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PubMed1991

Facilitation of spike-wave activity by the hypnotic etomidate in a rat model for absence epilepsy.

The epileptogenic effect of the short-acting hypnotic agent etomidate was investigated in WAG/Rij rats. Animals of this inbred strain show spontaneous spike-wave discharges and are regarded as a model for absence epilepsy. A dose-dependent increase in the total amount of spike-wave activity was found, when etomidate was injected intraperitoneally in doses of 1, 2.5, 5 and 10 mg/kg. At a dose of 10 mg/kg, spike-wave activity appeared almost uninterruptedly. Beginning with a dose of 5 mg/kg, the morphology of the spike-wave complexes changed after the administration of the drug; spike frequency decreased dose dependently from about 8 till about 4 Hz at 10 mg/kg. During spike-wave activity, animals were motionless and, certainly at 10 mg/kg of etomidate, were unresponsive to stimuli. For surgical anesthesia, a still higher dose of etomidate is necessary (20 mg/kg). It is concluded that etomidate facilitates the generation of spike-wave activity in rats with spontaneous absence seizures, presumably through its GABA-mimetic action.

Action Potentials↗
PubMedDate not supplied

Reflex absence epilepsy.

Epilepsy can be triggered by many unusual mechanisms. Some are exceedingly rare and bizarre, seemingly confined to one patient. This article reports the case of a 20-year-old woman who has had absence epilepsy for 11 years that is evoked by thinking or talking about driving an automobile. This stimulus consistently precipitated absence seizures, as defined by clinical and electroencephalographic criteria. An emotionally traumatic early childhood event may play a role in the triggering mechanism. A similar case has not been reported.

Adult↗
PubMed2005

Impaired regulation of thalamic pacemaker channels through an imbalance of subunit expression in absence epilepsy.

The role of hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channel isoforms and hyperpolarization-activated cation current (Ih) for seizure-related burst firing in thalamocortical (TC) neurons was investigated in a rat genetic model of absence epilepsy [Wistar Albino Glaxo rats, bred in Rijswijk (WAG/Rij)]. Burst discharges in TC neurons locked to seizure activity in vivo were prolonged during blockade of Ih by Cs+ and ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride). In vitro analyses revealed a hyperpolarizing shift of half-maximal Ih activation (Vh) in WAG/Rij (Vh = -93.2 mV) compared with nonepileptic controls [August x Copenhagen-Irish (ACI) (Vh = -88.0 mV)]. This effect is explained by a shift of the responsiveness of Ih to cAMP toward higher concentrations in TC neurons from WAG/Rij, as revealed by application of 8-bromo-cAMP and the phosphodiesterase inhibitor IBMX. During blockade of adenylyl cyclase activity, Ih activation was similar in the two strains, whereas the difference in cAMP responsiveness persisted, thereby voting against different ambient cAMP levels between strains. Increasing the intracellular cAMP level and shifting Ih activation led to a change from burst to tonic firing mode in WAG/Rij but not in ACI rats. Furthermore, HCN1 expression was significantly increased on mRNA and protein levels, with no changes in HCN2-4 expression. In conclusion, there is an increase in HCN1 expression in the epileptic thalamus, associated with a decrease in cAMP responsiveness of Ih in TC neurons and resulting impairment to control the shift from burst to tonic firing, which, in turn, will prolong burst activity after recruitment of Ih during absence seizures.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Inherited cortical HCN1 channel loss amplifies dendritic calcium electrogenesis and burst firing in a rat absence epilepsy model.

While idiopathic generalized epilepsies are thought to evolve from temporal highly synchronized oscillations between thalamic and cortical networks, their cellular basis remains poorly understood. Here we show in a genetic rat model of absence epilepsy (WAG/Rij) that a rapid decline in expression of hyperpolarization-activated cyclic-nucleotide gated (HCN1) channels (I(h)) precedes the onset of seizures, suggesting that the loss of HCN1 channel expression is inherited rather than acquired. Loss of HCN1 occurs primarily in the apical dendrites of layer 5 pyramidal neurons in the cortex, leading to a spatially uniform 2-fold reduction in dendritic HCN current throughout the entire somato-dendritic axis. Dual whole-cell recordings from the soma and apical dendrites demonstrate that loss of HCN1 increases somato-dendritic coupling and significantly reduces the frequency threshold for generation of dendritic Ca2+ spikes by backpropagating action potentials. As a result of increased dendritic Ca2+ electrogenesis a large population of WAG/Rij layer 5 neurons showed intrinsic high-frequency burst firing. Using morphologically realistic models of layer 5 pyramidal neurons from control Wistar and WAG/Rij animals we show that the experimentally observed loss of dendritic I(h) recruits dendritic Ca2+ channels to amplify action potential-triggered dendritic Ca2+ spikes and increase burst firing. Thus, loss of function of dendritic HCN1 channels in layer 5 pyramidal neurons provides a somato-dendritic mechanism for increasing the synchronization of cortical output, and is therefore likely to play an important role in the generation of absence seizures.

Action Potentials↗
PubMed1996

The selective GABAB antagonist CGP-35348 blocks spike-wave bursts in the cholesterol synthesis rat absence epilepsy model.

Slow IPSPs, which are believed to be involved in generation of the wave of spike-wave epileptiform discharges, are mediated by the GABAB receptor. We therefore examined the effect of the GABAB antagonist, Ciba Geigy Product, CGP-35348, in the cholesterol synthesis inhibitor model of absence epilepsy in rat. Rats received Ayerst-9944 (AY-9944), from 6-45 mg i.p. in the first few weeks of life. By 2 months after AY-9944 administration these rats exhibited recurrent spike-waves and behavioral arrests. In 10 such animals CGP-35348 was administered intraperitoneally in doses of 0 (vehicle), 10, 25 or 100 mg/kg. EEG recordings were obtained via previously implanted bone screws. Technologists blinded to treatment group counted spike-waves over a 4 h period post-injection. The average number of spike-wave burst seconds per 4 h of recording for all dosages and times was 52.4 +/- 81.4 (mean +/- S.D.) s. Mean burst times (seconds) were vehicle = 93.5 +/- 106.5; 10 mg/kg = 69.9 +/- 79.7; 25 mg/kg = 30.8 +/- 46.9; 100 mg/kg = 15.2 +/- 54, a mean 84% reduction at 100 mg/kg (ANOVA regression significant at 0.0001). Spike-waves were suppressed for at least 4 h after injection of CGP-35348. These findings supplement similar findings in other absence models, and support a potential role for GABAB antagonists in treatment of absence seizures.

Animals↗
PubMed2006

Genetic studies on the role of T-type Ca2+ channels in sleep and absence epilepsy.

Thalamocortical neurons in mammals fire action potentials in two different modes, burst or tonic, depending on the cellular state. The burst firing is driven by the low threshold Ca2+ spike that is generated by Ca2+ influx through T-type Ca2+ channels, and has long been implicated in the pathogenesis of absence epilepsy and the regulation of sleep rhythms. The recent availability of the knock-out mice for the alpha1G locus, encoding the predominant form of T-type channels in thalamocortical neurons, has provided an opportunity to examine those ideas at the level of organism. In this review we will describe recent results demonstrating the essential role of thalamic bursts in certain forms of absence seizures and in some of the sleep rhythms. Available information so far reveals the sensory gating role of thalamic bursts, and thus of alpha1G T-type channels. Understanding of the molecular targets involved in pathophysiological mechanisms will help develop drugs to control those pathological states.

Animals↗
PubMed2003

Single-unit analysis of substantia nigra pars reticulata neurons in freely behaving rats with genetic absence epilepsy.

PURPOSE: The substantia nigra pars reticulata (SNpr) is assumed to be involved in the control of several kinds of epileptic seizures, an assumption based mostly on neuropharmacologic evidence. However, only very few neurophysiological recordings from the basal ganglia support neuropharmacologic data. We investigated the electrophysiologic activity of SNpr neurons in rats with genetic absence epilepsy. METHODS: Electrocorticography (ECoG) and multi-unit recordings using permanently implanted tetrodes were obtained in freely behaving rats. After spike sorting, auto- and cross-correlation analysis was used to detect oscillatory neuronal activities and synchronizations. RESULTS: During interictal periods, neither oscillation nor synchronization could be observed in the firing patterns of SNpr neurons. At the beginning of the absence seizure, the firing rate increased significantly. The SNpr neurons started firing in bursts of action potentials. Bursts were highly correlated to the spike-and-wave discharges (SWDs) in the ECoG, mainly after the spike component of the cortical spike-and-wave complex. Moreover, pairs of SNpr neurons tended to fire synchronously. Before the end of the seizure, the firing rate decreased progressively, and the burst-firing pattern ended at or before the end of the SWDs. Once the SWDs had stopped, the SNpr neurons resumed their basal firing pattern as before the seizure onset. CONCLUSIONS: These results provide electrophysiologic evidence that firing patterns and synchronization of SNpr neurons are in phase with the occurrence of SWDs. The findings support the concept that nigral control mechanisms are involved in modulating the propagation of an ongoing generalized seizure.

Animals↗
PubMed2003

A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy.

Generalized epilepsy with febrile seizures plus (GEFS+) is a clinically and genetically heterogeneous syndrome with childhood onset, characterized by febrile seizures (FS) and a variety of afebrile epileptic seizure types. The authors performed a mutational analysis of SCN1B on 74 unrelated probands with GEFS+, FS, or FS plus (FS+). In a family with FS+ and early-onset absence epilepsy, a mutation was identified that predicts a deletion of five amino acids in the extracellular immunoglobulin-like domain of SCN1B and potential loss of function. SCN1B mutations are associated with GEFS+ and may have a role in the elicitation of absence seizures.

Age of Onset↗
PubMed1998

Childhood absence epilepsy with tonic-clonic seizures and electroencephalogram 3-4-Hz spike and multispike-slow wave complexes: linkage to chromosome 8q24.

Childhood absence epilepsy (CAE), a common form of idiopathic generalized epilepsy, accounts for 5%-15% of childhood epilepsies. To map the chromosomal locus of persisting CAE, we studied the clinical and electroencephalographic traits of 78 members of a five-generation family from Bombay, India. The model-free affected-pedigree member method was used during initial screening with chromosome 6p, 8q, and 1p microsatellites, and only individuals with absence seizures and/or electroencephalogram 3-4-Hz spike- and multispike-slow wave complexes were considered to be affected. Significant P values of .00000-.02 for several markers on 8q were obtained. Two-point linkage analysis, assuming autosomal dominant inheritance with 50% penetrance, yielded a maximum LOD score (Zmax) of 3.6 for D8S502. No other locus in the genome achieved a significant Zmax. For five smaller multiplex families, summed Zmax was 2.4 for D8S537 and 1.7 for D8S1761. Haplotypes composed of the same 8q24 microsatellites segregated with affected members of the large family from India and with all five smaller families. Recombinations positioned the CAE gene in a 3.2-cM interval.

California↗
PubMed1992

Human absence epilepsies.

A historical review of the concept of absence seizures. Their clinical features are very suggestive but a diagnosis made solely on clinical grounds is not always safe. Comparable pitfalls exist in the interpretation of EEG patterns. Absence seizures belong to several epileptic syndromes. They are briefly described.

Electroencephalography↗
PubMed1989

[Long-term follow-up of absence epilepsy].

This study dealt with 58 patients with absence, of whom 46 patients had started with absence and 12 with generalized tonic-clonic seizures (GTCs). Only those patients followed up for more than five years were included, and 30 patients (51.7%) were over eighteen years of age (up to 33). All patients received the present standard medication with ethosuximide and valproate in this study. In each case the diagnosis was confirmed by clinical observation and the typical EEG pattern. A seizure-free interval of at least 1 year was defined as seizure cessation for absence, and a seizure-free interval of at least 2 years for GTCs. Thirty-eight out of 43 patients (88.4%) with absence at onset (group A) and 18 out of 22 (81.8%) older than 18 years became seizure free. Only 8 of 15 (53.3%) patients with initial GTCs (group B) and 5 of 8 (62.5%) over 18 years became seizure free. In all, about 80% of the patients with absence seizures became seizure free as did those who were followed beyond 18 years of age. Out of 15 patients with initial GTCs, 8 of 10 (80%) patients who developed absence seizures later (group B-1) became seizure free, whereas none of 5 patients who had absence and GTC at the same time (group B-2) did. The social status was mainly favorable, even if seizures were uncontrolled. Adequate predictable factors for the development of GTCs were lacking, but the clinical courses in patients of group B-1 resembled those of group A and were rather benign.

Adolescent↗
PubMed1987

Mechanisms of anticonvulsant drug action. II. Drugs primarily used for absence epilepsy.

The usefulness of the anticonvulsant drugs is determined by the mechanisms by which the agent acts and its pharmacokinetics. The general mechanisms of action of these agents include (1) effects on neurotransmitter action, (2) effects on repetitive neuronal firing mechanisms, (3) effects on neuronal networks, and (4) effects on neuronal ionic transport. Ethosuximide, valproic acid and clonazepam are used primarily in absence epilepsy. Valproic acid is also effective against generalized tonic-clonic epilepsy. Diazepam is used primarily in status epilepticus. Valproic acid enhances gamma aminobutyric acid (GABA)-mediated inhibition, reduces repetitive firing, and reduces both inhibition and excitation in neuronal networks. Clonazepam and diazepam enhance the inhibitory action of GABA, decrease inhibition in neuronal networks and affect calcium ion transport with lesser effects on repetitive firing. Ethosuximide reduces inhibition in neuronal networks, may interact with dopamine, and possibly affects sodium and potassium ion transport. Further work is needed to assess the degree of involvement of these effects in the anticonvulsant action versus the adverse effects of these agents.

Anticonvulsants↗
PubMed1999

Non-linear analysis of epileptic seizures. I. Correlation-dimension measurements for absence epilepsy and near-periodic signals.

The study of six absence seizures from two patients confirmed the efficacy, in the search for low correlation dimensions, of using scaled-structure analysis, combined with the appropriate checking procedures. The analysis is directed towards characterizing an attractor not only by its correlation dimension, but also by its "quality" and by the probability for genuine identification. For near-periodic dynamics, we warn against: (1) artefacts that appear at high values of the correlation integral, in the form of apparent Grassberger-Procaccia scaling at very low values of the dimension (near-periodicity artefact); (2) erroneous interpretation of phase-randomization data, owing to destruction of the artefact by randomization rather than any evidence for low-dimensional dynamics. In single-channel analyses of two patients and six seizures altogether, high-quality attractors were found only for one seizure in two channels, at correlation dimensions 4.7 and 6, respectively. Furthermore, no attractor of measurable dimension was found from multichannel space reconstructions over durations approaching those of typical seizures. Both these results show that in an absence seizure, spatial extension of low-dimensional dynamics must be lost over such durations.

Action Potentials↗
PubMed1999

[Absence status epilepsy].

Absence status (AS), or "Petit Mal status" is a polymorphic condition that can complicate many epileptic syndromes. Diagnosis is difficult on the basis of clinical semiology alone, and requires emergency EEG. Although heterogeneous, the most typical ictal pattern is constituted by slow generalized rhythmic spike-waves (SW) or polyspike-waves (PSW) complexes. In a number of cases, clinical and EEG normalization is obtained after intravenous (i.v.) benzodiazepine (BZ) injection. In some difficult cases, neuropsychological investigations before and after BZ injection is useful: a significant improvement of the neuropsychological score should occur following BZ injection. On a nosographic point of view, literature data indicate that 4 types of AS may be recognized. Typical AS occurs as part of an idiopathic generalised epilepsy most often characterized by absences. Isolated impairment of consciousness, at times with subtle jerks of the eyelids, is the essential symptomatology. The EEG correlates with repetitive absence seizures and shows symmetric and bilateral synchronous SW or PSW complexes faster than 3 Hz. The immediate prognosis is excellent. Atypical AS occurs in patients with symptomatic or cryptogenic generalized epilepsies and is characterized by a fluctuating confusional state with more prominent tonic and/or myoclonic and/or lateralized ictal manifestations than occur in typical AS. The EEG shows continuous or intermittent diffuse irregular slow SW or PSW complexes. The immediate prognosis is guarded, as these episodes tend to recur and to be resistant to medication. "De novo" absence status of late onset is characterized by toxic or metabolic precipitating factors in middle-aged or elderly subjects with no previous history of epilepsy. Patients often have a history of psychiatric illness with multiple psychotropic drug intake. The electroclinical characteristics and the immediate prognosis are variable. These episodes of AS generally represent acute symptomatic seizures and may not recur if the triggering factors can be controlled or corrected. Long-term antiepileptic drugs may thus not be needed. Absence status with focal characteristics occur in subjects with a pre-existing or newly developing partial epilepsy, most often of extra-temporal origin. The EEG shows bilateral but often asymmetric ictal discharges. The immediate prognosis is variable. Some of these cases are difficult to distinguish from complex partial status epilepticus of frontal lobe origin.

Acute Disease↗
PubMed1996

Absence epilepsy in tottering mutant mice is associated with calcium channel defects.

Mutations at the mouse tottering (tg) locus cause a delayed-onset, recessive neurological disorder resulting in ataxia, motor seizures, and behavioral absence seizures resembling petit mal epilepsy in humans. A more severe allele, leaner (tg(la)), also shows a slow, selective degeneration of cerebellar neurons. By positional cloning, we have identified an alpha1A voltage-sensitive calcium channel gene that is mutated in tg and tg(la) mice. The alpha1A gene is widely expressed in the central nervous system with prominent, uniform expression in the cerebellum. alpha1A expression does not mirror the localized pattern of cerebellar degeneration observed in tg(la) mice, providing evidence for regional differences in biological function of alpha1A channels. These studies define the first mutations in a mammalian central nervous system-specific voltage-sensitive calcium channel and identify the first gene involved in absence epilepsy.

Amino Acid Sequence↗
PubMed2000

Ictal and interictal SPECT findings in childhood absence epilepsy.

The purpose of this study was to investigate the informative value of single photon emission tomography (SPECT) in relation to the pathophysiological functioning of the brain during absence seizures and the origin of ictal discharges in idiopathic generalized epilepsies (IGEs). Six patients with childhood absence epilepsy (CAE) were selected for the study and two consecutive SPECT sessions were performed concomitant with EEG recordings revealing normal results and during hyperventilation (HV) studies where the ictal discharges were induced either alone or accompanied by clinical absence seizures. All six patients had ictal discharges in their EEGs during HV and two of them also had clinical absences. SPECT findings during HV revealed an overall increase in the cerebral blood flow (CBF) with significantly higher values as compared to the baseline data. There was no indication for any focal origin in either the interictal or the ictal SPECT findings. Results of the study were supportive for the concept of subcortical origin for the absence seizures and they were also promising for the diagnostic value of ictal SPECT in epileptic cases with undetermined origin as to whether they were localization-related or generalized.

Adolescent↗
PubMed1998

JH8, a gene highly homologous to the mouse jerky gene, maps to the region for childhood absence epilepsy on 8q24.

Insertional inactivation of the jerky gene in transgenic mice resulted epileptic seizures, suggesting that the jerky gene was responsible for mouse epilepsy. To isolate a human homologue of the jerky gene, we screened an Expressed Sequence Tag (EST) database using the cDNA sequence of the mouse jerky gene and identified several EST clones which contained homologous sequences to mouse jerky gene. Using a clone which showed highest homology as a probe, we isolated cDNA clones from a human fetal brain cDNA library. Sequence analysis of these clones named JH8 (jerky homologue of Human on chromosome 8) indicated that it encoded a putative protein with 520 amino acid residues. The JH8 gene has 77% identity to the mouse jerky gene at the DNA level, and its protein has 76% identity and 84% similarity to the mouse protein at the amino acid level. Northern blot analysis showed that the JH8 gene is expressed ubiquitously with a major transcript of about 9.5 kb in size. Fluorescence in situ Hybridization (FISH) analysis and radiation hybrid panel mapping revealed that the JH8 gene was located on chromosome band 8q24.3 in a region that was syntenic to mouse chromosome 15, the mapping site of the mouse jerky gene. Childhood Absence Epilepsy (CAE), one type of Idiopathic Generalized Epilepsy (IGE), has been mapped to chromosome 8q24.3 by linkage analysis. These results suggest that JH8 is a strong candidate gene for CAE.

Animals↗
PubMed1982

Prediction of spike-wave bursts in absence epilepsy by EEG power-spectrum signals.

The EEGs of subjects with absence seizures were examined to determine if changes occurred prior to spike-wave bursts that could be used to predict bursts. A number of 20-s epochs of EEG prior to spike-wave bursts (preburst epochs) and during periods remote from bursts (control epochs) were examined in 5 subjects. Power-spectrum analysis was carried out on each epoch and frequency bands from 0 to 50 c/s were combined into 2-c/s bandwidths. Logarithmically transformed power values in each frequency band were entered into a discriminant analysis algorithm for each subject separately. Results were expressed in terms of a test for significant differences between preburst and control epochs (F statistic) and a "success ratio" of discriminant analysis classification, defined as the proportion of correct classifications in both groups, as obtained using a cross-validation procedure. A significant preburst EEG pattern was found in 4 of the 5 subjects, and success ratios ranged from 0.64. to 0.83. Each subject's preburst EEG seemed to be characterized by a unique pattern of changes, and thus no common prodromal signal was found. The EEG changes did not appear to be caused by overt behaviors, such as eye closure or drowsiness. The findings suggest that the preburst EEG pattern represents a functional alteration in brain activity which could arise from the burst-producing mechanism directly.

Adolescent↗