Sean Mathieson

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.

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.

Validation of an automated seizure detection algorithm for term neonates.

Highlights • Seizure detection algorithm (SDA) validated on unseen, unedited EEG of 70 neonates.• Results at SDA sensitivity settings of 0.5–0.3 acceptable for clinical use.• Seizure detection rate of 52.6–75.0%, false detection rate 0.04–0.36 FD/h.

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.

Long-Range Temporal Correlations in the EEG Bursts of Human Preterm Babies

The electrical activity in the very early human preterm brain, as recorded by scalp EEG, is mostly discontinuous and has bursts of high-frequency oscillatory activity nested within slow-wave depolarisations of high amplitude. The temporal organisation of the occurrence of these EEG bursts has not been previously investigated. We analysed the distribution of the EEG bursts in 11 very preterm (23–30 weeks gestational age) human babies through two estimates of the Hurst exponent. We found long-range temporal correlations (LRTCs) in the occurrence of these EEG bursts demonstrating that even in the very immature human brain, when the cerebral cortical structure is far from fully developed, there is non-trivial temporal structuring of electrical activity.

Recooling for Rebound Seizures After Rewarming in Neonatal Encephalopathy

Infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy are at risk for rebound seizures during and after the rewarming phase. We report a term male infant who was cooled for hypoxic ischemic encephalopathy. He developed electrographic seizures for the first time during the warming phase, which continued in the hours after rewarming. The seizures stopped within 30 minutes of recooling to 33.5°C without anticonvulsant medication. He was uneventfully cooled for an additional 24 hours and then rewarmed with no recurrence of seizures. Hypothermia appeared to have an antiepileptic effect in this case and may be worthy of additional investigation as an adjunct to antiepileptic drug therapy in newborns.

In-depth performance analysis of an EEG based neonatal seizure detection algorithm

Highlights • A novel method for in-depth analysis of neonatal seizure detection algorithms is proposed.• The analysis estimated how seizure features are exploited by automated detectors.• This method led to significant improvement of the ANSeR algorithm.

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.

Changes in Cerebral Oxidative Metabolism during Neonatal Seizures Following Hypoxic–Ischemic Brain Injury

Seizures are common following hypoxic–ischemic brain injury in newborn infants. Prolonged or recurrent seizures have been shown to exacerbate neuronal damage in the developing brain; however, the precise mechanism is not fully understood. Cytochrome-c-oxidase is responsible for more than 90% of ATP production inside mitochondria. Using a novel broadband near-infrared spectroscopy system, we measured the concentration changes in the oxidation state of cerebral cytochrome-c-oxidase (Δ[oxCCO]) and hemodynamics during recurrent neonatal seizures following hypoxic–ischemic encephalopathy in a newborn infant. A rapid increase in Δ[oxCCO] was noted at the onset of seizures along with a rise in the baseline of amplitude-integrated electroencephalogram. Cerebral oxygenation and cerebral blood volume fell just prior to the seizure onset but recovered rapidly during seizures. Δ[oxCCO] during seizures correlated with changes in mean electroencephalogram voltage indicating an increase in neuronal activation and energy demand. The progressive decline in the Δ[oxCCO] baseline during seizures suggests a progressive decrease of mitochondrial oxidative metabolism.

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

Highlights • Phenobarbital reduces both amplitude and propagation of neonatal seizures.• These changes may help to explain electroclinical uncoupling.• The performance of our seizure detection algorithm was unaffected.