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Objective: We aimed to test the hypothesis that computational features of the first several minutes of EEG recording can be used to estimate the risk for development of acute seizures in comatose critically-ill children., Methods: In a prospective cohort of 118 comatose children, we computed features of the first five minutes of artifact-free EEG recording (spectral power, inter-regional synchronization and cross-frequency coupling) and tested if these features could help identify the 25 children who went on to develop acute symptomatic seizures during the subsequent 48 hours of cEEG monitoring., Results: Children who developed acute seizures demonstrated higher average spectral power, particularly in the theta frequency range, and distinct patterns of inter-regional connectivity, characterized by greater connectivity at delta and theta frequencies, but weaker connectivity at beta and low gamma frequencies. Subgroup analyses among the 97 children with the same baseline EEG background pattern (generalized slowing) yielded qualitatively and quantitatively similar results., Conclusions: These computational features could be applied to baseline EEG recordings to identify critically-ill children at high risk for acute symptomatic seizures., Significance: If confirmed in independent prospective cohorts, these features would merit incorporation into a decision support system in order to optimize diagnostic and therapeutic management of seizures among comatose children., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: The identification of a biomarker for sudden unexpected death in epilepsy (SUDEP) has the potential to save lives. Generalized convulsive seizures and postictal generalized suppression on electroencephalography (EEG) most often precede sudden unexpected death in epilepsy (SUDEP) and are potential biomarkers. We identify the EEG and seizure characteristics associated with postictal generalized EEG suppression in children with epilepsy., Methods: Video EEGs were reviewed for seizure type, duration and semiology, and electrographic features. To identify predictors of postictal generalized EEG suppression, we identified 40 children with generalized convulsive seizures from a group of 399 patients who experienced an electroclinical seizure during video-EEG. Seventy-seven generalized convulsive seizures with and without postictal generalized EEG suppression were anayzed., Results: Age of seizure onset was older in 19 children with postictal generalized EEG suppression (mean 6.8 years old, 95% CI [4.7-8.9]) than in 21 without postictal generalized EEG suppression (3.0 years old, [1.1-4.1], P = 0.041). Postictal generalized EEG suppression occurred significantly more often from sleep than awake (point of estimate 16.67; 95% CI [0.97-32.36], P < 0.038). Shorter duration of the clonic phase (-0.76; [-1.338, -0.133], P = 0.018) was significantly associated with postictal generalized EEG suppression. Ictal symmetric tonic extension posturing significantly increased the odds of postictal generalized EEG suppression (42.94; [18.77, 67.12], P = 0.001). All 15 generalized convulsive seizures with a terminal burst-suppression pattern were followed by postictal generalized EEG suppression in contrast to 19 of 62 generalized convulsive seizures without burst-suppression (15.32, P < 0.001)., Conclusions: Ictal decerebrate-like symmetric tonic extension posturing with shorter clonic phase and a terminal burst-suppression pattern identify malignant generalized convulsive seizures, associated with postictal generalized EEG suppression and a potentially increased risk of sudden unexpected death in epilepsy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The neuronal ceroid lipofuscinoses (NCL) are neurodegenerative conditions that associate cognitive decline, progressive cerebellar atrophy, retinopathy, and myoclonic epilepsy. NCL result from the excessive accumulation of neuronal and extraneuronal lipopigments, despite having diverse underlying biochemical aetiologies. Here we review the clinical presentation, pathophysiology and genetics of these conditions as well as the approach to diagnosis and management.

Objective: To evaluate whether structural and microstructural brain abnormalities in neonates with congenital heart disease (CHD) correlate with neuronal network dysfunction measured by analysis of EEG connectivity., Methods: We studied a prospective cohort of 20 neonates with CHD who underwent continuous EEG monitoring before surgery to assess functional brain maturation and network connectivity, structural magnetic resonance imaging (MRI) to determine the presence of brain injury and structural brain development, and diffusion tensor MRI to assess brain microstructural development., Results: Neonates with MRI brain injury and delayed structural and microstructural brain development demonstrated significantly stronger high-frequency (beta and gamma frequency band) connectivity. Furthermore, neonates with delayed microstructural brain development demonstrated significantly weaker low-frequency (delta, theta, alpha frequency band) connectivity. Neonates with brain injury also displayed delayed functional maturation of EEG background activity, characterized by greater background discontinuity., Interpretation: These data provide new evidence that early structural and microstructural developmental brain abnormalities can have immediate functional consequences that manifest as characteristic alterations of neuronal network connectivity. Such early perturbations of developing neuronal networks, if sustained, may be responsible for the persistent neurocognitive impairment prevalent in adolescent survivors of CHD. These foundational insights into the complex interplay between evolving brain structure and function may have relevance for a wide spectrum of neurological disorders manifesting early developmental brain injury.

Objective: Burst-suppression is an electroencephalographic pattern observed during coma. In individuals without known brain pathologies undergoing deep general anesthesia, somatosensory stimulation transiently increases the occurrence of bursts. We investigated the reactivity of burst-suppression in children with acquired brain injury., Methods: Intensive care unit electroencephalographic monitoring recordings containing burst-suppression were obtained from 5 comatose children with acquired brain injury of various etiologies. Intermittent photic stimulation was performed at 1Hz for 1min to assess reactivity. We quantified reactivity by measuring the change in the burst ratio (fraction of time in burst) following photic stimulation., Results: Photic stimulation evoked bursts in all patients, resulting in a transient increase in the burst ratio, while the mean heart rate remained unchanged. The regression slope of the change in burst ratio, referred to as the standardized burst ratio reactivity, correlated with subjects' Glasgow Coma Scale scores., Conclusions: Reactivity of the burst-suppression pattern to photic stimulation occurs across diverse coma etiologies. Standardized burst ratio reactivity appears to reflect coma severity., Significance: Measurement of burst ratio reactivity could represent a simple method to monitor coma severity in critically ill children., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Investigators from Nationwide Children's Hospital performed an observational cohort study of early post-traumatic seizures (EPTS) among 34 children with moderate to severe traumatic brain injury (TBI) who received levetiracetam (LEV) prophylaxis following admission to their pediatric intensive care unit.

Objective: A post-spike slow wave (PSS) as part of a spike and slow wave is presumably related to inhibition of epileptic activity. In this study, we evaluated dynamic changes of PSS power toward seizure onset in patients with focal cortical dysplasia (FCD) type II., Methods: We collected data from 10 pediatric patients with FCD type II, who underwent invasive monitoring with subdural grids. The PSS were averaged based on spike-triggering in 30s epochs during both interictal and preictal periods. We quantitatively measured and compared PSS power and distribution between interictal and preictal periods, both within and outside the seizure onset zone (SOZ)., Results: PSS power was significantly higher in all areas during preictal period compared with interictal period. During preictal period, PSS power within SOZ was significantly higher than outside SOZ. From interictal to preictal period, the number of electrodes with high power PSS significantly increased within SOZ and decreased outside SOZ., Conclusions: Toward seizure onset, PSS power increased in all areas, predominantly within SOZ, and became confined into SOZ in a subset of FCD type II patients., Significance: Preictal PSS power increase and confinement into SOZ accompany transition to seizures., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: We analyzed the spatial distribution and concordance of fast (>10Hz) and slow (<5Hz) electroencephalogram (EEG) components of ictal activities and interictal epileptiform discharges (IIED) recorded by intracranial video EEG (IVEEG) in children with epileptic spasms (ES)., Methods: We studied eight children with ES, who underwent IVEEG before resective surgery for epilepsy. We quantified the root-mean-square (RMS) amplitude of the fast and slow components of ictal activities during ES and IIED. We compared the concordance between the spatial distributions of the fast and slow components of ES and IIED., Results: There was a larger concordance between the spatial distributions of the fast and slow components in IIED than in ES (p=0.0206 and 0.0401)., Conclusions: The spatial concordance between the fast and slow EEG components was significantly different between ES and IIED., Significance: The mechanisms underlying the generation of slow EEG components may differ between ES and IIED. The slow EEG components of ES might indicate an extensive epileptic network involving remote symptomatic zones for ES in either the cortical or subcortical areas. The high spatial concordance between the fast and slow components of IIED suggests the involvement of a local inhibitory process within the epileptic cortex., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Anti-glutamic acid decarboxylase directed antibodies are a rare cause of autoimmune limbic encephalitis that is relatively resistant to immunotherapy. Here we report a 15-year-old boy with nonparaneoplastic, anti-glutamic acid decarboxylase limbic encephalitis presenting with subacute headache, memory disturbance, psychiatric symptoms, and seizures. At onset, his memory disturbance manifested as transient global amnesia-like episodes. Clinical remission was achieved with rituximab, intravenous immunoglobulin, and corticosteroids.

Acute cerebral cortical trauma often leads to paroxysmal activities that terminate in a few hours, but several months later, patients can develop epilepsy. The process occurring between the initial acute triggered seizures and the onset of spontaneous unprovoked seizures is termed epileptogenesis. Here the authors summarize recent morphological, electrophysiological, and computational studies demonstrating that partial cortical isolation increases the number and duration of silent states in the cortical network, boosting neuronal connectivity and network excitability. These changes develop progressively, and after several weeks their synergetic action leads to epilepsy.

The subtle mechanisms of post-traumatic epileptogenesis remain unknown, although the incidence of chronic epilepsy after penetrating cortical wounds is high. Here, we investigated whether the increased frequency of seizures occurring within 6 weeks following partial deafferentation of the suprasylvian gyrus in cats is accompanied with a change in the ratio between the number of excitatory and inhibitory neurons. Immuno-histochemical labeling of all neurons with neuronal-specific nuclear protein (NeuN) antibody, and of the GABAergic inhibitory neurons with either gamma-aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD 65&67) antibodies, was performed on sections obtained from control and epileptic animals with chronically deafferented suprasylvian gyrus. Quantification of the labeled neurons was performed in control animals and at 2, 4, and 6 weeks following cortical deafferentation, in the suprasylvian and marginal gyri, both ipsi- and contra-lateral to the cortical trauma. In all epileptic animals, the neuronal loss was circumscribed to the deafferented suprasylvian gyrus. Inhibitory GABAergic neurons were particularly more sensitive to cortical deafferentation than excitatory ones, leading to a progressively increasing ratio between excitation and inhibition towards excitation, potentially explaining the increased propensity to seizures in chronic undercut cortex.

Some forms of electrographic seizures are generated at the level of the cortical network. Neocortical kindling exhibits a resistance to produce generalized convulsive seizures, and therefore, it was rather difficult to use it to study the cortical epileptogenesis. Here, using supra-threshold cortical kindling, we report electrophysiological patterns of field-potential synchronization and intracellular activities in chronically implanted non-anesthetized cats, during different states of vigilance, and during acute seizures elicited by prolonged (20-60 s) electrical stimulation. Acute seizures were easily elicited during transition from slow-wave sleep (SWS) to waking state. The seizures were mainly clonic accompanied with tonic components followed by prolonged postictal depression. Delayed rhythmic outlasting activities (OA) at approximately 1.5 Hz, first time reported here, followed the postictal depression, and lasted up to 2 h. These activities were clear during waking state, slightly reduced during SWS and completely absent during rapid-eye movement sleep. They started focally and following daily stimulations generalized over the entire cortical surface. Extra- and intracellular neuronal recordings during OA displayed spike-doublets, built on the summation of successive excitatory postsynaptic potentials and fast-prepotentials, entailing an increased dendritic excitation. Our results suggest that such rhythmic long-lasting oscillatory activity outlasting seizures are the key factor of epileptogenesis, leading to epilepsy.

Kindling is an essential operating paradigm of the nervous system extensively used both as a model of epileptogenesis and neuroplasticity. In a parallel study conducted on chronically implanted non-anesthetized kindled cats, we report the occurrence of long-lasting slow oscillatory patterns (1.5-2 Hz) called outlasting activities (OA) following the acute seizures (AS) induced by cortical stimulation. Here, we asked if OA observed in the neocortex of kindled animals are generated exclusively by the cortical networks or if they also rely on the burst firing of thalamic neurons. We analyzed the electrophysiological patterns of synchronization of cortical EEG (areas 4, 5, 7, 21, 17, 18, 22) and thalamic field (EThG) (ventral posterior lateral nucleus-VPL), and the influence of modulatory systems originating in the pedunculo-pontine tegmentum (PPT) and locus coeruleus (LC) on the discharge pattern of thalamic neurons during OA. Synchrony analysis of field recordings showed that during AS cortical paroxysmal activities preceded thalamic ones, while during OA this sequential order was reversed. During OA thalamic neurons regularly discharged bursts with the frequency of OA. Electrical stimulation of either PPT or LC during OA decreased both the probability of bursts in thalamocortical neurons and the amplitude of OA. Yet, neither of them was able to block completely the expression of OA. Following PPT/LC stimulation the burst firing of thalamocortical neurons was replaced by tonic firing. We conclude that the thalamus is involved in the mechanism of generation of OA but that it does not play an exclusive role.

To study the possible mechanism(s) underlying unresponsiveness following neocortical seizures, we recorded excitatory postsynaptic potentials (EPSPs) of cortical neurons evoked by ipsilateral cortical stimulation before and after spontaneous or elicited seizures. Regular-spiking neurons (n = 32) were intracellularly recorded in association area five of cats under ketamine-xylazine or barbiturate anesthesia. Compared with control responses, cortically evoked EPSPs were characterized by decreased amplitude after electrographic seizures. Synaptic responses and intrinsic properties were measured by applying extracellular electrical stimuli followed by intracellular hyperpolarizing current pulses. The input resistance decreased during seizures but quickly recovered to control level after the paroxysms, whereas the amplitude of evoked EPSPs remained lower following seizures, generally for 2-12 min, suggesting that the decreased EPSPs were not due to an alteration of intrinsic response. Data demonstrate a long-lasting decreased synaptic responsiveness following generalized spike-wave seizures slowly recovering in time.

We investigated the dependency of electrical seizures produced by cortical undercut upon behavioral states of vigilance in chronically implanted cats. Experiments were performed 1-12 weeks after white matter transection. Multisite field potentials and intracellular activity were recorded from suprasylvian and marginal gyri. Paroxysmal activity developed within days and consisted of spike-wave complexes at 3-4 Hz occurring during the waking state (correlated with eye movements), being enhanced during slow-wave sleep (SWS) and blocked during rapid eye movement (REM) sleep. Prolonged hyperpolarizing events were seen not only during SWS (which is the case in normal animals) but also during both waking and REM, thus resulting in bimodal distribution of the membrane potential in all 3 natural states of vigilance. The increased synchrony of field potential activity expressed by shorter time of propagation over the cortical surface and the tendency toward generalization are ascribed to changes in intrinsic neuronal properties and potential disinhibition following cortical undercut.

This study aims at understanding complex interactions between cortical neurons, glia and blood supply developing during the transition from slow-wave sleep to wakefulness. In spite of essential advances from in vitro and culture preparations, the basic mechanisms of glial interactions with their cellular and ionic environment had remained uninvestigated in vivo. Here we approach this issue by performing simultaneous intracellular recordings of cortical neurons and glia, together with measurements of cerebral blood flow (CBF), extracellular K+ concentrations and local field potentials in both anesthetized (ketamine-xylazine) and naturally behaving cats. Under anesthesia, cortical activation was elicited with electric stimulation of cholinergic nuclei (pedunculopontine tegmental in the brainstem and/or nucleus basalis in the basal forebrain). Iontophoretic application of acetylcholine on the recorded cells was also used. In the vast majority of cases (> 80%) glial cells were hyperpolarized during electric stimulation or spontaneous activation. This result was also obtained in all cases where iontophoresis was used or when glutamatergic kainate/quisqualate receptors were blocked with 6-cyano-7-nitroquinoxaline-2,3-dione. The glial hyperpolarization was associated with steady neuronal depolarization, increased CBF, lower extracellular K+ concentration, increased membrane resistance, decreased membrane capacitance and persistent positive DC field potentials. In some cases of cortical activation (< 20%), glial cells displayed sustained depolarizing potentials, in parallel with neuronal depolarization, decreased CBF and more negative DC field potentials. The above-mentioned effects of cholinergic activation were blocked by the muscarinic antagonist scopolamine. We propose that the glial response to cholinergic activation results from the balance between the direct hyperpolarizing action of acetylcholine and the depolarizing modulation of glutamate from the neighboring neurons, in addition to the modulation of the interglial communication pathway and/or the ionic traffic across blood vessels.

Cortical injury may lead to clinical seizures. We investigated the changing patterns of the sleeplike slow oscillation and its tendency to develop into paroxysmal activity consisting of spike-wave (SW) complexes at 2-4 Hz after partial deafferentation of the suprasylvian gyrus. Experiments were carried out in anesthetized cats, at different time intervals (wk 1 to wk 5, W1-W5) after cortical undercut. Multisite field potentials and single or dual intracellular recordings from the whole extent of the deafferented gyrus were used. The field components of the slow oscillation increased in amplitudes and were transformed into paroxysmal patterns, expressed by increased firing rates and tendency to neuronal bursting. The incidence of SW seizures was higher with transition from semiacute (W1) to chronic (W2-W5) stages after cortical undercut. The propagation delay of low-frequency activities decreased from W1 to W5, during both the slow oscillation and seizures. The initiation of seizures took place in territories contiguous to the relatively intact cortex (area 5 in the anterior part of the gyrus), as shown by cross-correlations of field potentials from different sites and simultaneous intracellular recordings from the anterior and posterior parts of the gyrus. The increased amplitudes of both slow oscillation and SW seizures, and their enhanced synchrony expressed by shorter time of propagation, are ascribed to increased neuronal and network excitability after cortical undercut.

We studied the mechanisms underlying CO(2)-dependent DC potential shifts, using epicranial, epidural, epicortical, intraventricular, and intraparenchymal (intraneuronal, intraglial, and field) recordings in ketamine-xylazine-anesthetized cats. DC shifts were elicited by changes in artificial ventilation, causing end-tidal CO(2) variations within a 2-5% range. Hypercapnia was consistently associated with negative scalp DC shifts (average shift -284.4 microV/CO(2)%, range -216 to -324 microV/CO(2)%), whereas hypocapnia induced positive scalp DC shifts (average shift 307.8 microV/CO(2)%, range 234 to 342 microV/CO(2)%) in all electrodes referenced versus the nasium bone. The former condition markedly increased intracranial pressure (ICP), whereas the latter only slightly reduced ICP. Breakdown of the blood-brain barrier (BBB) resulted in a positive DC shift and drastically reduced subsequent DC responses to hypo-/hypercapnia. Thiopental and isoflurane also elicited a dose-dependent positive DC shift and, at higher doses, hypo-/hypercapnia responses displayed reverted polarity. As to the possible implication of neurons in the production of DC shifts, no polarity reversal was recorded between scalp, various intracortical layers, and deep brain structures. Moreover, the membrane potential of neurons and glia did not show either significant or systematic variations in association with the scalp-recorded CO(2)-dependent DC shifts. Pathological activities of neurons during spike-wave seizures produced DC shifts of significantly smaller amplitude than those generated by hyper-/hypocapnia. DC shifts were still elicited when neuronal circuits were silent during anesthesia-induced burst-suppression patterns. We suggest that potentials generated by the BBB are the major source of epicortical/cranial DC shifts recorded under conditions affecting brain pH and/or cerebral blood flow.