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Epileptic Disorders

Volume 8
Number 2,
June 2006

Special article

Basic developmental rules and their implications for epilepsy in the immature brain

Yehezkel Ben-Ari

been described that are instrumental, in the sense that a failure of any one of them leads to dramatic, life-long consequences. Hence the importance of determining the sequential maturation of neurons, synapses and cortical maps. It is also important to determine how network-driven events become installed, as neuronal activity intervenes in all of these steps and modulates, for better or worse, the outcome. A fundamental consequence of these sequential events is that any disruption will have very different consequences depending on when it occurs, indeed, “when is as important as what”. An obvious aspect of these general features is related to seizures. In fact, the developing brain has both a higher incidence of seizures in human and animal models, and experiences seizures that can produce long-lasting consequences that are also stage-dependent.This seminar and the series of slides presented are an introduction to these issues, summing up several studies made notably by INMED researchers during the last two decades (http://www.inmednet.com). It concentrates on four basic developmental rules: i) the generation by very immature neurons, of very large currents mediated by the activation of receptors in neurons that bear no synapses. This is due to the release of GABA that diffuses to distal sites and acts as a paracrine factor; ii) the excitatory/inhibitory shift of the actions of GABA during development because of a progressive reduction in the intracellular chloride concentration; iii) the sequential formation of GABAergic synapses and networks before glutamatergic ones, implying that, at an early stage, all the excitatory drive will be GABAergic; iv) the presence, at an early stage, of a unique, primitive pattern in all developing structures, this pattern disappears when most GABAergic synapses have shifted to their adult configuration.Several consequences of these sequences are described including: i) a control of neuronal migration by GABA-acting drugs, and the possibility that migration disorders are also generated by environmental factors that include the effects of GABA-acting agents; ii) If GABA excites immature neurons and inhibits adult one, then GABA-acting agents will also produce different effects on the mother and the embryo; iii) early brain oscillations are generated by the periphery and propagate centrally – notably to the sensory-motor cortex, suggesting that peripherally-generated movements may provide an important signal for the formation of cortical maps, in keeping with the importance of embryonic movements; iv) “seizures beget seizures” in the developing brain. This has now been shown in a triple chamber with the two intact hippocampi that we developed, and with which it has been possible to show that only recurrent seizures that include high frequency oscillations can transform the naïve, contralateral hippocampus to an epileptic one that seizes spontaneously. Most interestingly, at an early developmental stage, when GABA excites many neurons and the density of glutamatergic synapses is not sufficiently high, purely glutamatergic seizures cannot lead to long-term consequences, the additional excitatory drive provided by GABAergic synapses is needed. In other words, at that stage, blocking GABA synapses generates seizures, as in adults, but these do not lead to long-term consequences. The mechanisms that underlie these differences is due to the need for high frequency oscillations (> 80 Hz or so), and these can only be generated when GABA synapses are operative in the developing brain: GABA receptor antagonists are ictogenic, but not epileptogenic.To facilitate teaching purposes the paper is published together with supplemental data (as a PowerPoint presentation included in the accompanying DVD), thus allowing an overview of important developmental steps and their implications.[Published with supplemental data on CD]

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Original article

Implacable images: why epileptiform events continue to be featured in film and television

Toba Schwaber Kerson, Lawrence A Kerson

present, it is unlikely that individuals who do not have a close relationship with someone with a seizure-disorder will witness a seizure. Because fictive and often incorrect images appear increasingly, many think of them as accurate depictions. The research addresses three questions in relation to these images: How do directors use the images? Why do uses of seizures in visual media not reflect contemporary scientific knowledge? Why have they persisted and increased in use? Data consist of material from 192 films and television episodes. The general category of seizures includes seizures in characters said to have epilepsy or some other condition, seizures related to drug or alcohol use, pseudoseizures and feigned seizures, and, a category in which, for example, someone is described as “having a fit.” The research demonstrates how epileptiform events drive the narrative, support the genre, evoke specific emotional reactions, accentuate traits of characters with seizures, highlight qualities of other characters through their responses to the seizures, act as catalysts for actions, and enhance the voyeuristic experience of the audience. Twenty video sequences are included in the manuscript. The authors conclude that the visual experience of seizures remains so enthralling that its use is most likely to increase particularly on television, and that as the public has less experience with real seizures, depictions in film will continue to be more concerned with what the image can do for the show and less interested in accurate portrayals. Ways to influence depictions are suggested. [Published with video sequences]

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Lingual epilepsia partialis continua in Rasmussen’s encephalitis

Dinesh Nayak, Mathew Abraham, Chandrasekharan Kesavadas, Kurupath Radhakrishnan

and electroencephalographic features were consistent with Rasmussen’s encephalitis, although, despite having had the disease for over 15 years, he did not exhibit any hemiparesis. The accompanying video illustrates the lingual EPC and its total resolution following a right frontal opercular focal cortical resection.[Published with video sequences].

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Measurement of seizure freedom in adjunctive therapy studies in refractory partial epilepsy: the levetiracetam experience

Ilo Leppik, Katrien De Rue, Pascal Edrich, Emilio Perucca

drugs (AEDs) in partial epilepsy, and two methodologies for long-term follow-up studies. Methods. Data from levetiracetam trials were used to illustrate the impact of different methodologies on seizure freedom rates. Seizure-freedom data for several new AEDs were identified from the published medical literature using MEDLINE and from a recent comprehensive textbook. Results. Most randomized, placebo-controlled add-on clinical trials of new AEDs contain little or no information about seizure freedom. Importantly, the methodology used can profoundly affect results when calculating seizure-free rates. Seizure freedom data should be reported as well as the methodology used. The minimum duration for assessing seizure freedom should be the entire stable dose period in short-term trials and at least six months for long-term follow-up studies. It is proposed that the seizure freedom rates be calculated and reported with at least two different methodologies, one that considers patients withdrawing from treatment without having had a seizure as successes, and one that considers the same patients as failures. For an effective and well-tolerated AED, seizure freedom rates will be consistent across the two methodologies. Conclusions. Seizure freedom is the ultimate goal of AED therapy and should be reported for all clinical trials. Methodological differences among the few clinical studies reporting seizure freedom rates make it difficult to compare results across trials. Improved reporting of methodologies and seizure-free rates is warranted.

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The origin of the focal spike in musicogenic epilepsy

Nobuyoshi Shibata, Fumio Kubota, Senichiro Kikuchi

Japanese man. He first experienced seizures at the age of 32 years; listening to his favorite piece of music frequently triggered them. His seizure type is partial (often complex, but sometimes simple). An interictal EEG examination revealed many focal spikes in F8 and T4. We estimated equivalent current dipoles (ECDs) using DTM. We performed one-dipole analyses on the peaks of the spikes using an EEG analyzer with a three-layer head model called the scalp-skull-brain (SSB) model. We analyzed the interictal EEG because there were no spikes during the seizure. The ECDs were located in the posterior transverse temporal gyrus. The characteristics in this patient not only bolstered arguments in favor of the role of the right temporal lobe in musicogenic epilepsy, but also showed that transverse temporal gyri, which are included in the auditory area, could play an important role in musicogenic epilepsy. [Published with video sequences].

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The effect of valproate on silent period and corticomotor excitability

Dimitrios A Kazis, Vasilios K Kimiskidis, Sotirios Papagiannopoulos, Kyriaki Sotirakoglou, Daniel Divanoglou, Nikolaos Vlaikidis, Kerry R Mills, Aristeidis Kazis

were studied at baseline, and re-examined 4 (S1) and 25 (S2) weeks after the administration of valproate (mean dose: 1040 ± 284 mg). Transcranial magnetic stimulation was performed with a figure of eight coil (recording, first dorsal interosseous). Threshold was measured at 1% steps. Silent period was measured using a recently described protocol. Briefly, silent periods were elicited at 5% increments from 0 to 100% maximum stimulus intensity. At each stimulus intensity, 4 silent periods were obtained and the average value of silent period duration was used to construct a stimulus/response curve of stimulus intensity versus silent period. The resulting curves were then fitted to a Boltzman function and were statistically compared. The motor-evoked potential recruitment curve was constructed under active conditions and analyzed in a similar way. Results. Valproate increased threshold from 36.5 ± 5.99% at baseline to 41.02 ± 7.84% at S1 (p &lt; 0.0001, paired t-test). The maximum value of the silent period curve decreased from 257.5 ± 3.9 ms at baseline to 230.3 ± 3.9 ms at S1 (p &lt; 0.0001, F-test and AIC) while the other best-fit values (V <sub>50</sub>, slope, threshold) were not significantly affected. Regarding the motor-evoked potential recruitment curve, the maximum value decreased significantly post-drug (from 0.449 ± 0.007 to 0.392 ± 0.009, p &lt; 0.01, F-test and AIC test), whereas the rest of the best-fit values remained unaffected. Conclusion. In patients with idiopathic generalized epilepsy, valproate increases threshold and reduces the maximum values of the silent period curve and the motor-evoked potential recruitment curve. These findings probably reflect valproate’s effects on voltage-dependent Na <sup>+</sup> channels, as well as an activation of GABA <sub>A</sub> receptors.

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Stimulus-sensitive burst-spiking in burst-suppression in children: implications for management of refractory status epilepticus

Bernard Dan, Stewart G Boyd

of convulsive status epilepticus in children (stimulus-sensitive burst-spiking in burst-suppression). We reviewed retrospectively clinical and EEG features in six children (three months to ten years), with status epilepticus requiring intensive care, in whom tactile, auditory and visual stimulation induced myoclonic jerks and bursts of EEG spikes. Sensitivity was not present at onset, but appeared after 24 hours as myoclonic jerks of the eyes, face and limbs, irrespective of the modality and site of stimulation. These were associated with burst-suppression in the EEG, the induced spiking forming the burst component. Various antiepileptic drugs, including GABAergic and NMDA blockers had no effect, but halogenated agents (used in two patients) abolished the sensitivity. Two children died, but the remainder returned to their previous clinical state. We conclude that stimulus sensitivity may appear in the context of refractory status epilepticus treated with high-dose barbiturates. Outcome may be more favorable than previously reported in adults, mostly in the context of post-anoxic or toxic coma. Evaluation of ventilated children in status epilepticus should include electroclinical assessment using sensory stimulation. If present, the drug regime should be reviewed and halogenated agents considered.

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Ketogenic diet in patients with myoclonic-astatic epilepsy

Roberto Horacio Caraballo, Ricardo Oscar Cersósimo, Diego Sakr, Araceli Cresta, Nidia Escobal, Natalio Fejerman

is one of the malignant epilepsy syndromes that often proves refractory to antiepileptic drugs treatment. Objective. In this prospective study we assess the efficacy and tolerability of the ketogenic diet in patients with myoclonic-astatic epilepsy. Material and methods. Between March 1, 1990 and August 31, 2004, 30 patients who met diagnostic criteria of myoclonic-astatic epilepsy were seen at our department. Eleven of them were placed on the ketogenic diet using the Hopkins protocol and were followed for a minimum of 18 months. Results. The children had previously received a mean of 5.2 different antiepileptic drugs and were on a mean of 2.2 antiepileptic drugs when the diet was started. Eighteen months after initiating the diet, six of the patients (54.5%) remained on the diet. Two patients (18%) were seizure-free, two (18%) had a 75-99% decrease in seizures, and the remaining two children (18%) had a 50% to 74% decrease in seizures. The first two patients were tapered off the diet after remaining seizure-free, without antiepileptic drugs for several years. In the two patients who had sporadic seizures, antiepileptic drugs were reduced to one, and in the last two the seizure frequency was significantly reduced. No differences in seizure control were found when compared for age, sex, or seizure type. Five of our patients discontinued the ketogenic diet in less than 3 months (four because of lack of effectiveness and one because of persistent vomiting). Conclusion. The ketogenic diet is a promising therapy for patients with myoclonic-astatic epilepsy, with over half the children showing a > 50% reduction in seizures, and seizure-freedom in 18%. In drug resistant cases of myoclonic-astatic epilepsy, the diet should be considered early in the course of this syndrome and not as a last resort.

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Non-epileptic clinical diagnoses in children referred for an outpatient EEG using video monitoring

Okwuchi Apakama, Richard Appleton

of epilepsy syndromes. An additional benefit from the observation of the child on CCTV is the possible identification of specific clinical, including genetic, conditions. This three-year prospective study of 2780 consecutive children undergoing routine EEG investigations identified 17 conditions that had not previously been diagnosed by the clinicians who had requested the EEG.

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