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.

Early qualitative and quantitative amplitude-integrated electroencephalogram and raw electroencephalogram for predicting long-term neurodevelopmental outcomes in extremely preterm infants in the Netherlands: a 10-year cohort study.

BACKGROUND: Extremely preterm infants (<28 weeks of gestation) are at great risk of long-term neurodevelopmental impairments. Early amplitude-integrated electroencephalogram (aEEG) accompanied by raw EEG traces (aEEG-EEG) has potential for predicting subsequent outcomes in preterm infants. We aimed to determine whether and which qualitative and quantitative aEEG-EEG features obtained within the first postnatal days predict neurodevelopmental outcomes in extremely preterm infants. METHODS: This study retrospectively analysed a cohort of extremely preterm infants (born before 28 weeks and 0 days of gestation) who underwent continuous two-channel aEEG-EEG monitoring during their first 3 postnatal days at Wilhelmina Children's Hospital, Utrecht, the Netherlands, between June 1, 2008, and Sept 30, 2018. Only infants who did not have genetic or metabolic diseases or major congenital malformations were eligible for inclusion. Features were extracted from preprocessed aEEG-EEG signals, comprising qualitative parameters grouped in three types (background pattern, sleep-wake cycling, and seizure activity) and quantitative metrics grouped in four categories (spectral content, amplitude, connectivity, and discontinuity). Machine learning-based regression and classification models were used to evaluate the predictive value of the extracted aEEG-EEG features for 13 outcomes, including cognitive, motor, and behavioural problem outcomes, at 2-3 years and 5-7 years. Potential confounders (gestational age at birth, maternal education, illness severity, morphine cumulative dose, the presence of severe brain injury, and the administration of antiseizure, sedative, or anaesthetic medications) were controlled for in all prediction analyses. FINDINGS: 369 infants were included and an extensive set of 339 aEEG-EEG features was extracted, comprising nine qualitative parameters and 330 quantitative metrics. The machine learning-based regression models showed significant but relatively weak predictive performance (ranging from r=0·13 to r=0·23) for nine of 13 outcomes. However, the machine learning-based classifiers exhibited acceptable performance in identifying infants with intellectual impairments from those with optimal outcomes at age 5-7 years, achieving balanced accuracies of 0·77 (95% CI 0·62-0·90; p=0·0020) for full-scale intelligence quotient score and 0·81 (0·65-0·96; p=0·0010) for verbal intelligence quotient score. Both classifiers maintained identical performance when solely using quantitative features, achieving balanced accuracies of 0·77 (95% CI 0·63-0·91; p=0·0030) for full-scale intelligence quotient score and 0·81 (0·65-0·96; p=0·0010) for verbal intelligence quotient score. INTERPRETATION: These findings highlight the potential benefits of using early postnatal aEEG-EEG features to automatically recognise extremely preterm infants with poor outcomes, facilitating the development of an interpretable prognostic tool that aids in decision making and therapy planning. FUNDING: European Commission Horizon 2020.

Early recognition of characteristic conventional and amplitude-integrated EEG patterns of seizures in SCN2A and KCNQ3-related epilepsy in neonates.

PURPOSE: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pattern was described in neonates with KCNQ2-related epilepsy. We report a similar aEEG pattern in seizures caused by SCN2A- and KCNQ3-pathogenic variants, as well as conventional EEG (cEEG) descriptions. METHODS: International multicentre descriptive study, reporting clinical characteristics, aEEG and cEEG findings of 13 neonates with seizures due to pathogenic SCN2A- and KCNQ3-variants. As a comparison group, aEEGs and cEEGs of neonates with seizures due to hypoxic-ischemic encephalopathy (n = 117) and other confirmed genetic causes affecting channel function (n = 55) were reviewed. RESULTS: In 12 out of 13 patients, the aEEG showed a characteristic sequence of brief onset with a decrease, followed by a quick rise, and then postictal amplitude attenuation. This pattern correlated with bilateral EEG onset attenuation, followed by rhythmic discharges ending in several seconds of post-ictal amplitude suppression. Apart from patients with KCNQ2-related epilepsy, none of the patients in the comparison groups had a similar aEEG or cEEG pattern. DISCUSSION: Seizures in SCN2A- and KCNQ3-related epilepsy in neonates can usually be recognized by a characteristic ictal aEEG pattern, previously reported only in KCNQ2-related epilepsy, extending this unique feature to other channelopathies. Awareness of this pattern facilitates the prompt initiation of precision treatment with sodium channel blockers even before genetic results are available.

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.

Outcome of non-cooled asphyxiated infants with under-recognised or delayed-onset encephalopathy.

OBJECTIVE: To describe the clinical characteristics, MRI findings and neurodevelopmental outcome of infants with documented perinatal asphyxia and seizure onset within 24 hours after birth who were not selected for therapeutic hypothermia (TH). DESIGN: Retrospective cohort study. SETTING AND PATIENTS: (Near-)term infants with documented perinatal asphyxia referred to two Dutch level III neonatal units with neonatal encephalopathy (NE) and seizures <24 hours after birth not treated with TH. Infants with a diagnosis other than NE following perinatal asphyxia causing the seizures were excluded. MAIN OUTCOME MEASURES: Clinical characteristics, findings on cranial MRI performed within 8 days after birth and neurodevelopmental outcome assessed using the Griffiths Mental Development Scales at 18 months or Bayley Scales of Infant and Toddler Development-Third Edition at 2 years of age. RESULTS: 39 infants were included. All had abnormalities on MRI. Predominant white matter/watershed injury was the most common pattern of injury, 23 (59%). 7 (18%) infants had predominant basal ganglia/thalamus injury, 3 (8%) near total brain injury, 5 (13%) arterial ischaemic stroke, 1 (3%) an intraventricular haemorrhage. Adverse outcome was seen in 51%: 6 died, 11 developed cerebral palsy (spastic n=8, dyskinetic n=3), 2 had neurodevelopmental delay, 1 had severe hearing impairment. CONCLUSIONS: All infants with documented perinatal asphyxia and seizure onset within 24 hours after birth who did not receive TH had abnormalities on MRI. 51% had an adverse outcome. Better methods for recognition of infants who might benefit from TH and careful neurodevelopmental follow-up are urgently needed.

MRI Score Ability to Detect Abnormalities in Mild Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Magnetic resonance imaging (MRI) scores have been well validated in moderate/severe hypoxic-ischemic encephalopathy (HIE). Infants with mild HIE can have different patterns of injury, yet different scores have not been compared in this group of infants. Our objective was to compare the ability of three = MRI scores to detect abnormalities in infants with mild HIE, and infants with moderate/severe HIE were included for comparison. METHODS: This is a single-center prospective cohort study of infants ≥36 weeks' gestation with HIE born at a level III neonatal intensive care unit from 2017 to 2019. All infants with HIE underwent an MRI, but only infants with moderate/severe HIE underwent therapeutic hypothermia. At least two experienced MRI readers who were unaware of all clinical variables independently assigned three scores (Barkovich, NICHD NRN, and Weeke). RESULTS: A total of 42 newborns with varying HIE severity underwent MRI on day five of life. In the overall cohort, abnormalities were reported in three (7%) infants using the Barkovich, in 10 (24%) using the NICHD NRN, and in 24 (57%) using the Weeke score. Agreement was excellent for each score: Barkovich score (k = 1.0), NICHD NRN (k = 0.92), and Weeke score (k = 0.9). CONCLUSIONS: Subtle injury due to mild HIE was detected with the highest frequency using the Weeke score, while inter-rater reliability was excellent for all three scores. These findings suggest that infants with mild HIE and subtle MRI abnormalities may benefit from detailed scoring systems, which is important for studies investigating the benefit of hypothermia in mild HIE.

Delay in Treatment of Neonatal Seizures: A Retrospective Cohort Study.

INTRODUCTION: Neonatal seizures are common and caused by a variety of underlying disorders. There is increasing evidence that neonatal seizures result in further brain damage. OBJECTIVE: To describe the time interval between diagnosis of amplitude-integrated electroencephalography (aEEG)-confirmed seizures and administration of anti-epileptic drugs (AEDs). METHODS: Single-centre retrospective cohort study, with full-term infants (n = 106) admitted to a level III neonatal intensive care unit between 2012 and 2017 with seizures confirmed on 2-channel aEEG and corresponding raw electroencephalography traces, treated with AEDs. The time interval between the first seizure on the aEEG registration and AED administration was calculated. Factors associated with early treatment were analysed. RESULTS: The median time interval of initiating treatment of aEEG-confirmed seizures was 01:50 h (interquartile range 00:43-4:30 h). Treatment of aEEG-confirmed seizures was initiated <1 h in 34/106 infants (32.1%), between 1 and 2 h in 21/106 infants (19.8%), 2-4 h in 23/106 infants (21.7%), 4-8 h in 14/106 infants (13.2%), and ≥8 h in 14/106 infants (13.2%). Seizures treated <1 h were significantly more often recognized by the seizure detection algorithm (SDA) compared to seizures treated >1 h (67 vs. 42%, p = 0.02) and showed more clinical signs (79.4 vs. 37.5%, p < 0.01). There was no difference for out-of-office hours (23.5 vs. 22.2%, p = 0.88). CONCLUSION: With only 32.1% of the seizures being treated <1 h, there is room for improvement. Timely treatment occurred more often when seizures were clinical or recognised by the SDA. aEEG is a helpful tool for diagnosing seizures 24/7.

Increased Use of Therapeutic Hypothermia in Infants with Milder Neonatal Encephalopathy due to Presumed Perinatal Asphyxia.

INTRODUCTION: Adverse outcomes have been reported in infants with mild neonatal encephalopathy (NE). Increasing clinical experience with the application of therapeutic hypothermia (TH) may have resulted in the treatment of newborns with milder NE during recent years. OBJECTIVE: To determine whether infants treated with TH in the initial years following implementation had a higher degree of NE than infants treated during subsequent years. METHODS: Infants with NE treated with TH from February 2008 until July 2017 were included. Thompson and Sarnat scores, amplitude-integrated electroencephalography (aEEG) background patterns before the start of TH, and neurodevelopmental outcome at 2 years were compared between infants treated from February 2008 until October 2012 (period 1) and infants treated from November 2012 until July 2017 (period 2). RESULTS: 211 newborns with NE were treated with TH (period 1: n = 109, period 2: n = 102). Sarnat scores in period 1 and 2 were mild in 7.3 vs. 28.4%, moderate in 66.1 vs. 44.1%, and severe in 26.6 vs. 22.5%, respectively (p = 0.008). Thompson scores were lower in period 2 (median = 9, IQR 7-12) than in period 1 (median = 10, IQR 8.5-13.5, p = 0.018). The aEEGs and neurodevelopmental outcomes were comparable between the periods. CONCLUSIONS: Based on Thompson and Sarnat scores, but not aEEG background patterns, infants treated during the second period had milder NE than infants treated during the first years following implementation of TH. There was no difference in 2 years neurodevelopmental outcome. Further research is necessary to evaluate the value of TH for infants with clinically mild NE.

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.

The development and validation of a cerebral ultrasound scoring system for infants with hypoxic-ischaemic encephalopathy.

BACKGROUND: Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality in neonates. When the gold standard MRI is not feasible, cerebral ultrasound (CUS) might offer an alternative. In this study, the association between a novel CUS scoring system and neurodevelopmental outcome in neonates with HIE was assessed. METHODS: (Near-)term infants with HIE and therapeutic hypothermia, a CUS on day 1 and day 3-7 after birth and available outcome data were retrospectively included in cohort I. CUS findings on day 1 and day 3-7 were related to adverse outcome in univariate and the CUS of day 3-7 also in multivariable logistic regression analyses. The resistance index, the sum of deep grey matter and of white matter involvement were included in multivariable logistic regression analyses. A comparable cohort from another hospital was used for validation (cohort II). RESULTS: Eighty-three infants were included in cohort I and 35 in cohort II. The final CUS scoring system contained the sum of white matter (OR = 2.6, 95% CI 1.5-4.7) and deep grey matter involvement (OR = 2.7, 95% CI 1.7-4.4). The CUS scoring system performed well in cohort I (AUC = 0.90) and II (AUC = 0.89). CONCLUSION: This validated CUS scoring system is associated with neurodevelopmental outcome in neonates with HIE.

Perinatal thalamic injury: MRI predictors of electrical status epilepticus in sleep and long-term neurodevelopment.

OBJECTIVE: Perinatal thalamic injury is associated with epilepsy with electrical status epilepticus in sleep (ESES). The aim of this study was to prospectively quantify the risk of ESES and to assess neuroimaging predictors of neurodevelopment. METHODS: We included patients with perinatal thalamic injury. MRI scans were obtained in the neonatal period, around three months of age and during childhood. Thalamic and total brain volumes were obtained from the three months MRI. Diffusion characteristics were assessed. Sleep EEGs distinguished patients into ESES (spike-wave index (SWI) >85%), ESES-spectrum (SWI 50-85%) or no ESES (SWI < 50%). Serial Intelligence Quotient (IQ)/Developmental Quotient (DQ) scores were obtained during follow-up. Imaging and EEG findings were correlated to neurodevelopmental outcome. RESULTS: Thirty patients were included. Mean thalamic volume at three months was 8.11 (±1.67) ml and mean total brain volume 526.45 (±88.99) ml. In the prospective cohort (n = 23) 19 patients (83%) developed ESES (-spectrum) abnormalities after a mean follow-up of 96 months. In the univariate analysis, larger thalamic volume, larger total brain volume and lower SWI correlated with higher mean IQ/DQ after 2 years (Pearson's r = 0.74, p = 0.001; Pearson's r = 0.64, p = 0.005; and Spearman's rho -0.44, p = 0.03). In a multivariable mixed model analysis, thalamic volume was a significant predictor of IQ/DQ (coefficient 9.60 [p < 0.001], i.e., corrected for total brain volume and SWI and accounting for repeated measures within patients, a 1 ml higher thalamic volume was associated with a 9.6 points higher IQ). Diffusion characteristics during childhood correlated with IQ/DQ after 2 years. SIGNIFICANCE: Perinatal thalamic injury is followed by electrical status epilepticus in sleep in the majority of patients. Thalamic volume and diffusion characteristics correlate to neurodevelopmental outcome.

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.

Amplitude-Integrated Electroencephalography for Early Recognition of Brain Injury in Neonates with Critical Congenital Heart Disease.

OBJECTIVE: To study perioperative amplitude-integrated electroencephalography (aEEG) as an early marker for new brain injury in neonates requiring cardiac surgery for critical congenital heart disease (CHD). STUDY DESIGN: This retrospective observational cohort study investigated 76 neonates with critical CHD who underwent neonatal surgery. Perioperative aEEG recordings were evaluated for background pattern (BGP), sleep-wake cycling (SWC), and ictal discharges. Spontaneous activity transient (SAT) rate, inter-SAT interval (ISI), and percentage of time with an amplitude <5 µV were calculated. Routinely obtained preoperative and postoperative magnetic resonance imaging of the brain were reviewed for brain injury (moderate-severe white matter injury, stroke, intraparenchymal hemorrhage, or cerebral sinovenous thrombosis). RESULTS: Preoperatively, none of the neonates showed an abnormal BGP (burst suppression or worse) or ictal discharges. Postoperatively, abnormal BGP was seen in 18 neonates (24%; 95% CI, 14%-33%) and ictal discharges was seen in 13 neonates (17%; 95% CI, 8%-26%). Abnormal BGP and ictal discharges were more frequent in neonates with new postoperative brain injury (P = .08 and .01, respectively). Abnormal brain activity (ie, abnormal BGP or ictal discharges) was the single risk factor associated with new postoperative brain injury in multivariable logistic regression analysis (OR, 4.0; 95% CI, 1.3-12.3; P = .02). Postoperative SAT rate, ISI, or time <5 µV were not associated with new brain injury. CONCLUSION: Abnormal brain activity is an early, bedside marker of new brain injury in neonates undergoing cardiac surgery. Not only ictal discharges, but also abnormal BGP, should be considered a clear sign of underlying brain pathology.

A Novel Magnetic Resonance Imaging Score Predicts Neurodevelopmental Outcome After Perinatal Asphyxia and Therapeutic Hypothermia.

OBJECTIVE: To assess the predictive value of a novel magnetic resonance imaging (MRI) score, which includes diffusion-weighted imaging as well as assessment of the deep grey matter, white matter, and cerebellum, for neurodevelopmental outcome at 2 years and school age among term infants with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia. STUDY DESIGN: This retrospective cohort study (cohort 1, The Netherlands 2008-2014; cohort 2, Sweden 2007-2012) including infants born at >36 weeks of gestational age treated with therapeutic hypothermia who had an MRI in the first weeks of life. The MRI score consisted of 3 subscores: deep grey matter, white matter/cortex, and cerebellum. Primary adverse outcome was defined as death, cerebral palsy, Bayley Scales of Infant and Toddler Development, third edition, motor or cognitive composite scores at 2 years of <85, or IQ at school age of <85. RESULTS: In cohort 1 (n = 97) and cohort 2 (n = 76) the grey matter subscore was an independent predictor of adverse outcome at 2 years (cohort 1, OR, 1.6; 95% CI, 1.3-1.9; cohort 2, OR, 1.4; 95% CI, 1.2-1.6), and school age (cohort 1, OR, 1.3; 95% CI, 1.2-1.5; cohort 2, OR, 1.3; 95% CI, 1.1-1.6). The white matter and cerebellum subscore did not add to the predictive value. The positive predictive value, negative predictive value, and area under the curve for the grey matter subscore were all >0.83 in both cohorts, whereas the specificity was >0.91 with variable sensitivity. CONCLUSION: A novel MRI score, which includes diffusion-weighted imaging and assesses all brain areas of importance in infants with therapeutic hypothermia after perinatal asphyxia, has predictive value for outcome at 2 years of age and at school age, for which the grey matter subscore can be used independently.

Rhythmic EEG patterns in extremely preterm infants: Classification and association with brain injury and outcome.

OBJECTIVE: Classify rhythmic EEG patterns in extremely preterm infants and relate these to brain injury and outcome. METHODS: Retrospective analysis of 77 infants born <28 weeks gestational age (GA) who had a 2-channel EEG during the first 72 h after birth. Patterns detected by the BrainZ seizure detection algorithm were categorized: ictal discharges, periodic epileptiform discharges (PEDs) and other waveforms. Brain injury was assessed with sequential cranial ultrasound (cUS) and MRI at term-equivalent age. Neurodevelopmental outcome was assessed with the BSITD-III (2 years) and WPPSI-III-NL (5 years). RESULTS: Rhythmic patterns were observed in 62.3% (ictal 1.3%, PEDs 44%, other waveforms 86.3%) with multiple patterns in 36.4%. Ictal discharges were only observed in one and excluded from further analyses. The EEG location of the other waveforms (p<0.05), but not PEDs (p=0.238), was significantly associated with head position. No relation was found between the median total duration of each pattern and injury on cUS and MRI or cognition at 2 and 5 years. CONCLUSIONS: Clear ictal discharges are rare in extremely preterm infants. PEDs are common but their significance is unclear. Rhythmic waveforms related to head position are likely artefacts. SIGNIFICANCE: Rhythmic EEG patterns may have a different significance in extremely preterm infants.

A Distinctive Ictal Amplitude-Integrated Electroencephalography Pattern in Newborns with Neonatal Epilepsy Associated with KCNQ2 Mutations.

BACKGROUND: Recurrent and prolonged seizures are harmful for the developing brain, emphasizing the importance of early seizure recognition and effective therapy. Amplitude-integrated electroencephalography (aEEG) has become a valuable tool to diagnose epileptic seizures, and, in parallel, genetic etiologies are increasingly being recognized, changing the paradigm of the workup and management of neonatal seizures. OBJECTIVE: To report the ictal aEEG pattern in neonates with KCNQ2-related epilepsy. SUBJECTS AND METHODS: In this multicenter descriptive study, clinical data and aEEG findings of 9 newborns with KCNQ2 mutations are reported. RESULTS: Refractory seizures occurred in the early neonatal period with similar seizure type, including tonic features, apnea, and desaturation. A distinct aEEG seizure pattern, consisting of a sudden rise of the lower and upper margin of the aEEG, followed by a marked depression of the aEEG amplitude, was found in 8 of the 9 patients. Prompt recognition of this pattern led to early treatment with carbamazepine in the 2 most recent cases. CONCLUSION: Early recognition of the electroclinical phenotype by using aEEG may direct genetic testing and a precision medicine approach with sodium channel blockers in neonates with KCNQ2 mutations.

Effect of general anesthesia on neonatal aEEG-A cohort study of patients with non-cardiac congenital anomalies.

INTRODUCTION: The aim of the current study was to determine the effect of general anesthesia on neonatal brain activity using amplitude-integrated EEG (aEEG). METHODS: A prospective cohort study of neonates (January 2013-December 2015), who underwent major neonatal surgery for non-cardiac congenital anomalies. Anesthesia was administered at the discretion of the anesthetist. aEEG monitoring was started six hours preoperatively until 24 hours after surgery. Analysis of classes of aEEG background patterns, ranging from continuous normal voltage to flat trace in six classes, and quantitative EEG-measures, using spontaneous activity transients (SATs) and interSATintervals (ISI), was performed. RESULTS: In total, 111 neonates were included (36 preterm/75 full-term), age at time of surgery was (median (range) 2 (0-32) days. During anesthesia depression of brain activity was seen, with background patterns ranging from flat trace to discontinuous normal voltage. In most patients brain activity was two background pattern classes lower during anesthesia. After cessation of anesthesia, recovery to preoperative brain activity occurred within 24 hours in 86% of the preterm and 96% of the term infants. Gestational age and the dose of sevoflurane were significantly associated with SAT-rate (F(2,68) = 9.288, p < 0.001) and ISI- durations during surgery (F(3,71) = 12.96, p < 0.001). Background pattern and quantitative EEG-values were not associated with brain lesions (χ2(4) = 2.086, ns). CONCLUSION: aEEG shows a variable reduction of brain activity in response to anesthesia in neonates with noncardiac congenital anomalies, with fast recovery after cessation of anesthesia. This reduction is related to gestational age and the dose of sevoflurane. The aEEG offers the opportunity to monitor the depth of anesthesia in the neonate.

Carbon Dioxide Fluctuations Are Associated with Changes in Cerebral Oxygenation and Electrical Activity in Infants Born Preterm.

OBJECTIVES: To evaluate the effects of acute arterial carbon dioxide partial pressure changes on cerebral oxygenation and electrical activity in infants born preterm. STUDY DESIGN: This retrospective observational study included ventilated infants born preterm with acute fluctuations of continuous end-tidal CO2 (etCO2) as a surrogate marker for arterial carbon dioxide partial pressure, during the first 72 hours of life. Regional cerebral oxygen saturation and fractional tissue oxygen extraction were monitored with near-infrared spectroscopy. Brain activity was monitored with 2-channel electroencephalography. Spontaneous activity transients (SATs) rate (SATs/minute) and interval between SATs (in seconds) were calculated. Ten-minute periods were selected for analysis: before, during, and after etCO2 fluctuations of ≥5 mm Hg. RESULTS: Thirty-eight patients (mean ± SD gestational age of 29 ± 1.8 weeks) were included, with 60 episodes of etCO2 increase and 70 episodes of etCO2 decrease. During etCO2 increases, brain oxygenation increased (regional cerebral oxygen saturation increased, fractional tissue oxygen extraction decreased; P < .01) and electrical activity decreased (SATs/minute decreased, interval between SATs increased; P < .01). All measures recovered when etCO2 returned to baseline. During etCO2 decreases, brain oxygenation decreased (regional cerebral oxygen saturation decreased, fractional tissue oxygen extraction decreased; P < .01) and brain activity increased (SATs/minute increased, P < .05), also with recovery after return of etCO2 to baseline. CONCLUSION: An acute increase in etCO2 is associated with increased cerebral oxygenation and decreased brain activity, whereas an acute decrease is associated with decreased cerebral oxygenation and slightly increased brain activity. Combining continuous CO2 monitoring with near-infrared spectroscopy may enable the detection of otherwise undetected fluctuations in arterial carbon dioxide partial pressure that may be harmful to the neonatal brain.

A Comparison of the Thompson Encephalopathy Score and Amplitude-Integrated Electroencephalography in Infants with Perinatal Asphyxia and Therapeutic Hypothermia.

BACKGROUND: In previous studies clinical signs or amplitude-integrated electroencephalography (aEEG)-based signs of encephalopathy were used to select infants with perinatal asphyxia for treatment with hypothermia. AIM: The objective of this study was to compare Thompson encephalopathy scores and aEEG, and relate both to outcome. SUBJECTS AND METHODS: Thompson scores, aEEG, and outcome were compared in 122 infants with perinatal asphyxia and therapeutic hypothermia. Of these 122 infants, 41 died and 7 had an adverse neurodevelopmental outcome. A receiver operating characteristics (ROC) analysis was also performed. RESULTS: Thompson scores were higher in infants with more abnormal aEEG background patterns (ANOVA, p < 0.001). The ROC analysis demonstrated that a Thompson score of 11 or higher or an aEEG background pattern of continuous low voltage or worse was associated with an adverse outcome (AUC 0.84 for both). CONCLUSIONS: High Thompson scores and a suppressed aEEG background pattern are associated with an adverse outcome after perinatal asphyxia and therapeutic hypothermia. Further studies are needed to identify the best technique with which to select patients for therapeutic hypothermia.