Renate Swarte

Automated neonatal seizure detection mimicking a human observer reading EEG

OBJECTIVE The description and evaluation of a novel patient-independent seizure detection for the EEG of the newborn term infant. METHODS We identified characteristics of neonatal seizures by which a human observer is able to detect them. Neonatal seizures were divided into two types. For each type, a fully automated detection algorithm was developed based on the identified human observer characteristics. The first algorithm analyzes the correlation between high-energetic segments of the EEG. The second detects increases in low-frequency activity (<8 Hz) with high autocorrelation. RESULTS The complete algorithm was tested on multi-channel EEG recordings of 21 patients with and 5 patients without electrographic seizures, totaling 217 h of EEG. Sensitivity of the combined algorithms was found to be 88%, Positive Predictive Value (PPV) 75% and the false positive rate 0.66 per hour. CONCLUSIONS Our approach to separate neonatal seizures into two types yields a high sensitivity combined with a good PPV and much lower false positive rate than previously published algorithms. SIGNIFICANCE The proposed algorithm significantly improves neonatal seizure detection and monitoring.

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 Communitys Seventh Framework Programme.

Automated artifact removal as preprocessing refines neonatal seizure detection

OBJECTIVE The description and evaluation of algorithms using Independent Component Analysis (ICA) for automatic removal of ECG, pulsation and respiration artifacts in neonatal EEG before automated seizure detection. METHODS The developed algorithms decompose the EEG using ICA into its underlying sources. The artifact source was identified using the simultaneously recorded polygraphy signals after preprocessing. The EEG was reconstructed without the corrupting source, leading to a clean EEG. The impact of the artifact removal was measured by comparing the performance of a previously developed seizure detector before and after the artifact removal in 13 selected patients (9 having artifact-contaminated and 4 having artifact-free EEGs). RESULTS A significant decrease in false alarms (p=0.01) was found while the Good Detection Rate (GDR) for seizures was not altered (p=0.50). CONCLUSIONS The techniques reduced the number of false positive detections without lowering sensitivity and are beneficial in long term EEG seizure monitoring in the presence of disturbing biological artifacts. SIGNIFICANCE The proposed algorithms improve neonatal seizure monitoring.

Validation of a new automated neonatal seizure detection system: A clinician’s perspective

OBJECTIVE To validate an improved automated electroencephalography (EEG)-based neonatal seizure detection algorithm (NeoGuard) in an independent data set. METHODS EEG background was classified into eight grades based on the evolution of discontinuity and presence of sleep-wake cycles. Patients were further sub-classified into two groups; gpI: mild to moderate (grades 1-5) and gpII: severe (grades 6-8) EEG background abnormalities. Seizures were categorised as definite and dubious. Seizure characteristics were compared between gpI and gpII. The algorithm was tested on 756 h of EEG data from 24 consecutive neonates (median 25 h per patient) with encephalopathy and recorded seizures during continuous monitoring (cEEG). No selection was made regarding the quality of EEG or presence of artefacts. RESULTS Seizure amplitudes significantly decreased with worsening EEG background. Seizures were detected with a total sensitivity of 61.9% (1285/2077). The detected seizure burden was 66,244/97,574 s (67.9%). Sensitivity per patient was 65.9%, with a mean positive predictive value (PPV) of 73.7%. After excluding four patients with severely abnormal EEG background, and predominantly having dubious seizures, the algorithm showed a median sensitivity per patient of 86.9%, PPV of 89.5% and false positive rate of 0.28 h(-1). Sensitivity tended to be better for patients in gpI. CONCLUSIONS The algorithm detects neonatal seizures well, has a good PPV and is suited for cEEG monitoring. Changes in electrographic characteristics such as amplitude, duration and rhythmicity in relation to deteriorating EEG background tend to worsen the performance of automated seizure detection. SIGNIFICANCE cEEG monitoring is important for detecting seizures in the neonatal intensive care unit (NICU). Our automated algorithm reliably detects neonatal seizures that are likely to be clinically most relevant, as reflected by the associated EEG background abnormality.

Introduction of hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders

Background: Therapeutic hypothermia was introduced in the Netherlands and Flanders, Belgium, in 2008. Since then, an increasing number of patients has been treated - up to 166 in 2010. Complications and outcome were registered in an online database. Objectives: The aim of this study was to analyse complications and outcome after implementation. Methods: Data were retrieved from an online database to which all centres had contributed. Results: In 3 years, 332 patients were treated. Excluding 24 patients with congenital abnormalities or metabolic disorders, mortality was 31.8%. Of the 210 survivors without congenital malformations, 21 had cerebral palsy, another 19 a developmental delay of more than 3 months at the age of at least 24 months, and 2 had severe hearing loss. The total adverse outcome, combining death and adverse neurodevelopment, in 308 patients without congenital malformations is 45.5%, which is similar to that of the large trials. Conclusions: The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful, with results similar to findings in the randomised controlled trials.

Relationship of EEG sources of neonatal seizures to acute perinatal brain lesions seen on MRI: A pilot study

Even though it is known that neonatal seizures are associated with acute brain lesions, the relationship of electroencephalographic (EEG) seizures to acute perinatal brain lesions visible on magnetic resonance imaging (MRI) has not been objectively studied. EEG source localization is successfully used for this purpose in adults, but it has not been sufficiently explored in neonates. Therefore, we developed an integrated method for ictal EEG dipole source localization based on a realistic head model to investigate the utility of EEG source imaging in neonates with postasphyxial seizures. We describe here our method and compare the dipole seizure localization results with acute perinatal lesions seen on brain MRI in 10 full‐term infants with neonatal encephalopathy. Through experimental studies, we also explore the sensitivity of our method to the electrode positioning errors and the variations in neonatal skull geometry and conductivity. The localization results of 45 focal seizures from 10 neonates are compared with the visual analysis of EEG and MRI data, scored by expert physicians. In 9 of 10 neonates, dipole locations showed good relationship with MRI lesions and clinical data. Our experimental results also suggest that the variations in the used values for skull conductivity or thickness have little effect on the dipole localization, whereas inaccurate electrode positioning can reduce the accuracy of source estimates. The performance of our fused method indicates that ictal EEG source imaging is feasible in neonates and with further validation studies, this technique can become a useful diagnostic tool. Hum Brain Mapp 34:2402–2417, 2013.

Hearing Loss by Week of Gestation and Birth Weight in Very Preterm Neonates

OBJECTIVE To gain insight into health and related costs associated with very preterm births, one needs accurate information about the prevalence of the disabling conditions, including neonatal hearing loss (NHL). STUDY DESIGN We assessed the prevalence of NHL by week of gestation and categories of birth weight in very preterm neonates. Results of the 2-stage Automated Auditory Brainstem Response nationwide Newborn Hearing Screening Program in Dutch Neonatal Intensive Care Units and diagnostic examinations were centrally registered between October 1998 and December 2012 and included in this study. NHL was defined as impaired when the neonate conventional Auditory Brainstem Response level exceeded 35 dB near Hearing Level at diagnostic examination. Birth weight was stratified into <750 g, 750-999 g, 1000-1249 g, 1250-1499 g, and ≥ 1500 g, and by small for gestational age (SGA; <10th percentile) vs appropriate for gestational age. Logistic regression analyses and recursive partitioning were performed. RESULTS In total, 18,564 very preterm neonates were eligible. The prevalence of NHL consistently increased with decreasing week of gestation (1.2%-7.5% from 31 to 24 weeks) and decreasing birth weight (1.4%-4.8% from ≥ 1500 g to <750 g, all P < .002). Most vulnerable to NHL were girls <28 weeks, boys <30 weeks, and SGA neonates. The SGA effect started at 27 weeks. CONCLUSIONS Gestational age and birth weight quantify the risk of NHL. This information can be used at the individual level for parent counseling and at the population level for medical decision making.

Technical standards for recording and interpretation of neonatal electroencephalogram in clinical practice

Neonatal electroencephalogram (EEG), though often perceived as being difficult to record and interpret, is relatively easy to study due to the immature nature of the brain, which expresses only a few well-defined set of patterns. The EEG interpreter needs to be aware of the maturational changes as well as the effect of pathological processes and medication on brain activity. It gives valuable information for the treatment and prognostication in encephalopathic neonates. In this group, serial EEGs or EEG monitoring often gives additional information regarding deterioration/improvement of the brain function or occurrence of seizures.

Automated EEG inter-burst interval detection in neonates with mild to moderate postasphyxial encephalopathy

EEG inter-burst interval (IBI) and its evolution is a robust parameter for grading hypoxic encephalopathy and prognostication in newborns with perinatal asphyxia. We present a reliable algorithm for the automatic detection of IBIs. This automated approach is based on adaptive segmentation of EEG, classification of segments and use of temporal profiles to describe the global distribution of EEG activity. A pediatric neurologist has blindly scored data from 8 newborns with perinatal postasphyxial encephalopathy varying from mild to severe. 15 minutes of EEG have been scored per patient, thus totaling 2 hours of EEG that was used for validation. The algorithm shows good detection accuracy and provides insight into challenging cases that are difficult to detect.

Heart rate changes are insensitive for detecting postasphyxial seizures in neonates

We studied heart rate (HR) changes during 169 seizures (mean 12 per patient, range 8 to 18) in 14 neonates with severe birth asphyxia. HR changes were found in 21 seizures (12.4%) in eight patients (HR increases in four, decreases in one, and both patterns in three patients), suggesting the existence of neonatal cerebral hemispheric connections with brainstem autonomic regulatory centers. HR monitoring appears to be insensitive for detecting postasphyxial neonatal seizures.