Sampsa Vanhatalo

Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis

Febrile seizures are frequent during early childhood, and prolonged (complex) febrile seizures are associated with an increased susceptibility to temporal lobe epilepsy. The pathophysiological consequences of febrile seizures have been extensively studied in rat pups exposed to hyperthermia. The mechanisms that trigger these seizures are unknown, however. A rise in brain pH is known to enhance neuronal excitability. Here we show that hyperthermia causes respiratory alkalosis in the immature brain, with a threshold of 0.2–0.3 pH units for seizure induction. Suppressing alkalosis with 5% ambient CO2 abolished seizures within 20 s. CO2 also prevented two long-term effects of hyperthermic seizures in the hippocampus: the upregulation of the Ih current and the upregulation of CB1 receptor expression. The effects of hyperthermia were closely mimicked by intraperitoneal injection of bicarbonate. Our work indicates a mechanism for triggering hyperthermic seizures and suggests new strategies in the research and therapy of fever-related epileptic syndromes.

Evaluation of commercially available electrodes and gels for recording of slow EEG potentials

OBJECTIVE To test the applicability of different types of commercially available electrodes and electrode gels or pastes for recording of slow EEG potentials. METHODS Experiments were carried out on six types of reusable electrodes (silver, tin and gold cup electrodes, sintered silver-silver chloride (Ag|AgCl), platinum, stainless steel), six disposable Ag|AgCl electrode models, and nine gels or pastes. We studied the parameters, which are critical in slow-potential recording, such as polarization, initial and long-term stability and low-frequency noise. RESULTS The best results were obtained with the reusable sintered Ag|AgCl electrodes. The six disposable Ag|AgCl electrode models also proved to have appropriate electrical properties. Other types of reusable electrodes suffered from diverse degrees of polarization, baseline drift, low-frequency noise, high resistance, and changes in properties due to wear and tear. Seven out of nine gels or pastes contained a significant amount of chloride, which is a prerequisite for DC stability of Ag|AgCl electrodes, whereas the absolute concentration of chloride had little effect. CONCLUSIONS Direct current (DC) coupled recording of EEG is critically dependent on the choice of electrode and gel. SIGNIFICANCE Our results provide rigorous criteria for choosing DC-stable electrodes and gels for DC-coupled or long time-constant AC-coupled recordings of slow EEG potentials.

Slow endogenous activity transients and developmental expression of K + -Cl ) cotransporter 2 in the immature human cortex

Spontaneous transients of correlated activity are a characteristic feature of immature brain structures, where they are thought to be crucial for the establishment of precise neuronal connectivity. Studies on experimental animals have shown that this kind of early activity in cortical structures is composed of long‐lasting, intermittent network events, which undergo a developmental decline that is closely paralleled by the maturation of GABAergic inhibition. In order to examine whether similar events occur in the immature human cortex, we performed direct current‐coupled electroencephalography (EEG) recordings from sleeping preterm babies. We show now that much of the preterm EEG activity is confined to spontaneous, slow activity transients. These transients are characterized by a large voltage deflection that nests prominent oscillatory activity in several frequency bands covering the whole frequency spectrum of the preterm EEG (<0.1–30 Hz). The slow voltage deflections had an amplitude of up to 800 µV. Most of these ‘giant’ events originated in the temporo‐occipital areas, with a maximum rate of about 8/min, and their occurrence as well as amplitude showed a decline by the time of normal birth. In age‐matched fetal brain tissue, this decrease in the spontaneous activity transients was associated with a developmental up‐regulation of the neuronal chloride extruder K+–Cl− cotransporter 2, a crucial molecule for the generation of inhibitory GABAergic Cl– currents. Our work indicates that slow endogenous activity transients in the immature human neocortex are mostly confined to the prenatal stage and appear to be terminated in parallel with the maturation of functional GABAergic inhibition.

Full-band EEG (FbEEG): an emerging standard in electroencephalography

While enormous resources have been recently invested into the development of a variety of neuroimaging techniques, the bandwidth of the clinical EEG, originally set by trivial technical limitations, has remained practically unaltered for over 50 years. An increasing amount of evidence shows that salient EEG signals are observed beyond the bandwidth of the routine clinical EEG, which is typically around 0.5-50 Hz. Physiological and pathological EEG activity ranges at least from 0.01 Hz to several hundred Hz, as demonstrated in recordings of spontaneous activity in the immature human brain, as well as during epileptic seizures, or various kinds of cognitive tasks and states in the adult brain. In the present paper, we will review several arguments leading to the conclusion that elimination of the lower (infraslow) or higher (ultrafast) bands of the EEG frequency spectrum in routine EEG leads to situations where salient and physiologically meaningful features of brain activity are ignored. Recording the full, physiologically relevant range of frequencies is readily attained with commercially available direct-current (DC) coupled amplifiers, which have a wide dynamic range and a high sampling rate. Such amplifiers, combined with appropriate DC-stable electrode-skin interface, provide a genuine full-band EEG (FbEEG). FbEEG is mandatory for a faithful, non-distorted and non-attenuated recording, and it does not have trade-offs that would favor any frequency band at the expense of another. With the currently available electrode, amplifier and data acquisition technology, FbEEG is likely to become the standard approach for a wide range of applications in both basic science and in the clinic.

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.

DC-EEG discloses prominent, very slow activity patterns during sleep in preterm infants.

OBJECTIVES The objective of this study is to test the hypothesis that the immature human brain exhibits slow electrical activity that is not detected by conventional (i.e. high-pass filtered) electroencephalography (EEG). METHODS Six healthy preterm infants (conceptional age 33-37 weeks) were recorded bedside with direct current (DC) EEG during sleep. Epochs with quiet sleep were selected to study the delta frequency bursts during discontinuous EEG patterns (trace discontinu or trace alternant), and we compared the waveforms obtained without filtering (i.e. genuine DC-EEG) to those seen after high pass filtering of the same traces. RESULTS In all infants, DC-EEG demonstrated that the typical delta frequency bursts are consistently embedded in very large amplitude (200-700 microV) and long lasting (1-5s) occipitally negative transients, which are not seen in conventional EEG. CONCLUSIONS AND SIGNIFICANCE Our study demonstrates that (i) the most prominent spontaneous EEG activity of a sleeping preterm infant consists of very slow, large amplitude transients, and (ii) the most salient features of these transients are not seen in conventional EEG. Proper recording of this type of brain activity by DC-EEG provides a novel way for non-invasive assessment of neonatal brain function.

Very slow EEG responses lateralize temporal lobe seizures An evaluation of non-invasive DC-EEG

Background: This study tested the idea that very slow EEG responses (direct current [DC] potential shifts) could be detected noninvasively during temporal lobe (TL) seizures, and that these shifts give lateralizing information consistent with that obtained by other methods. Methods: Seven patients with TL epilepsy (TLE) were recorded with scalp DC-EEG technique at bedside. All recordings were performed simultaneously with conventional EEG (scalp in five, and intracranially in two; two patients with scalp recordings were recorded intracranially later). Seizures in five patients originated in the mesial TL. Ictal DC shifts were evaluated by comparing them to the temporal evolution of ictal discharges, and by comparing the laterality of these shifts to the side of seizure onset defined by routine EEG and other presurgical diagnostic tests. Results: All seizures (35/35) were associated with negative DC shifts at temporal derivations (30 to 150 μV relative to vertex), beginning at the electrical seizure onset, and lasting for the whole seizure. In eight seizures (five patients) with documented mesial TL onset, the polarity of the DC shift was initially positive followed by a negative one after lateral spread of seizure activity. In all cases, the side of the EEG shift agreed with other diagnostic tests, and, at times, was more clearly lateralized than the conventional scalp EEG. Conclusions: DC-EEG recordings are practical and achievable at the bedside. Ictal DC shifts are consistently observed in scalp recordings in TL seizures, and reliably lateralize them. This method may hold promise in reducing the need for invasive monitoring in patients with TLE where other noninvasive tests are equivocal.

Neurturin is a neurotrophic factor for penile parasympathetic neurons in adult rat

Neurturin (NRTN), a member of the GDNF family of neurotrophic factors, promotes the survival and function of several neuronal populations in the peripheral and central nervous system. Recent gene ablation studies have shown that NRTN is a neurotrophic factor for many cranial parasympathetic and enteric neurons, whereas its significance for the sacral parasympathetic neurons has not been studied. NRTN signals via a receptor complex composed of the high-affinity binding receptor component GFRalpha2 and the transmembrane tyrosine kinase Ret. The aim of this study was to determine whether NRTN could be an endogenous trophic factor for penis-projecting parasympathetic neurons. NRTN mRNA was expressed in smooth muscle of penile blood vessels and corpus cavernosum in adult rat as well as in several intrapelvic organs, whereas GFRalpha2 and Ret mRNAs were expressed in virtually all cell bodies of the penile neurons, originating in the major pelvic ganglia. (125)I-NRTN injected into the shaft of the penis was retrogradely transported into the major pelvic and dorsal root ganglia. Mice lacking the GFRalpha2 receptor component had significantly less nitric oxide synthase-containing nerve fibers in the dorsal penile and cavernous nerves. In conclusion, these data suggest that NRTN acts as a target-derived survival and/or neuritogenic factor for penile erection-inducing postganglionic neurons.

Visual Field Constriction in 91 Finnish Children Treated with Vigabatrin

Summary:  Purpose: To study the prevalence and features of visual field constrictions (VFCs) associated with vigabatrin (VGB) in children.

Development of the spontaneous activity transients and ongoing cortical activity in human preterm babies

Recent experimental studies have shown that developing cortex in several animals species, including humans, exhibits spontaneous intermittent activity that is believed to be crucial for the proper wiring of early brain networks. The present study examined the developmental changes in these spontaneous activity transients (SAT) and in other ongoing cortical activities in human preterm babies. Full-band electroencephalography (FbEEG) recordings were obtained from 16 babies at conceptional ages between 32.8 and 40 wk. We examined the SATs and the intervening ongoing cortical activities (inter-SAT; iSAT) with average waveforms, their variance and power, as well as with wavelet-based time-frequency analyses. Our results show, that the low frequency power and the variance of the average waveform of SAT decrease during development. There was a simultaneous increase in the activity at higher frequencies, with most pronounced increase at theta-alpha range (4-9 Hz). In addition to the overall increase, the activity at higher frequencies showed an increased grouping into bursts that are nested in the low frequency (0.5-1 Hz) waves. Analysis of the iSAT epochs showed a developmental increase in power at lower frequencies in quiet sleep. There was an increase in a wide range of higher frequencies (4-16 Hz), whereas the ratio of beta (16-30 Hz) and theta-alpha (4-9 Hz) range activity declined, indicating a preferential increase at theta-alpha range activity. Notably, SAT and iSAT activities remained distinct throughout the development in all measures used in our study. The present results are consistent with the idea that SAT and the other ongoing cortical activities are distinct functional entities. Recognition of these two basic mechanisms in the cortical activity in preterm human babies opens new rational approaches for an evaluation and monitoring of early human brain function.