopmental outcomes in children with hypoplastic left heart syndrome.

OBJECTIVES: Despite improved survival in children with hypoplastic left heart syndrome (HLHS), significant concern persists regarding their neurodevelopmental (ND) outcomes. Previous studies have identified patient factors, such as prematurity and genetic syndromes, to be associated with worse ND outcomes. However, no consistent relationships have been identified among modifiable management factors, including cardiopulmonary bypass strategies, and ND outcomes after cardiac surgery in infancy. Studies in immature animals, including primates, have demonstrated neurodegeneration and apoptosis in the brain after certain levels and extended durations of anesthetic exposure. Retrospective human studies have also suggested relationships between adverse ND effects and anesthetic exposure. METHODS: Cumulative minimum alveolar concentration hours (MAC-hrs) of exposure to volatile anesthetic agents (VAA) (desflurane, halothane, isoflurane, and sevoflurane) were collected from an anesthetic database and medical record review for 96 patients with HLHS or variants. ND testing was performed between ages 4 and 5 years, including full-scale IQ, verbal IQ, performance IQ, and processing speed. Four generalized linear modes were hypothesized a priori and tested using a Gaussian (normal) distribution with an identity link. RESULTS: Cumulative VAA exposure ranged from 0 to 35.3 MAC-hrs (median 7.5 hours). Using specified covariates identified previously as significant predictors of ND outcomes, statistically significant relationships were identified between total MAC-hrs exposure and worse full-scale IQ and verbal IQ scores (P's < .05) alone and after adjusting for relevant covariates. CONCLUSIONS: Increased cumulative MAC-hrs exposure to VAA is associated with worse ND outcomes in certain domains in children with HLHS and variants.

An MRI study of neurological injury before and after congenital heart surgery.

BACKGROUND: Neurological deficits are observed in patients with congenital heart disease (CHD) before and after neonatal surgery, the etiology being multifactorial. To understand the impact of preoperative events and to characterize the evaluation of neurological injury, we performed serial magnetic resonance imaging (MRI) studies of the brain in a cohort of neonates undergoing open-heart surgery. METHODS AND RESULTS: Twenty-four term neonates with CHD were studied prospectively with brain MRI: before surgery, within 2 weeks of surgery, and several months after surgery. Preoperative MRI examinations showed periventricular leukomalacia (PVL) in 4 patients (16%) and infarct in 2 subjects (8%). MR spectroscopy was performed in 19 subjects preoperatively and revealed elevated brain lactate in 53%. An early postoperative MRI (n=21) identified new PVL in 48%, new infarct in 19%, and new parenchymal hemorrhage in 33%. New lesions or worsening of preoperative lesions occurred in 67% of subjects. No patient- or procedure-related factors for the development of early postoperative lesions were identified. A late postoperative MRI (n=17) demonstrated resolution of early lesions in 8 and mild cerebral atrophy in 2. CONCLUSIONS: Mild ischemic lesions, primarily in the form of PVL, occur in a number of neonates with CHD before surgery and >50% of patients postoperatively. Resolution of these lesions is common 4 to 6 months after surgery. Longer-term follow-up is needed to determine the significance of perioperative ischemic lesions on functional outcome.

Late neurodevelopmental outcome after repair of total anomalous pulmonary venous connection.

Objective We sought to define the neurodevelopmental status of school-aged survivors of total anomalous pulmonary venous connection repaired during infancy. Methods All school-aged survivors of total anomalous pulmonary venous connection repair performed at a single institution were eligible. Thirty children returned for neurologic examination and neurodevelopmental testing. Results The median age at total anomalous pulmonary venous connection repair was 16 days (range, 1-141 days), and age at testing was 11 years (range, 6-19 years). Pulmonary venous return was supracardiac in 14 patients, infracardiac in 12 patients, cardiac in 3 patients, and mixed in 1 patient. Preoperative obstructed total anomalous pulmonary venous connection was present in 6 patients. Circulatory arrest was used in all repairs, with a median duration of 35 minutes (range, 17-55 minutes). At follow-up, microcephaly (head circumference <5%) was present in 28%. Neuromuscular examination was suspect or abnormal in 27%. Mean Full-scale IQ (95.3 +/- 18.5) and Verbal IQ (98.6 +/- 20.2) were not different from population norms, but Performance IQ (92.3 +/- 16.9) was significantly lower than population norms ( P = .02). Fine motor skills and visual-motor coordination were significantly impaired ( P < .01 for Grooved Pegboard and Test of Visual-Motor Integration). Patients with total anomalous pulmonary venous connection also had difficulty with tests of attention (Test of Everyday Attention for Children, P < .01), but results of tests of memory function were not significantly different from population norms. Conclusions School-aged survivors of infant total anomalous pulmonary venous connection repair exhibit a significant incidence of neurodevelopmental difficulties. Fine motor function, visual-motor integration, and attention are the most commonly affected domains. Evaluation of these children is indicated to identify those who are at risk for learning disabilities and who could benefit from early intervention.

Interobserver agreement for neonatal seizure detection using multichannel EEG.

OBJECTIVE: To determine the interobserver agreement (IOA) of neonatal seizure detection using the gold standard of conventional, multichannel EEG. METHODS: A cohort of full-term neonates at risk of acute encephalopathy was included in this prospective study. The EEG recordings of these neonates were independently reviewed for seizures by three international experts. The IOA was estimated using statistical measures including Fleiss' kappa and percentage agreement assessed over seizure events (event basis) and seizure duration (temporal basis). RESULTS: A total of 4066 h of EEG recordings from 70 neonates were reviewed with an average of 2555 seizures detected. The IOA was high with temporal assessment resulting in a kappa of 0.827 (95% CI: 0.769-0.865; n = 70). The median agreement was 83.0% (interquartile range [IQR]: 76.6-89.5%; n = 33) for seizure and 99.7% (IQR: 98.9-99.8%; n = 70) for nonseizure EEG. Analysis of events showed a median agreement of 83.0% (IQR: 72.9-86.6%; n = 33) for seizures with 0.018 disagreements per hour (IQR: 0.000-0.090 per hour; n = 70). Observers were more likely to disagree when a seizure was less than 30 sec. Overall, 33 neonates were diagnosed with seizures and 28 neonates were not, by all three observers. Of the remaining nine neonates with contradictory EEG detections, seven presented with low total seizure burden. INTERPRETATION: The IOA is high among experts for the detection of neonatal seizures using conventional, multichannel EEG. Agreement is reduced when seizures are rare or have short duration. These findings support EEG-based decision making in the neonatal intensive care unit, inform EEG interpretation guidelines, and provide benchmarks for seizure detection algorithms.

Clinical and histopathological outcomes in patients with SCN1A mutations undergoing surgery for epilepsy.

OBJECT: Mutations in the sodium channel alpha 1 subunit gene (SCN1A) have been associated with a wide range of epilepsy phenotypes including Dravet syndrome. There currently exist few histopathological and surgical outcome reports in patients with this disease. In this case series, the authors describe the clinical features, surgical pathology, and outcomes in 6 patients with SCN1A mutations and refractory epilepsy who underwent focal cortical resection prior to uncovering the genetic basis of their epilepsy. METHODS: Medical records of SCN1A mutation-positive children with treatment-resistant epilepsy who had undergone resective epilepsy surgery were reviewed retrospectively. Surgical pathology specimens were reviewed. RESULTS: All 6 patients identified carried diagnoses of intractable epilepsy with mixed seizure types. Age at surgery ranged from 18 months to 20 years. Seizures were refractory to surgery in every case. Surgical histopathology showed evidence of subtle cortical dysplasia in 4 of 6 patients, with more neurons in the molecular layer of the cortex and white matter. CONCLUSIONS: Cortical resection is unlikely to be beneficial in these children due to the genetic defect and the unexpected neuropathological finding of mild diffuse malformations of cortical development. Together, these findings suggest a diffuse pathophysiological mechanism of the patients' epilepsy which will not respond to focal resective surgery.

Subclinical seizures identified by postoperative electroencephalographic monitoring are common after neonatal cardiac surgery.

OBJECTIVES: The American Clinical Neurophysiology Society recommends continuous electroencephalographic monitoring after neonatal cardiac surgery because seizures are common, often subclinical, and associated with worse neurocognitive outcomes. We performed a quality improvement project to monitor for postoperative seizures in neonates with congenital heart disease after surgery with cardiopulmonary bypass. METHODS: We implemented routine continuous electroencephalographic monitoring and reviewed the results for an 18-month period. Clinical data were collected by chart review, and continuous electroencephalographic tracings were interpreted using standardized American Clinical Neurophysiology Society terminology. Electrographic seizures were classified as electroencephalogram-only or electroclinical seizures. Multiple logistic regression was used to assess associations between seizures and potential clinical and electroencephalogram predictors. RESULTS: A total of 161 of 172 eligible neonates (94%) underwent continuous electroencephalographic monitoring. Electrographic seizures occurred in 13 neonates (8%) beginning at a median of 20 hours after return to the intensive care unit after surgery. Neonates with all types of congenital heart disease had seizures. Seizures were electroencephalogram only in 11 neonates (85%). Status epilepticus occurred in 8 neonates (62%). In separate multivariate models, delayed sternal closure or longer deep hypothermic circulatory arrest duration was associated with an increased risk for seizures. Mortality was higher among neonates with than without seizures (38% vs 3%, P < .001). CONCLUSIONS: Continuous electroencephalographic monitoring identified seizures in 8% of neonates after cardiac surgery with cardiopulmonary bypass. The majority of seizures had no clinical correlate and would not have been otherwise identified. Seizure occurrence is a marker of greater illness severity and increased mortality. Further study is needed to determine whether seizure identification and management lead to improved outcomes.

Preoperative cerebral blood flow is diminished in neonates with severe congenital heart defects.

OBJECTIVE: Impaired neurodevelopmental outcome represents a major morbidity for survivors of infant heart surgery for congenital heart defects. Previous studies in these neonates have reported preoperative microcephaly, periventricular leukomalacia, and other findings. The hypothesis of this study is that preoperative cerebral blood flow is substantially diminished and might relate to preoperative neurologic conditions. METHODS: Preoperative brain magnetic resonance imaging was performed. Cerebral blood flow measurements in infants with congenital heart defects were obtained by using a novel noninvasive magnetic resonance imaging technique, pulsed arterial spin-label perfusion magnetic resonance imaging. Cerebral blood flow was measured before the operation under standard ventilation and repeated after increased carbon dioxide. RESULTS: A total of 25 term infants were studied. The average age at the time of the operation was 4.4 +/- 4.6 days. Congenital heart defects varied widely. Microcephaly occurred in 24% (6/25). Baseline cerebral blood flow was 19.7 +/- 9.2 mL . 100 g -1 . min -1 (8.0-42.2 mL . 100 g -1 . min -1 ). Five patients had cerebral blood flow measurements of less than 10 mL . 100 g -1 . min -1 . Mean hypercarbic cerebral blood flow increased to 40.1 +/- 20.3 mL . 100 g -1 . min -1 (11.4-94.0 mL . 100 g -1 . min -1 , P < .001). Pairwise analyses found that low hemoglobin levels were associated with higher baseline cerebral blood flow values ( P = .04). Periventricular leukomalacia occurred in 28% (7/25) and was associated with decreased baseline cerebral blood flow values ( P = .05) and a smaller change in cerebral blood flow with hypercarbia ( P = .003). CONCLUSIONS: Structural brain abnormalities are common in these neonates before surgical intervention. Preoperative cerebral blood flow for this cohort was low and drastically reduced in some patients. Low cerebral blood flow values were associated with periventricular leukomalacia. Carbon dioxide reactivity was preserved but might be compromised by some aspects of the cardiac anatomy. The full spectrum of cerebral blood flow measurements with this technique in congenital heart defects and their long-term significance require continued investigation.