A novel de novo variant of GABRA1 causes increased sensitivity for GABA in vitro.

The GABRA1 gene encodes one of the most conserved and highly expressed subunits of the GABAA receptor family. Variants in this gene are causatively implicated in different forms of epilepsy and also more severe epilepsy-related neurodevelopmental syndromes. Here we study functional consequences of a novel de novo missense GABRA1 variant, p.(Ala332Val), identified through exome sequencing in an individual affected by early-onset syndromic epileptic encephalopathy. The variant is localised within the transmembrane domain helix 3 (TM3) and in silico prediction algorithms suggested this variant to be likely pathogenic. In vitro assessment revealed unchanged protein levels, regular assembly and forward trafficking to the cell surface. On the functional level a significant left shift of the apparent GABA potency in two-electrode voltage clamp electrophysiology experiments was observed, as well as changes in the extent of desensitization. Additionally, apparent diazepam potency was left shifted in radioligand displacement assays. During prenatal development mainly alpha2/3 subunits are expressed, whereas after birth a switch to alpha1 occurs. The expression of alpha1 in humans is upregulated during the first years. Thus, the molecular change of function reported here supports pathogenicity and could explain early-onset of seizures in the affected individual.

The impact of extrauterine life on visual maturation in extremely preterm born infants.

BACKGROUND: Extrauterine life is an important factor when considering brain maturation. Few studies have investigated the development of visual evoked potentials (VEP) in extremely preterm infants, and only a minority have taken into consideration the impact of extrauterine life. The aim of this study was to assess the normal maturation of VEP in infants born prior to 29 weeks gestational age (GA) and to explore the potential influence of extrauterine life. METHODS: VEP were prospectively recorded in extremely preterm infants, and principal peaks (N0, N1, P1, N2, P2, N3) were identified. The mean of peak-time and percentages of peak appearances were assessed for three GA groups (23/24, 25/26, 27/28 weeks) and four subgroups of increasing postnatal age (PNA), up to 8 weeks after birth. RESULTS: A total of 163 VEP recordings in 38 preterm infants were analyzed. With increasing GA at birth, peak-times decreased. When comparing infants with equal GA but longer extrauterine life, those with the highest PNA demonstrated the shortest VEP peak-times. However, this effect was less present in infants born prior to 25 weeks GA. CONCLUSION: Provided that a certain maturational threshold is reached, extrauterine life appears to accelerate maturation of the visual system in preterm infants.

Automated classification of neonatal sleep states using EEG.

OBJECTIVE: To develop a method for automated neonatal sleep state classification based on EEG that can be applied over a wide range of age. METHODS: We collected 231 EEG recordings from 67 infants between 24 and 45weeks of postmenstrual age. Ten minute epochs of 8 channel polysomnography (N=323) from active and quiet sleep were used as a training dataset. We extracted a set of 57 EEG features from the time, frequency, and spatial domains. A greedy algorithm was used to define a reduced feature set to be used in a support vector machine classifier. RESULTS: Performance tests showed that our algorithm was able to classify quiet and active sleep epochs with 85% accuracy, 83% sensitivity, and 87% specificity. The performance was not substantially lowered by reducing the epoch length or EEG channel number. The classifier output was used to construct a novel trend, the sleep state probability index, that improves the visualisation of brain state fluctuations. CONCLUSIONS: A robust EEG-based sleep state classifier was developed. It performs consistently well across a large span of postmenstrual ages. SIGNIFICANCE: This method enables the visualisation of sleep state in preterm infants which can assist clinical management in the neonatal intensive care unit.

Amplitude-integrated electroencephalography shows that doxapram influences the brain activity of preterm infants.

AIM: The aim of this study was to measure the brain activity of preterm infants treated with caffeine citrate and doxapram for preterm apnoea, using amplitude-integrated electroencephalography (aEEG), to identify any adverse effects on cerebral function. METHODS: We analysed the aEEG tracings of 13 preterm infants <30 weeks of gestation before, during and after doxapram treatment, with regard to background activity (percentages of continuous and discontinuous patterns), occurrence of sleep-wake cycling and appearance of electrographic seizure activity. They were also compared with 61 controls without doxapram treatment. RESULTS: During doxapram treatment, aEEG tracings showed an increase in continuous background activity (19 ± 30% before treatment, 38 ± 35% during treatment) and a decrease in discontinuous patterns. In addition, they showed more frequent electrographic seizure activity (0% before treatment, 15 ± 37% during treatment) and less frequent sleep-wake cycling (92 ± 27% before treatment, 85 ± 37% during treatment) could be observed. These results were confirmed when compared to the control group. CONCLUSION: Doxapram treatment influences aEEG in preterm infants, showing higher percentages of continuous activity as well as more electrographic seizure activity and less sleep-wake cycling. It should, therefore, be used with caution in very preterm infants.

Effect of maturation on suprasegmental speech processing in full- and preterm infants: a mismatch negativity study.

Infants born prematurely are at higher risk for later linguistic deficits present in delayed or atypical processing of phonetic and prosodic information. In order to be able to specify the nature of this atypical development, it is important to investigate the role of early experience in language perception. According to the concept of Gonzalez-Gomez and Nazzi (2012) there is a special intrauterine sensitivity to the prosodic features of languages that should have a special role in language acquisition. Therefore, we may also assume that pre- and full-term infants having months difference in intrauterine experience show different maturation patterns of processing prosodic and phonetic information present at word level. The aim of our study was to investigate the effect of these differences on word stress pattern vs. phoneme information processing. Two age groups of infants (6 and 10 month-olds) were included in our study. 21 of 46 of the total of infants investigated were prematurely born with low birth weight. We used the mismatch negativity (MMN) event related brain potential (ERP) component, a widely used electrophysiological correlate of acoustic change detection, for testing the assumed developmental changes of phoneme and word stress discrimination. In a passive oddball paradigm we used a word as standard, a pseudo-word as phoneme deviant, and an illegally uttered word as stress deviant. Our results showed no differences in MMN responses in the phoneme deviant condition between the groups, meaning a relatively intact maturation of phoneme processing of preterm infants as compared to their contemporaries. However, the mismatch responses measured in the stress condition revealed significant between-group differences. These results strengthen the view that the total length of intrauterine experience influences the time of emergence of prosodic processing.

Can neurophysiological assessment improve timing of intervention in posthaemorrhagic ventricular dilatation?

OBJECTIVE: Intraventricular haemorrhage is still the most common cause of brain lesion in preterm infants and development of a posthaemorrhagic ventricular dilatation (PHVD) can lead to additional neurological sequelae. Flash visual evoked potentials (fVEP) and amplitude-integrated electroencephalography (aEEG) are non-invasive neurophysiological monitoring tools. The aim of the study was to evaluate fVEPs and aEEGs in preterm infants with progressive PHVD prior to and after neurosurgical intervention for cerebrospinal fluid removal and to correlate the findings with severity of ventricular dilatation. DESIGN: fVEPs and aEEGs were performed weekly in infants with developing PHVD. As soon as the ventricular index reached the 97th percentile recordings were performed twice a week. METHODS: 17 patients admitted to the neonatal intensive care unit of the Medical University of Vienna who developed progressive PHVD were evaluated using fVEP and aEEG until and after reduction of intracranial pressure by placement of an external ventricular drainage. RESULTS: In all 17 cases (100%) wave latencies of fVEP increased above normal range and aEEG showed increased suppression in 13 patients (76%) with increasing ventricular dilatation. Both methods showed normalisation of patterns mostly within a week of successful therapeutic intervention (mean 8.5 days). Both changes in fVEP latencies and aEEG background patterns were detected before clinical signs of elevated intracranial pressure occurred. In only 10 patients (58.8%) ventricular width exceeded the 97th percentile+4 mm. CONCLUSIONS: fVEP and aEEG are useful additional tools for the evaluation of preterm infants with progressive PHVD.

Experiences in the perinatal management of congenital diaphragmatic hernia during the last 15 years in a tertiary referral institute.

OBJECTIVE: Review of cases of perinatally diagnosed congenital diaphragmatic hernias with special regard to time of diagnosis, organs herniated into the thorax, associated malformations, and outcomes. METHODS: We analyzed the data of 106 cases between July 1, 1990, and June 30, 2005. The observation period was analyzed in two parts. RESULTS: Prenatal ultrasound was performed in 89.6% (95/106) of the cases. 51.7% (46/89) of the pre- and postnatally verified congenital diaphragmatic hernia cases were diagnosed before the 24th week of gestation. 11% (11/100) of the hernias were identified postnatally. 71% (71/100) of the cases were associated with other malformations. The hernia was on the left side in 86% (86/100) and bilateral in 5% (5/100) of the cases. Between 1990 and 1997, the proportion of right-sided hernias was 4.3% (2/46), while during the second period it was 13% (7/54). 27.5% (14/51) of the newborns survived the perinatal period. The survival rate of the newborns delivered by caesarean section was three times higher than that of infants delivered vaginally. In the latter group, the rate of premature deliveries was considerably higher. The pregnancy was terminated in 45% (40/89) of the cases. 15% (6/40) of the terminated cases were isolated. Intrauterine or intrapartum deaths occurred in 5.6% (5/89) of the prenatally diagnosed cases. Simultaneous thoracic herniation of liver, spleen, or stomach decreased the survival rate. In these cases, the discharge rate was between 6 and 22%. CONCLUSIONS: According to the analysis of 15-year data, the herniated organs, multiple malformations, as well as the mode of delivery influence the survival in a large number of cases. Early diagnosis predicts a large hernia, a higher malformation rate, and a less favourable prognosis.