Seizure Discharge Propagation Research Articles

Dependence of spontaneous neuronal firing and depolarisation block on astroglial membrane transport mechanisms

Exposed to a sufficiently high extracellular potassium concentration ([K( + )]₀), the neuron can fire spontaneous discharges or even become inactivated due to membrane depolarisation ('depolarisation block'). Since these phenomena likely are related to the maintenance and propagation of seizure discharges, it is of considerable importance to understand the conditions under which excess [K( + )]₀ causes them. To address the putative effect of glial buffering on neuronal activity under elevated [K( + )](o) conditions, we combined a recently developed dynamical model of glial membrane ion and water transport with a Hodgkin-Huxley type neuron model. In this interconnected glia-neuron model we investigated the effects of natural heterogeneity or pathological changes in glial membrane transporter density by considering a large set of models with different, yet empirically plausible, sets of model parameters. We observed both the high [K( + )]₀-induced duration of spontaneous neuronal firing and the prevalence of depolarisation block to increase when reducing the magnitudes of the glial transport mechanisms. Further, in some parameter regions an oscillatory bursting spiking pattern due to the dynamical coupling of neurons and glia was observed. Bifurcation analyses of the neuron model and of a simplified version of the neuron-glia model revealed further insights about the underlying mechanism behind these phenomena. The above insights emphasise the importance of combining neuron models with detailed astroglial models when addressing phenomena suspected to be influenced by the astroglia-neuron interaction. To facilitate the use of our neuron-glia model, a CellML version of it is made publicly available.

Possible Exploitation of Non-Neuronal and Non-Chemical Synaptic Signalling Pathways in Epilepsy Therapy

Although approximately 1% of the human population suffers from epilepsy, the cellular basis of this disease remains largely unresolved, and about 30% of all epilepsies are refractory to therapies using currently available drugs. Until recently, synchronous neuronal activity during seizures has been thought to be, entirely of neuronal origin, and the main stream of epilepsy research has focused on changes in membrane properties of neurons and on classical chemical neurotransmission between them. However, recent discoveries about neuron-astrocyte bidirectional communication strongly challenge this concept. These functions of astrocyte are proving significant in the understanding of epilepsy, stroke and many other neurological diseases. In addition, the most important function reported for gap junctional communication in the nervous system is the increased synchronous activity of the coupled cells. Based on the emergent evidence, it is likely that gap junctional communication plays a definite role in the associated neuronal/astrocytic networks being involved in the generation and propagation of seizure discharges in the epileptic brain. Therefore astrocytes and gap junctions as potentially new cellular targets may open new perspectives for targeted molecular therapeutic interventions and allow the development of new antiepileptic as well as anticonvulsant drugs.

Neuroleptic Malignant Syndrome‐like State in an Epileptic Patient with Organic Brain Comorbidity Treated with Zonisamide and Carbamazepine

Neuroleptic Malignant Syndrome‐like State in an Epileptic Patient with Organic Brain Comorbidity Treated with Zonisamide and Carbamazepine

Die Behandlung der Epilepsien und verhaltensneurologische Aspekte

About 50% of patients with newly diagnosed epilepsy become seizure-free (for at least one year) with the first antiepileptic drug (AED). From those patients who are switched to a second antiepileptic drug because of inadequate seizure or adverse events, 13% respond satisfactorily, in particular if adverse events were the reason. About 40% have difficulties treating or are pharmacoresistant. The response to the first antiepileptic drug is the most important prognostic factor. Pharmacoresistance is a prerequisite for epilepsy surgery and is usually clinically defined as non-response to two antiepileptic drugs of first choice in successive monotherapy and in combination. Non-compliance is a frequent reason for non-response to prescribed antiepileptic drug. In true pharmacoresistance several biological factors have to be considered: severity and type of the syndrome and underlying neuropathology, abnormal neuronal circuits (e.g. hippocampal sclerosis, cortical dysplasia), hyperexcitable or disinhibited network reorganisation, alterations of neurotransmitter receptors, pathologies of ion channels, reactive autoimmune processes and altered penetration of antiepileptic drugs into the focus, e.g. P-glycoprotein (Pgp) expression at the blood-brain barrier. Lipophilic antiepileptic drugs are potential substrates for P-glycoprotein. Over-expression of P-glycoprotein in the endothelia of the blood-brain barrier has been found in pharmacoresistant epilepsy patients who underwent surgery and indicates that this might be the cause for diminished antiepileptic drug uptake into the brain. If pharmacoresistance is established, the patient should be considered a candidate for epilepsy surgery and undergo presurgical evaluation, which has to answer the following questions: (1) Is the patient suffering from a surgically amenable syndrome? (2) Can the seizure-generating zone be delineated with the precision and certainty necessary for a resective surgical intervention? (3) Can the seizure-generating zone be resected without the risks of intolerable neurological or neuropsychological deficits? And (4) if curative surgery with the aim of postoperative freedom of is not possible, can epilepsy surgery be offered, with the aim of improving the patient's seizure situation and quality of life? From a methodological point of view the presurgical evaluation aims to define several conceptual of an epileptic focus: (a) the epileptogenic lesion, (b) the seizure-generating or epileptogenic (c) the irritative zone and (d) the symptomatogenic zone. It is obvious that these various zones are not the same but can overlap. The mode of propagation of seizure discharges (seizure spread) via preferential pathways is of great importance for the definition of the symptomatogenic zone, but is also important for the definition of the resection borders. In certain palliative surgeries the inaccessible primary seizure-generating zone is only partly removed or even left behind and the secondary epileptogenic pacemaker is removed or preferential pathways for seizure spread are disrupted, such as is the case in corpus callosotomy (CCT). Curative epilepsy surgery is not only able to control seizures in a high proportion of patients but has the potential to cure in the sense that a considerable proportion of patients can discontinue their antiepileptic drugs. In the Zurich selective amygdalohippocampectomy series 90% of those patients who achieved complete seizure and aura freedom since operation (ILAE outcome class la) were without antiepileptic drugs in the 8th postoperative year. Neurobehavioural and psychiatric aspects of the epilepsies in general, and of temporal lobe epilepsy in particular play an important role in the discussion whether some epilepsy syndromes, such as the mesial temporal lobe epilepsy, may show a disease-related progressive course.

Sleep and arousal mechanisms in experimental epilepsy: epileptic components of NREM and antiepileptic components of REM sleep.

Neural generators related to different sleep components have different effects on seizure discharge. These sleep-related systems can provoke seizure discharge propagation during nonrapid eye movement (NREM) sleep and can suppress propagation during REM sleep. Experimental manipulations of discrete physiological components were conducted in feline epilepsy models, mostly in the systemic penicillin epilepsy model of primary generalized epilepsy and the amygdala kindling model of the localization-related seizure disorder, temporal lobe epilepsy. The sleep-wake state distribution of seizures was quantified before and after discrete lesions, systemic and localized drug administration, and/or photic stimulation, as well as in relation to microdialysis of norepinephrine. We found that (1) neural generators of synchronous EEG oscillations--including tonic background slow waves and phasic "arousal" events (sleep EEG transients such as sleep spindles and k-complexes)--combine to promote electrographic seizure propagation during NREM and drowsiness, and antigravity muscle tone permits seizure-related movement; (2) neural generators of asynchronous neuronal discharge patterns reduce electrographic seizures during alert waking and REM sleep, and skeletal motor paralysis blocks seizure-related movement during REM; (3) there are a number of similarities between amygdala-kindled kittens and children with Landau-Kleffner Syndrome (LKS) that suggest a link among seizures, sleep disorders, and behavioral abnormalities/regression.

Continuous potential display of ictal electrocorticography.

The objective of this study was to determine whether the animation of electrical activity recorded on ictal electrocorticograms (ECoGs) can demonstrate the propagation of seizure discharges from the epileptogenic zone (EZ) to the surrounding cortical area. A computer program, continuous potential display (CPD), was designed to animate the color-coded potential changes in 5-msec intervals at each recorded site. This program was used to analyze 35 ictal ECoGs recorded by subdural grid electrodes from 11 subjects who underwent epilepsy surgery for intractable partial seizures. Continuous potential display demonstrated recurrent cycles of seizure propagation from the EZ to the surrounding cortical area even when seizure discharges appeared widespread on ECoG. Hence, the EZ could be mapped at any time during the seizure course. The EZ mapped by analyzing a small fraction of ECoG during widespread seizure discharges using CPD only overlapped 69 +/- 24% (mean +/- standard deviation) of the surgical area. The EZ mapped by CPD had 34 +/- 22% false positives and 35 +/- 27% false negatives. Animation of potential changes recorded by ictal ECoG can assist in studying the temporal and spatial patterns of seizure propagation and in mapping the EZ for surgical resection.

Physiological basis: how NREM sleep components can promote and REM sleep components can suppress seizure discharge propagation

Objectives: To describe how the neural generators of different sleep components can provoke seizure discharge propagation during NREM sleep and can suppress it during REM sleep. Methods: Experimental manipulations of discrete physiological components were conducted in feline epilepsy models ( n=64), mostly in the systemic penicillin epilepsy model of primary generalized epilepsy and the amygdala kindling model of the localization-related seizure disorder, temporal lobe epilepsy. Procedures included seizure induction as well as quantifying norepinephrine concentrations (microdialysis) and the sleep-waking state distribution of seizures before and after lesions, systemic and localized drug administration and/or photic stimulation. Results: (1) Neural generators of synchronous EEG oscillations, including tonic background slow waves and phasic ‘arousal’ events (sleep EEG transients such as sleep spindles, k-complexes), can combine to promote electrographic seizure propagation during NREM and drowsiness; anti-gravity muscle tone permits seizure-related movement. (2) Neural generators of asynchronous neuronal discharge patterns can reduce electrographic seizures during alert waking and REM sleep; skeletal motor paralysis blocks seizure-related movement during REM. (3) Etiology of the seizure disorder can interact with sleep and arousal mechanisms to determine sleep-waking state distribution of interictal and ictal events. Conclusions: Differential effects of NREM versus REM sleep components on seizure discharge propagation are to some extent non-specific and in other ways specific to seizure etiology.

Epileptic seizure of El mouse initiates at the parietal cortex: depth EEG observation in freely moving condition using buffer amplifier

The initiation site of seizure discharges and the relationship between behavioral manifestations and electroencephalography were investigated in the El mouse, a hereditary epilepsy model. The chronic depth electrodes were implanted stereotaxically into the frontal cortex, parietal cortex, temporal cortex, hippocampus, striatum, amygdaloid complex, non-specific nuclei of thalamus and substantia nigra. Electrical activities were recorded in freely moving condition with use of the buffer amplifier devised in the laboratory and behaviors were monitored simultaneously. Seizure spike discharges started in the parietal cortex and spread out into other brain areas. When the hippocampus was involved, the tonic convulsion occurred behaviorally. The paper describes the first direct evidence of the initiation and propagation of seizure discharges in the brain of El mouse.

Analysis of Foramen Ovale Electrode‐Recorded Seizures and Correlation with Outcome Following Amygdalohippocampectomy

We report a detailed electroclinical analysis of 320 seizures recorded by foramen ovale electrodes in 77 potential candidates for selective temporal lobe surgery because of antiepileptic drug-resistant seizures. The exact localization of the origin of seizure discharges, the electroencephalographic (EEG) seizure onset patterns, transhemispheric propagation, propagation time, duration of discharge, laterality of discharge termination, postictal focal slowing, correspondence between foramen ovale recordings and the scalp EEG, and the influence of antiepileptic drug modifications were studied and correlated with the clinical seizure semiology and with postoperative outcome following selective amygdalohippocampectomy. In general, the foramen ovale electrode technique provided good neurophysiological information in candidates for selective amygdalohippocampectomy. The following ictal signs predicted a good surgical outcome: (a) unilateral and anterior mediobasal temporal lobe seizure onset, (b) short seizure duration, (c) no or infrequent contralateral seizure discharge propagation, and (d) if propagation to the contralateral mediobasal temporal lobe occurred, the postoperative outcome was better the later the contralateral mediobasal temporal lobe was affected. Postoperative outcome was also better the less frequently contralateral interictal spikes occurred. No direct predictive value could be attributed to the presence of an initial arrest reaction.

An Analytical Study by the Selective Averaging Method of Seizure Discharge Propagation in Human Subcortical Structures

An Analytical Study by the Selective Averaging Method of Seizure Discharge Propagation in Human Subcortical Structures

Effects of carbon dioxide in the rhinencephalon in the marsupial phalanger.

The effects of CO2 on the propagation of seizure discharges in the hippocampus in the marsupial phalanger have been examined. In addition, the effects produced by CO2 in the fornix-hippocampal system have been compared with simultaneous changes in conduction occurring in a thalamocortical system. Ten per cent and thirty per cent concentrations of CO2 raise the threshold for seizure discharges in the hippocampus, and have a greater effect on the fornix-hippocampal system than the thalamocortical system.