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.

Human IFNAR2 deficiency: Lessons for antiviral immunity.

Type I interferon (IFN-α/ß) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/ß in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/ß receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/ß. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/ß responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/ß in human antiviral immunity.

The temporal evolution of electrographic seizure burden in neonatal hypoxic ischemic encephalopathy.

PURPOSE: Hypoxic ischemic encephalopathy (HIE) accounts for 60% of all neonatal seizures. There is emerging evidence that seizures cause additional injury to the developing brain that has sustained hypoxic ischemic injury. Temporal evolution of clinical seizure burden in HIE has been characterized, with maximum clinical seizure burden (the period of maximum seizure activity) being observed between 12 and 24 h of age. The purpose of our study was to investigate the distribution of electrographic seizure burden (the accumulated duration of seizures over a defined time period), following the initial hypoxic ischemic insult. METHODS: Fifteen full-term newborns with HIE and seizures, and a minimum of 48 h of continuous video-electroencephalography (EEG), were included in this retrospective study. Medical records of the infants were reviewed and details of clinical seizures and antiepileptic drugs were recorded. The time of maximum seizure burden was defined as the midpoint of an hour-long window, shifted in time by 1 s across the full EEG recording, which contained the maximum duration of seizures. The degree of temporal evolution of seizure burden within this period was tested. Temporal evolution was further analyzed by segmenting the time series into two periods; the time between the first recorded seizure and the maximum seizure burden (T(1)), and the time between the maximum seizure burden and the last recorded seizure (T(2)). Seizure burden, duration, and number of seizures per hour were analyzed within each time period. KEY FINDINGS: EEG was commenced at a median of 14 h of age. Maximum electrographic seizure burden was reached at a median age of 22.7 h. Time from first recorded seizure to maximum seizure burden (T(1)) was significantly shorter than time from maximum seizure burden to last recorded seizure (T(2)) (p-value = 0.01). Median seizure burden during T(1) was significantly higher than during T(2) (p-value = 0.007). There is temporal evolution of electrographic seizure burden in full-term newborns with HIE. There is a short period of high seizure burden (T(1)) followed by a longer period of lower seizure burden (T(2)). SIGNIFICANCE: Understanding the temporal evolution of seizure burden in HIE contributes further to our understanding of neonatal seizures, helps identify an optimal therapeutic window for seizure treatment, and provides a benchmark against which to measure the efficacy of new and innovative forms of neuroprotection and antiepileptic medication.