Temporal evolution of electrographic seizures in newborn infants with hypoxic-ischaemic encephalopathy requiring therapeutic hypothermia: a secondary analysis of the ANSeR studies.

BACKGROUND: Despite extensive research on neonatal hypoxic-ischaemic encephalopathy, detailed information about electrographic seizures during active cooling and rewarming of therapeutic hypothermia is sparse. We aimed to describe temporal evolution of seizures and determine whether there is a correlation of seizure evolution with 2-year outcome. METHODS: This secondary analysis included newborn infants recruited from eight European tertiary neonatal intensive care units for two multicentre studies (a randomised controlled trial [NCT02431780] and an observational study [NCT02160171]). Infants were born at 36+0 weeks of gestation with moderate or severe hypoxic-ischaemic encephalopathy and underwent therapeutic hypothermia with prolonged conventional video-electroencephalography (EEG) monitoring for 10 h or longer from the start of rewarming. Seizure burden characteristics were calculated based on electrographic seizures annotations: hourly seizure burden (minutes of seizures within an hour) and total seizure burden (minutes of seizures within the entire recording). We categorised infants into those with electrographic seizures during active cooling only, those with electrographic seizures during cooling and rewarming, and those without seizures. Neurodevelopmental outcomes were determined using the Bayley's Scales of Infant and Toddler Development, Third Edition (BSID-III), the Griffiths Mental Development Scales (GMDS), or neurological assessment. An abnormal outcome was defined as death or neurodisability at 2 years. Neurodisability was defined as a composite score of 85 or less on any subscales for BSID-III, a total score of 87 or less for GMDS, or a diagnosis of cerebral palsy (dyskinetic cerebral palsy, spastic quadriplegia, or mixed motor impairment) or epilepsy. FINDINGS: Of 263 infants recruited between Jan 1, 2011, and Feb 7, 2017, we included 129 infants: 65 had electrographic seizures (43 during active cooling only and 22 during and after active cooling) and 64 had no seizures. Compared with infants with seizures during active cooling only, those with seizures during and after active cooling had a longer seizure period (median 12 h [IQR 3-28] vs 68 h [35-86], p<0·0001), more seizures (median 12 [IQR 5-36] vs 94 [24-134], p<0·0001), and higher total seizure burden (median 69 min [IQR 22-104] vs 167 min [54-275], p=0·0033). Hourly seizure burden peaked at about 20-24 h in both groups, and infants with seizures during and after active cooling had a secondary peak at 85 h of age. When combined, worse EEG background (major abnormalities and inactive background) at 12 h and 24 h were associated with the seizure group: compared with infants with a better EEG background (normal, mild, or moderate abnormalities), infants with a worse EEG background were more likely to have seizures after cooling at 12 h (13 [54%] of 24 vs four [14%] of 28; odds ratio 7·09 [95% CI 1·88-26·77], p=0·0039) and 24 h (14 [56%] of 25 vs seven [18%] of 38; 5·64 [1·81-17·60], p=0·0029). There was a significant relationship between EEG grade at 12 h (four categories) and seizure group (p=0·020). High total seizure burden was associated with increased odds of an abnormal outcome at 2 years of age (odds ratio 1·007 [95% CI 1·000-1·014], p=0·046), with a medium negative correlation between total seizure burden and BSID-III cognitive score (rS=-0·477, p=0·014, n=26). INTERPRETATION: Overall, half of infants with hypoxic-ischaemic encephalopathy had electrographic seizures and a third of those infants had seizures beyond active cooling, with worse outcomes. These results raise the importance of prolonged EEG monitoring of newborn infants with hypoxic-ischaemic encephalopathy not only during active cooling but throughout the rewarming phase and even longer when seizures are detected. FUNDING: Wellcome Trust, Science Foundation Ireland, and the Irish Health Research Board.

Neonatal Seizure Management: Is the Timing of Treatment Critical?

OBJECTIVE: To assess the impact of the time to treatment of the first electrographic seizure on subsequent seizure burden and describe overall seizure management in a large neonatal cohort. STUDY DESIGN: Newborns (36-44 weeks of gestation) requiring electroencephalographic (EEG) monitoring recruited to 2 multicenter European studies were included. Infants who received antiseizure medication exclusively after electrographic seizure onset were grouped based on the time to treatment of the first seizure: antiseizure medication within 1 hour, between 1 and 2 hours, and after 2 hours. Outcomes measured were seizure burden, maximum seizure burden, status epilepticus, number of seizures, and antiseizure medication dose over the first 24 hours after seizure onset. RESULTS: Out of 472 newborns recruited, 154 (32.6%) had confirmed electrographic seizures. Sixty-nine infants received antiseizure medication exclusively after the onset of electrographic seizure, including 21 infants within 1 hour of seizure onset, 15 between 1 and 2 hours after seizure onset, and 33 at >2 hours after seizure onset. Significantly lower seizure burden and fewer seizures were noted in the infants treated with antiseizure medication within 1 hour of seizure onset (P = .029 and .035, respectively). Overall, 258 of 472 infants (54.7%) received antiseizure medication during the study period, of whom 40 without electrographic seizures received treatment exclusively during EEG monitoring and 11 with electrographic seizures received no treatment. CONCLUSIONS: Treatment of neonatal seizures may be time-critical, but more research is needed to confirm this. Improvements in neonatal seizure diagnosis and treatment are also needed.

Heart rate variability analysis for the prediction of EEG grade in infants with hypoxic ischaemic encephalopathy within the first 12†h of birth.

Background and aims: Heart rate variability (HRV) has previously been assessed as a biomarker for brain injury and prognosis in neonates. The aim of this cohort study was to use HRV to predict the electroencephalography (EEG) grade in neonatal hypoxic-ischaemic encephalopathy (HIE) within the first 12 h. Methods: We included 120 infants with HIE recruited as part of two European multi-centre studies, with electrocardiography (ECG) and EEG monitoring performed before 12 h of age. HRV features and EEG background were assessed using the earliest 1 h epoch of ECG-EEG monitoring. HRV was expressed in time, frequency and complexity features. EEG background was graded from 0-normal, 1-mild, 2-moderate, 3-major abnormalities to 4-inactive. Clinical parameters known within 6 h of birth were collected (intrapartum complications, foetal distress, gestational age, mode of delivery, gender, birth weight, Apgar at 1 and 5, assisted ventilation at 10 min). Using logistic regression analysis, prediction models for EEG severity were developed for HRV features and clinical parameters, separately and combined. Multivariable model analysis included 101 infants without missing data. Results: Of 120 infants included, 54 (45%) had normal-mild and 66 (55%) had moderate-severe EEG grade. The performance of HRV model was AUROC 0.837 (95% CI: 0.759-0.914) and clinical model was AUROC 0.836 (95% CI: 0.759-0.914). The HRV and clinical model combined had an AUROC of 0.895 (95% CI: 0.832-0.958). Therapeutic hypothermia and anti-seizure medication did not affect the model performance. Conclusions: Early HRV and clinical information accurately predicted EEG grade in HIE within the first 12 h of birth. This might be beneficial when EEG monitoring is not available in the early postnatal period and for referral centres who may want some objective information on HIE severity.

A machine-learning algorithm for neonatal seizure recognition: a multicentre, randomised, controlled trial.

BACKGROUND: Despite the availability of continuous conventional electroencephalography (cEEG), accurate diagnosis of neonatal seizures is challenging in clinical practice. Algorithms for decision support in the recognition of neonatal seizures could improve detection. We aimed to assess the diagnostic accuracy of an automated seizure detection algorithm called Algorithm for Neonatal Seizure Recognition (ANSeR). METHODS: This multicentre, randomised, two-arm, parallel, controlled trial was done in eight neonatal centres across Ireland, the Netherlands, Sweden, and the UK. Neonates with a corrected gestational age between 36 and 44 weeks with, or at significant risk of, seizures requiring EEG monitoring, received cEEG plus ANSeR linked to the EEG monitor displaying a seizure probability trend in real time (algorithm group) or cEEG monitoring alone (non-algorithm group). The primary outcome was diagnostic accuracy (sensitivity, specificity, and false detection rate) of health-care professionals to identify neonates with electrographic seizures and seizure hours with and without the support of the ANSeR algorithm. Neonates with data on the outcome of interest were included in the analysis. This study is registered with ClinicalTrials.gov, NCT02431780. FINDINGS: Between Feb 13, 2015, and Feb 7, 2017, 132 neonates were randomly assigned to the algorithm group and 132 to the non-algorithm group. Six neonates were excluded (four from the algorithm group and two from the non-algorithm group). Electrographic seizures were present in 32 (25·0%) of 128 neonates in the algorithm group and 38 (29·2%) of 130 neonates in the non-algorithm group. For recognition of neonates with electrographic seizures, sensitivity was 81·3% (95% CI 66·7-93·3) in the algorithm group and 89·5% (78·4-97·5) in the non-algorithm group; specificity was 84·4% (95% CI 76·9-91·0) in the algorithm group and 89·1% (82·5-94·7) in the non-algorithm group; and the false detection rate was 36·6% (95% CI 22·7-52·1) in the algorithm group and 22·7% (11·6-35·9) in the non-algorithm group. We identified 659 h in which seizures occurred (seizure hours): 268 h in the algorithm versus 391 h in the non-algorithm group. The percentage of seizure hours correctly identified was higher in the algorithm group than in the non-algorithm group (177 [66·0%; 95% CI 53·8-77·3] of 268 h vs 177 [45·3%; 34·5-58·3] of 391 h; difference 20·8% [3·6-37·1]). No significant differences were seen in the percentage of neonates with seizures given at least one inappropriate antiseizure medication (37·5% [95% CI 25·0 to 56·3] vs 31·6% [21·1 to 47·4]; difference 5·9% [-14·0 to 26·3]). INTERPRETATION: ANSeR, a machine-learning algorithm, is safe and able to accurately detect neonatal seizures. Although the algorithm did not enhance identification of individual neonates with seizures beyond conventional EEG, recognition of seizure hours was improved with use of ANSeR. The benefit might be greater in less experienced centres, but further study is required. FUNDING: Wellcome Trust, Science Foundation Ireland, and Nihon Kohden.

Learning from claims: hyperbilirubinaemia and kernicterus.

We examined claims made against the National Health Service (NHS) involving neonatal jaundice in order to determine whether there were lessons that could be learnt from common themes.This was a retrospective anonymised study using information from the NHS Resolution database for 2001-2011.Twenty cases (16 males) had sufficient information for analysis. Fifteen had confirmed cerebral palsy and two young children had damage to the globus pallidus without confirmed CP. In three cases, the outcome was uncertain. Two were extremely preterm, five were born at 34-36 weeks' gestation. Jaundice was typically present very early in life; in four cases, it was noted at less than 24hours of age, and in 14 cases, it was first noted on the second to third day. There was a lag between recognition and readmission, with a range of 26-102 hours. The peak serum bilirubin level was over 600 µmol/L in all the babies born at term. An underlying diagnosis was found in all but two; six had glucose-6-phosphatase deficiency (one also had Gilbert's syndrome); five were diagnosed with ABO incompatibility; three with Rh haemolytic disease; one with spherocytosis and three preterm. The total cost of these claims by August 2017 was almost £150.5 million. This figure is likely to rise.These data show that, in the group who litigate, babies who develop kernicterus generally have an underlying diagnosis. We recommend adherence to theNational Institute for Health and Care Excellence guideline that recommends measuring the bilirubin level within 6 hours in all babies who are visibly jaundiced.

Characterisation of neonatal seizures and their treatment using continuous EEG monitoring: a multicentre experience.

OBJECTIVE: The aim of this multicentre study was to describe detailed characteristics of electrographic seizures in a cohort of neonates monitored with multichannel continuous electroencephalography (cEEG) in 6 European centres. METHODS: Neonates of at least 36 weeks of gestation who required cEEG monitoring for clinical concerns were eligible, and were enrolled prospectively over 2 years from June 2013. Additional retrospective data were available from two centres for January 2011 to February 2014. Clinical data and EEGs were reviewed by expert neurophysiologists through a central server. RESULTS: Of 214 neonates who had recordings suitable for analysis, EEG seizures were confirmed in 75 (35%). The most common cause was hypoxic-ischaemic encephalopathy (44/75, 59%), followed by metabolic/genetic disorders (16/75, 21%) and stroke (10/75, 13%). The median number of seizures was 24 (IQR 9-51), and the median maximum hourly seizure burden in minutes per hour (MSB) was 21 min (IQR 11-32), with 21 (28%) having status epilepticus defined as MSB>30 min/hour. MSB developed later in neonates with a metabolic/genetic disorder. Over half (112/214, 52%) of the neonates were given at least one antiepileptic drug (AED) and both overtreatment and undertreatment was evident. When EEG monitoring was ongoing, 27 neonates (19%) with no electrographic seizures received AEDs. Fourteen neonates (19%) who did have electrographic seizures during cEEG monitoring did not receive an AED. CONCLUSIONS: Our results show that even with access to cEEG monitoring, neonatal seizures are frequent, difficult to recognise and difficult to treat. OBERSERVATION STUDY NUMBER: NCT02160171.

Neonatal jaundice: aetiology, diagnosis and treatment.

A significant proportion of term and preterm infants develop neonatal jaundice. Jaundice in an otherwise healthy term infant is the most common reason for readmission to hospital. Jaundice is caused by an increase in serum bilirubin levels, largely as a result of breakdown of red blood cells. Bilirubin is conveyed in the blood as 'unconjugated' bilirubin, largely bound to albumin. The liver converts bilirubin into a conjugated form which is excreted in the bile. Very high levels of unconjugated bilirubin are neurotoxic. Phototherapy is a simple and effective way to reduce the bilirubin level. Most term babies have 'physiological' jaundice which responds to a short period of phototherapy, and requires no other treatment. A few babies have rapidly rising bilirubin levels which place them at risk of kernicterus. Current management of jaundice in the UK is guided by the NICE guideline. Any infant with high serum bilirubin or a rapidly rising bilirubin level needs to be treated urgently to avoid neurotoxicity. High levels of conjugated bilirubin in a term baby can indicate biliary atresia, and babies with persisting jaundice must have their level of conjugated bilirubin measured. Preterm infants on long-term parenteral nutrition may develop conjugated jaundice which generally improves with the introduction of enteral feed and weaning of intravenous nutrition.

Term admissions to neonatal units in England: a role for transitional care? A retrospective cohort study.

OBJECTIVE: To identify the primary reasons for term admissions to neonatal units in England, to determine risk factors for admissions for jaundice and to estimate the proportion who can be cared for in a transitional setting without separation of mother and baby. DESIGN: Retrospective observational study using neonatal unit admission data from the National Neonatal Research Database and data of live births in England from the Office for National Statistics. SETTING: All 163 neonatal units in England 2011-2013. PARTICIPANTS: 133 691 term babies born ≥37 weeks gestational age and admitted to neonatal units in England. PRIMARY AND SECONDARY OUTCOMES: Primary reasons for admission, term babies admitted for the primary reason of jaundice, patient characteristics, postnatal age at admission, total length of stay, phototherapy, intravenous fluids, exchange transfusion and kernicterus. RESULTS: Respiratory disease was the most common reason for admission overall, although jaundice was the most common reason for admission from home (22% home vs 5% hospital). Risk factors for admission for jaundice include male, born at 37 weeks gestation, Asian ethnicity and multiple birth. The majority of babies received only a brief period of phototherapy, and only a third received intravenous fluids, suggesting that some may be appropriately managed without separation of mother and baby. Admission from home was significantly later (3.9 days) compared with those admitted from elsewhere in the hospital (1.7 days) (p<0.001). CONCLUSION: Around two-thirds of term admissions for jaundice may be appropriately managed in a transitional care setting, avoiding separation of mother and baby. Babies with risk factors may benefit from a community midwife postnatal visit around the third day of life to enable early referral if necessary. We recommend further work at the national level to examine provision and barriers to transitional care, referral pathways between primary and secondary care, and community postnatal care.

Phenobarbital reduces EEG amplitude and propagation of neonatal seizures but does not alter performance of automated seizure detection.

OBJECTIVE: Phenobarbital increases electroclinical uncoupling and our preliminary observations suggest it may also affect electrographic seizure morphology. This may alter the performance of a novel seizure detection algorithm (SDA) developed by our group. The objectives of this study were to compare the morphology of seizures before and after phenobarbital administration in neonates and to determine the effect of any changes on automated seizure detection rates. METHODS: The EEGs of 18 term neonates with seizures both pre- and post-phenobarbital (524 seizures) administration were studied. Ten features of seizures were manually quantified and summary measures for each neonate were statistically compared between pre- and post-phenobarbital seizures. SDA seizure detection rates were also compared. RESULTS: Post-phenobarbital seizures showed significantly lower amplitude (p<0.001) and involved fewer EEG channels at the peak of seizure (p<0.05). No other features or SDA detection rates showed a statistical difference. CONCLUSION: These findings show that phenobarbital reduces both the amplitude and propagation of seizures which may help to explain electroclinical uncoupling of seizures. The seizure detection rate of the algorithm was unaffected by these changes. SIGNIFICANCE: The results suggest that users should not need to adjust the SDA sensitivity threshold after phenobarbital administration.

Short-Term Effects of Phenobarbitone on Electrographic Seizures in Neonates.

BACKGROUND: Phenobarbitone is the most common first-line anti-seizure drug and is effective in approximately 50% of all neonatal seizures. OBJECTIVE: To describe the response of electrographic seizures to the administration of intravenous phenobarbitone in neonates using seizure burden analysis techniques. METHODS: Multi-channel conventional EEG, reviewed by experts, was used to determine the electrographic seizure burden in hourly epochs. The maximum seizure burden evaluated 1 h before each phenobarbitone dose (T-1) was compared to seizure burden in periods of increasing duration after each phenobarbitone dose had been administered (T+1, T+2 to seizure offset). Differences were analysed using linear mixed models and summarized as means and 95% CI. RESULTS: Nineteen neonates had electrographic seizures and met the inclusion criteria for the study. Thirty-one doses were studied. The maximum seizure burden was significantly reduced 1 h after the administration of phenobarbitone (T+1) [-14.0 min/h (95% CI: -19.6, -8.5); p < 0.001]. The percentage reduction was 74% (IQR: 36-100). This reduction was temporary and not significant within 4 h of administrating phenobarbitone. Subgroup analysis showed that only phenobarbitone doses at 20 mg/kg resulted in a significant reduction in the maximum seizure burden from T-1 to T+1 (p = 0.002). CONCLUSIONS: Phenobarbitone significantly reduced seizures within 1 h of administration as assessed with continuous multi-channel EEG monitoring in neonates. The reduction was not permanent and seizures were likely to return within 4 h of treatment.

Validation of an automated seizure detection algorithm for term neonates.

OBJECTIVE: The objective of this study was to validate the performance of a seizure detection algorithm (SDA) developed by our group, on previously unseen, prolonged, unedited EEG recordings from 70 babies from 2 centres. METHODS: EEGs of 70 babies (35 seizure, 35 non-seizure) were annotated for seizures by experts as the gold standard. The SDA was tested on the EEGs at a range of sensitivity settings. Annotations from the expert and SDA were compared using event and epoch based metrics. The effect of seizure duration on SDA performance was also analysed. RESULTS: Between sensitivity settings of 0.5 and 0.3, the algorithm achieved seizure detection rates of 52.6-75.0%, with false detection (FD) rates of 0.04-0.36FD/h for event based analysis, which was deemed to be acceptable in a clinical environment. Time based comparison of expert and SDA annotations using Cohen's Kappa Index revealed a best performing SDA threshold of 0.4 (Kappa 0.630). The SDA showed improved detection performance with longer seizures. CONCLUSION: The SDA achieved promising performance and warrants further testing in a live clinical evaluation. SIGNIFICANCE: The SDA has the potential to improve seizure detection and provide a robust tool for comparing treatment regimens.

The temporal characteristics of seizures in neonatal hypoxic ischemic encephalopathy treated with hypothermia.

PURPOSE: The characteristics of electrographic seizures in newborns with hypoxic-ischaemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) are poorly described. This retrospective, observational study provides reference data on the characteristics of seizures and their evolution over time in newborns with HIE receiving whole-body TH. METHOD: The cohort under analysis included 23 infants with HIE and seizures defined by multi-channel EEG recordings. Clinical presentation, details of TH and antiepileptic drugs used were recorded. Time from first to last-recorded electrographic seizure (seizure period) was calculated. Temporal characteristics of seizures - total burden, duration, number, burden in minutes per hour, distribution of burden over time (temporal evolution), time from seizure onset to maximum seizure burden (Tmsb), T1, and time from Tmsb to seizure offset, T2 - were analysed. RESULTS: The median age at electrographic seizure onset was 13.1h (IQR: 11.4 to 22.0). Tmsb was reached at a median age of 19.4 hours (IQR: 12.2 to 29.7). Median seizure period was 16.5h (IQR: 7.0 to 49.7), median number of seizures per hour was 1.9 (IQR: 1.0 to 3.3). The seizure burden was 4.0 min/h (IQR: 2.0 to 7.0). There was no consistent pattern in the temporal evolution of seizures in neonates treated with TH. The skewness was neither positive nor negative (p-value=0.15), there was no difference between the duration of T1 and T2 (p-value=0.09) and no difference in the seizure burden between T1 and T2 (p=0.09). There was an association between Tmsb and Phenobarbital (PB) administration (r=0.76, p-value<0.001). CONCLUSION: There is no consistent temporal evolution of seizure burden in neonates treated with TH. Seizures are diffuse, and their characteristics are variable.

Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial.

BACKGROUND: Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. METHODS: In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. FINDINGS: Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. INTERPRETATION: Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. FUNDING: European Community's Seventh Framework Programme.

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.

Early postnatal EEG features of perinatal arterial ischaemic stroke with seizures.

BACKGROUND: Stroke is the second most common cause of seizures in term neonates and is associated with abnormal long-term neurodevelopmental outcome in some cases. OBJECTIVE: To aid diagnosis earlier in the postnatal period, our aim was to describe the characteristic EEG patterns in term neonates with perinatal arterial ischaemic stroke (PAIS) seizures. DESIGN: Retrospective observational study. PATIENTS: Neonates >37 weeks born between 2003 and 2011 in two hospitals. METHOD: Continuous multichannel video-EEG was used to analyze the background patterns and characteristics of seizures. Each EEG was assessed for continuity, symmetry, characteristic features and sleep cycling; morphology of electrographic seizures was also examined. Each seizure was categorized as electrographic-only or electroclinical; the percentage of seizure events for each seizure type was also summarized. RESULTS: Nine neonates with PAIS seizures and EEG monitoring were identified. While EEG continuity was present in all cases, the background pattern showed suppression over the infarcted side; this was quite marked (>50% amplitude reduction) when the lesion was large. Characteristic unilateral bursts of theta activity with sharp or spike waves intermixed were seen in all cases. Sleep cycling was generally present but was more disturbed over the infarcted side. Seizures demonstrated a characteristic pattern; focal sharp waves/spike-polyspikes were seen at frequency of 1-2 Hz and phase reversal over the central region was common. Electrographic-only seizure events were more frequent compared to electroclinical seizure events (78 vs 22%). CONCLUSIONS: Focal electrographic and electroclinical seizures with ipsilateral suppression of the background activity and focal sharp waves are strong indicators of PAIS. Approximately 80% of seizure events were the result of clinically unsuspected seizures in neonates with PAIS. Prolonged and continuous multichannel video-EEG monitoring is advocated for adequate seizure surveillance.

Anticonvulsant effect of xenon on neonatal asphyxial seizures.

Xenon, a monoatomic gas with very high tissue solubility, is a non-competitive inhibitor of N-methyl-D-aspartate (NMDA) glutamate receptor, has antiapoptotic effects and is neuroprotective following hypoxic ischaemic injury in animals. Xenon may be expected to have anticonvulsant effects through glutamate receptor blockade, but this has not previously been demonstrated clinically. We examined seizure activity on the real time and amplitude integrated EEG records of 14 full-term infants with perinatal asphyxial encephalopathy treated within 12 h of birth with 30% inhaled xenon for 24 h combined with 72 h of moderate systemic hypothermia. Seizures were identified on 5 of 14 infants. Seizures stopped during xenon therapy but recurred within a few minutes of withdrawing xenon and stopped again after xenon was restarted. Our data show that subanaesthetic levels of xenon may have an anticonvulsant effect. Inhaled xenon may be a valuable new therapy in this hard-to-treat population.

Outcome following neonatal seizures.

Neonatal seizures are the most common manifestation of neurological disorders in the newborn period and an important determinant of outcome. Overall, for babies born at full term, mortality following seizures has improved in the last decade, typical current mortality rates being 10% (range: 7-16%), down from 33% in reports from the 1990s. By contrast, the prevalence of adverse neurodevelopmental sequelae remains relatively stable, typically 46% (range: 27-55%). The strongest predictors of outcome are the underlying cause, together with the background electroencephalographic activity. In preterm babies, for whom the outlook tends to be worse as background mortality and disability are high, seizures are frequently associated with serious underlying brain injury and therefore subsequent impairments. When attempting to define the prognosis for a baby with neonatal seizures, we propose a pathway involving history, examination, and careful consideration of all available results (ideally including brain magnetic resonance imaging) and the response to treatment before synthesizing the best estimate of risk to be conveyed to the family.

Post-mortem apparent resolution of fetal ventriculomegaly: evidence from magnetic resonance imaging.

OBJECTIVE: This study aims to determine the accuracy of post-mortem magnetic resonance imaging (MRI) and autopsy for confirmation of sonographically detected fetal ventriculomegaly. METHODS: This study uses retrospective review of fetuses with sonographically diagnosed ventriculomegaly, where the pregnancy was terminated and post-mortem examination was performed during a period in which post-mortem MRI was being offered. RESULTS: Sixteen cases were identified. In nine (56%), autopsy and/or post-mortem MRI confirmed the prenatal findings. In the other seven, both autopsy and post-mortem MRI demonstrated no ventriculomegaly, but antenatal MRI confirmed the ultrasound findings in 6/7 cases where it had been performed. Post-mortem investigations confirmed antenatal findings in 8/9 cases with severe ventriculomegaly (posterior horn measurement >15 mm), whereas only 2/7 in which ventriculomegaly was not confirmed had severe ventriculomegaly. CONCLUSIONS: Post-mortem examination, both by traditional neuropathological examination, and post-mortem MRI may fail to confirm prenatal ventriculomegaly in around half of cases. The post-mortem MRI findings indicate that this is due to resolution of ventriculomegaly rather than autopsy artefact, and is presumably a consequence of post-mortem fluid redistribution. Parents should be advised before termination of pregnancy that post-mortem confirmation of ventriculomegaly, especially in mild cases, may not be possible. Antenatal MRI may be a better approach for confirming prenatal ultrasound findings.