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PubMed1992

The National General Practice Study of Epilepsy. The syndromic classification of the International League Against Epilepsy applied to epilepsy in a general population.

In this prospective, population-based study of 594 cases of newly diagnosed epilepsy, proportions in categories as defined by the International League Against Epilepsy (ILAE) were as follows: (1) localization-related epilepsies: 1.1* idiopathic, 1.2%; 1.2* symptomatic, 16.2%; and 1.3 cryptogenic, 24.6%; (2) generalized epilepsies: 2.1* idiopathic (idiopathic generalized epilepsy) with 3-Hz spike and wave: absence epilepsy, 2.2%; juvenile myoclonic epilepsy, 1.5%; and nonspecific idiopathic generalized epilepsy, 5.6%; 2.3.1* symptomatic generalized epilepsies, 1.5%; 2.3.2* specific syndromes with generalized epilepsy, 0.3%; 3.2 seizures without unequivocal focal or generalized features, 32%; 4.1 situation-related syndromes, isolated seizures, 9.9%; seizures due to acute toxic or metabolic cause,* 4.5%. Only 33.6% were in diagnostic ILAE categories (asterisks) and many rare syndromes were not represented. The remainder (66.4%) were in various nonspecific categories. Only 24% of localization-related epilepsies could be clinically localized to a single ILAE-proposed site of origin and of these best localized cases, 14% had strongly discordant imaging or electroencephalograms. These major problems in applying the ILAE classification to epilepsy in the general population and its underemphasis of modern imaging techniques are discussed.

Cerebral Cortex↗

PubMed1988

Comparison of monotherapy with valproate and other antiepileptic drugs in the treatment of seizure disorders.

Comparative data strongly suggest that valproate is the drug of choice for patients with primary and secondarily generalized epilepsies and that it is as effective as other antiepileptic drugs in the treatment of less clearly defined or partial epilepsies beginning in adult life. In simple absence epilepsy, several studies found no significant difference in efficacy between valproate and ethosuximide. In all primary generalized epilepsies, valproate has in many studies produced an excellent response, with one comparative study showing that valproate was as effective as phenytoin. Infantile spasms responded as well to valproate as to adrenocorticotropic hormone in several studies, while valproate produced fewer side effects. More long-term studies designed to compare the efficacy of monotherapy with valproate with that of other antiepileptic drugs are needed, and several are underway in both Europe and the United States.

Anticonvulsants↗

PubMed1996

Prevalence and characteristics of epilepsy in children in northern Sweden.

Active epilepsy was assessed in all children aged 0-16 years in an area of northern Sweden with about 250,000 inhabitants and around 50,000 children in the age group. One hundred and fifty-five children fulfilled the criteria of active epilepsy giving a prevalence rate of 4.2/1000. The proportion of boys to girls was 1:1.1. This dominance of girls had also been seen in a prospective study of incidence of epilepsy in the same area. Partial seizures were more common than generalized. Among the syndromes benign childhood epilepsy with centrotemporal spikes occurred in 17.4%, absence epilepsy in 6.5% and Lennox-Gastaut syndrome in 5.8%. Children with neurodeficit (ND) more often had generalized epileptic syndromes while the non-ND groups more often had localisation related syndromes. The aetiology was regarded to be remote symptomatic in 42%, idiopathic in 28% and cryptogenic in 30% of the children. Almost all children were on antiepileptic treatment, three quarters of them on monotherapy. Neurodeficit was noted in 42%. The prevalence of epilepsy and mental retardation was 1.7/1000. Relatively few children with neurodeficit had been seizure free during the last year, 43% had more than one seizures per month compared to 19% in the non-ND group.

Adolescent↗

PubMed2004

Cortical control of generalized absence seizures: effect of lidocaine applied to the somatosensory cortex in WAG/Rij rats.

The role of the somatosensory cortex (SmI) in the incidence of spike-wave discharges (SWDs) was studied in a genetic model of absence epilepsy, WAG/Rij rats. SWDs were recently shown to initiate at the perioral area of the SmI and spread over the cortex and thalamus within a few milliseconds [J. Neurosci. 22 (2002) 1480]. It was hypothesized that functional deactivation of the SmI might reduce the appearance of SWDs. This was tested using unilateral microinjections (1 microl) of 2% lidocaine into the SmI in 13 WAG/Rij rats. Electrocorticogram (ECoG) was recorded in free moving animals from four cortical sites after lidocaine and control (saline) injections. Lidocaine effectively diminished the power of the ECoG spectra mostly in the area surrounding the injection site. Deactivation of the perioral region of the SmI reduced the incidence of SWDs at the entire cortex in both hemispheres. The number of SWDs gradually reached control level at the end of the second hour after injections of lidocaine. These data show that proper functioning of SmI is important for the occurrence of SWDs, supporting the idea that absence seizures might have a focal cortical origin.

Animals↗

PubMed2001

Contribution of GABA(A) and GABA(B) receptors to thalamic neuronal activity during spontaneous absence seizures in rats.

The contribution of GABAergic mechanisms in thalamic relay nuclei to spike and wave discharges (SWDs) during spontaneous seizures was assessed using the WAG/Rij strain of rats, an established genetic model of absence epilepsy, in combination with single-unit recordings and microiontophoretic techniques in the ventrobasal thalamic complex in vivo. Spontaneous SWDs occurring on the electroencephalogram at 5-9 Hz were associated with burst firing in thalamocortical neurons, which was phase-locked with the spike component. Microiontophoretic application of the GABA(A) receptor antagonist bicuculline significantly increased the magnitude of SWD-related firing in all tested cells. Application of the GABA(B) receptor antagonist CGP 55845A exerted a statistically insignificant modulatory effect on neuronal activity during spontaneous SWDs but significantly attenuated the bicuculline-evoked aggravation of SWD-related firing. The data indicate that, in thalamocortical neurons, (1) GABA(A) receptor-mediated events are recruited with each SWD, (2) SWD-related activity can be evoked with no significant contribution of GABA(B) receptors, and (3) blockade of GABA(A) receptors potentiates SWD-related activity, presumably through an indirect effect mediated through GABA(B) receptors. These results vote against a predominant or even exclusive contribution of GABA(B) receptors to spontaneous SWDs in thalamic relay nuclei in the WAG/Rij strain, but rather point to a critical role of GABA(A) receptor activation. This conclusion is in support of the view that the two subtypes of GABA receptors play a differential role in fast (5-10 Hz) and slow (3 Hz) spike-wave paroxysms observed during absence seizures.

Action Potentials↗

PubMed1993

Effects of cholinergic drugs on genetic absence seizures in rats.

Wistar rats of a selected strain show spontaneous generalized non-convulsive seizures with bilateral synchronous spike-wave discharges on the cortical electroencephalograph (EEG). The 7 to 9 c/s spike-wave discharges occur predominantly in waking states of inactivity. The effects of cholinergic drugs on the cumulated duration of spike-wave discharges were investigated in this rat model of absence epilepsy. I.p. injections of drugs which potentiate cholinergic neurotransmission, namely the acetylcholinesterase inhibitor, physostigmine (0.1-0.5 mg/kg), the muscarinic receptor agonists, oxotremorine (0.25-1 mg/kg) and pilocarpine (0.125-2 mg/kg), and the nicotinic receptor agonist, nicotine (0.062-2 mg/kg), suppressed discharges in a dose-dependent manner and induced an arousal-like cortical EEG. The muscarinic receptor antagonist, scopolamine, increased the spike-wave discharges at doses below 0.05 mg/kg; at higher doses (0.05-1 mg/kg) it decreased discharges and induced a sleep-like EEG. The nicotinic receptor antagonist, mecamylamine (0.5-6 mg/kg), had no effect on spike-wave discharges or the EEG. These results suggest that cholinergic activity accounts for the preferential occurrence of absence seizures in states of reduced arousal.

Animals↗

PubMed1997

Felbamate and meprobamate: a comparison of their anticonvulsant properties.

The anticonvulsant effect of felbamate and meprobamate were compared in a series of models for seizure activity and regarding their neurotoxic action. In the MES test, felbamate was active below neurotoxic doses. Meprobamate had an ED50 in the range of neurotoxic doses. The s.c. PTZ test was influenced by meprobamate in a fairly low dosage (ED50 66 mg/kg), but for felbamate no clearly dose-related effect could be shown up to 150 mg/kg. Reflex epilepsy in gerbils was stronger suppressed by meprobamate (ED50 34 mg/kg) than by felbamate (ED50 63 mg/kg). In amygdala kindled rats, meprobamate proved to be the most active compound, both regarding treatment of fully kindled rats, development of kindling and independent discharges from a mirror focus (secondary epileptogenesis), which were fully suppressed by oral treatment with 80 mg/kg for 30 days. Both drugs were weakly effective in a model for absence epilepsy in rats. The unexpectedly high activity of meprobamate justifies a second look at the anticonvulsant properties of the drug, especially since it was extensively used as an anxiolytic drug in the past with few obvious serious side effects.

Animals↗

PubMed2006

Exploration of the genetic architecture of idiopathic generalized epilepsies.

PURPOSE: Idiopathic generalized epilepsy (IGE) accounts for approximately 20% of all epilepsies and affects about 0.2% of the general population. The etiology of IGE is genetically determined, but the complex pattern of inheritance suggests an involvement of a large number of susceptibility genes. The objective of the present study was to explore the genetic architecture of common IGE syndromes and to dissect out susceptibility loci predisposing to absence or myoclonic seizures. METHODS: Genome-wide linkage scans were performed in 126 IGE-multiplex families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy. Each family had at least two siblings affected by IGE. To search for seizure type-related susceptibility loci, linkage analyses were carried out in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic-clonic seizures on awakening. RESULTS: Nonparametric linkage scans revealed evidence for complex and heterogeneous genetic architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22-q31, and 19q13. The signal patterns differed in their composition, depending on the predominant seizure type in the families. CONCLUSIONS: Our results are consistent with heterogeneous configurations of susceptibility loci associated with different IGE subtypes. Genetic determinants on 11q13 and 13q22-q31 seem to predispose preferentially to absence seizures, whereas loci on 5q34, 6p12, and 19q13 confer susceptibility to myoclonic and generalized tonic-clonic seizures on awakening.

Chromosome Mapping↗

PubMed2006

NMDA-NR1 and AMPA-GluR4 receptor subunit immunoreactivities in the absence epileptic WAG/Rij rat.

From an age of 2-3 months onwards, the WAG/Rij rat, a genetic model for absence epilepsy, develops spike-wave discharges (SWD). SWD start in the peri-oral somatosensory cortex (POsc), whereas the rostral reticular thalamic nucleus (rRTN) contributes to synchronizing the thalamo-cortical oscillations. We hypothesize that N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptors in the POsc and rRTN are involved in, respectively, the initiation and synchronization of SWD activity. As a first step to test this hypothesis, 3 months old non-epileptic and 6 months old absence epileptic WAG/Rij rats were compared with age-matched non-epileptic ACI control rats. The presence of NMDA and AMPA receptors was assessed by quantifying immunostaining for the NMDA-NR1 subunit and the AMPA-GluR4 subunit, respectively. In the POsc, WAG/Rij rats of both ages showed less NMDA-NR1 (-14.7%) and AMPA-GluR4 (-8.7%) subunit staining than ACI rats. From 3 to 6 months, AMPA-GluR4 subunit staining more strongly increased in the rRTN of WAG/Rij rats than of ACI rats. Further studies should support our assumption that in the POsc of the WAG/Rij rat, SWD start as a result of reduced NMDA- and AMPA-mediated glutamatergic stimulation, and that AMPA-GluR4 containing neurons in the rRTN of this rat strain contribute to synchronization of thalamic and cortical neurons.

Aging↗

PubMed1992

Mapping of cerebral energy metabolism in rats with genetic generalized nonconvulsive epilepsy.

The quantitative 2-[14C]deoxyglucose autoradiographic method was applied to measure local cerebral metabolic rates of glucose (LCMRglc) in a model of genetic petit-mal-like seizures in a strain of Wistar rats. During the experimental period, epileptic rats exhibited synchronous spike-and-wave discharges, whereas the EEG pattern of control animals was normal. Overall, LCMRglc was consistently higher in epileptic rats than in the non-epileptic controls. The increase in LCMRglc was widespread and concerned all cerebral functional systems studied, whether they exhibit spike-and-wave discharges (neocortex and thalamus), or not (limbic system). These results are in good accordance with positron-emission tomography measurements in humans with typical childhood absence epilepsy. There appears to be a lack of anatomical correlation between areas demonstrating hypermetabolism and areas where spike-and-wave discharges are recorded. The administration of 200 mg/kg ethosuximide completely suppressed spike-and-wave discharges in epileptic rats and did not change the EEG pattern in controls. However, LCMRglc were increased to the same extent over control values in epileptic rats whether they were injected with ethosuximide or untreated. By contrast, when epileptic rats were given 2 mg/kg haloperidol, the frequency and the length of spike-and-wave discharges increased, inducing almost a permanent petit-mal status epilepticus. Haloperidol did not change EEG pattern in controls. In haloperidol-treated epileptic rats, LCMRglc decreased to levels comparable to those measured in untreated control rats. In the presence of haloperidol, LCMRglc were similar in both control and epileptic rats. Thus, the diffuse increase in cerebral energy metabolism in epileptic rats as compared to controls is not directly related to the occurrence of spike-and-wave discharges, and may rather be associated with inhibitory mechanisms involved in their termination and suppression, as well as their spread to limbic and motor structures.

Animals↗

PubMed1998

The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit.

Stargazer mice have spike-wave seizures characteristic of absence epilepsy, with accompanying defects in the cerebellum and inner ear. We describe here a novel gene, Cacng2, whose expression is disrupted in two stargazer alleles. It encodes a 36-kD protein (stargazin) with structural similarity to the gamma subunit of skeletal muscle voltage-gated calcium (Ca2+) channels. Stargazin is brain-specific and, like other neuronal Ca2+-channel subunits, is enriched in synaptic plasma membranes. In vitro, stargazin increases steady-state inactivation of alpha1 class A Ca2+ channels. The anticipated effect in stargazer mutants, inappropriate Ca2+ entry, may contribute to their more pronounced seizure phenotype compared with other mouse absence models with Ca2+-channel defects. The discovery that the stargazer gene encodes a gamma subunit completes the identification of the major subunit types for neuronal Ca2+ channels, namely alpha1, alpha2delta, beta and gamma, providing a new opportunity to understand how these channels function in the mammalian brain and how they may be targeted in the treatment of neuroexcitability disorders.

Amino Acid Sequence↗

PubMed1995

Topographic EEG mapping of 3/s spike-and-wave complexes during absence seizures.

Topographic color mapping has recently been introduced for the study of ictal EEG manifestations of absences. We recorded 2-4 3/s spike-and-wave (sw) bursts in 12 patients with absence epilepsy, and performed a spectral analysis of the EEG under baseline conditions and during the 2 sec preceding the 3/s sw bursts. An increase in delta and theta bands was found in preseizure conditions. Moreover, the serial mapping of the sw complexes showed a different field distribution of the various components when the first sw was compared with the subsequent ones. In particular, the negative peak of the spike was mainly frontal during the first complex, with a tangentially oriented dipole, but it became better represented over the midline in the following sw, with a radially oriented dipole. We conclude that EEG changes can be detected before the onset of 3/s sw activity in absences, and that they are probably related to the strong inhibitory mechanisms acting in this type of seizure; moreover a frontal cortical mechanism seems to be prevalently active at the beginning of the seizure, which is soon captured by a cortico-subcortical process as the attack progresses.

Brain↗

PubMedDate not supplied

Melatonin and petit-mal epilepsy: an hypothesis.

Intraventricular administration of the opioid peptide leucine-enkephalin has been reported to induce petit-mal-like seizures in rats. These seizures have been found to be an age-dependent phenomenon. In rats, the full manifestation of these seizures develops after 4 weeks of age during which time ethosuximide was effective in aborting these seizures, while phenytoin and phenobarbital were ineffective. The period associated with the development of enkephalin-induced seizures in rats coincides with an important milestone in pineal chronobiology. In rats, melatonin plasma levels peak at 3 weeks of age, a period which also corresponds with the emergence of melatonin circadian rhythms. It is proposed that melatonin mediates the anticonvulsant action of drugs effective for petit-mal (absence) epilepsy and that the pineal gland is implicated in the pathogenesis of this form of childhood epilepsy.

Animals↗

PubMed2004

The influence of strain and housing on two types of spike-wave discharges in rats.

WAG/Rij rats, a genetic model of absence epilepsy, show two types of spike-wave discharges (Type 1 and Type 2) in their EEG activity. The large interindividual variation in the expression of the phenotypes (number and mean duration of spike-wave discharges) suggests that as well as genetic, environmental factors also play a role. The aim of our study was to establish effects of strain and housing on the incidence and expression of both types of paroxysms. Therefore, WAG/Rij and ACI rats were housed from weaning in either an enriched or impoverished environment for 60 days. At three months of age the EEG of the rats was recorded for four hours to examine the effects of strain and housing on the incidence and expression of the two types of paroxysms. Generally, enriched housing led to worsening of Type 1 and Type 2 spike-wave discharges (SWD). However, the number of affected rats and the expression (number and mean duration) of Type 1 and Type 2 spike-wave discharges were differently influenced by strain and housing. This suggests that Type 1 and Type 2 spike-wave discharges are independent phenomena and that number and mean duration of these paroxysms are controlled by different mechanisms. Finally, the worsening of absence seizures after enrichment is different from what has been found for convulsive seizures.

Animals↗

PubMed2006

Environmental manipulations early in development alter seizure activity, Ih and HCN1 protein expression later in life.

Although absence epilepsy has a genetic origin, evidence from an animal model (Wistar Albino Glaxo/Rijswijk; WAG/Rij) suggests that seizures are sensitive to environmental manipulations. Here, we show that manipulations of the early rearing environment (neonatal handling, maternal deprivation) of WAG/Rij rats leads to a pronounced decrease in seizure activity later in life. Recent observations link seizure activity in WAG/Rij rats to the hyperpolarization-activated cation current (Ih) in the somatosensory cortex, the site of seizure generation. Therefore, we investigated whether the alterations in seizure activity between rats reared differently might be correlated with changes in Ih and its channel subunits hyperpolarization-activated cation channel HCN1, 2 and 4. Whole-cell recordings from layer 5 pyramidal neurons, in situ hybridization and Western blot of the somatosensory cortex revealed an increase in Ih and HCN1 in neonatal handled and maternal deprived, compared to control rats. The increase was specific to HCN1 protein expression and did not involve HCN2/4 protein expression, or mRNA expression of any of the subunits (HCN1, 2, 4). Our findings provide the first evidence that relatively mild changes in the neonatal environment have a long-term impact of absence seizures, Ih and HCN1, and suggest that an increase of Ih and HCN1 is associated with absence seizure reduction. Our findings shed new light on the role of Ih and HCN in brain functioning and development and demonstrate that genetically determined absence seizures are quite sensitive for early interventions.

Animals↗

PubMed2006

Cortical and thalamic coherence during spike-wave seizures in WAG/Rij rats.

The study examines cortico-cortical and cortico-thalamic network synchronization at the onset of spike-wave discharges (SWD) in a genetic model of absence epilepsy, WAG/Rij rats. Coherence was measured between multiple cortical areas (intracortical), reticular and rely thalamic nuclei (intrathalamic) and between the cortex and the thalamus. SWD-related increase of coherence (5-60 Hz) was found in all investigated pairs. The highest increase of coherence was around the mean frequency of SWD (8-11.5 Hz) and in the harmonic band 16-21.5 Hz with two central maxima around 10 and 20 Hz. The frequency profile of coherence was different in different intracortical networks, therefore latter were divided into local, global and transhemispheric networks. The presumable source of SWD in the somatosensory cortex and its closest surroundings formed a minimal (local) circuit, in which occurrence of SWD was facilitated by a consistent shift of network synchrony from delta to alpha/beta frequencies. Transhemispheric coherence revealed the largest increase with an additional 16 Hz peak, suggesting a crucial involvement of the corpus callosum in the pathophysiology of absence seizures. The increase in interhemispheric coherence was largest between relatively remote somatosensory or frontal areas, supporting the assumption that SWD originate from the lateral fronto-parietal cortical area.

Analysis of Variance↗

PubMed1995

Kappa opioid receptor agonists suppress absence seizures in WAG/Rij rats.

Involvement of the kappa opioid receptor in the regulation of epileptic activity was studied in WAG/Rij rats, a genetic model of absence epilepsy. I.c.v. administration of the kappa agonists U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), U69,593 (5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-(1-pyrrolidinyl)-1- oxaspiro(4,5)dec-8-yl)benzeneacetamide) or PD117,302 ((+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzo[b]thiophene-4-acetamide), 50 and 150 micrograms/5 microliter each, dose-dependently decreased the number and mean duration of spike wave discharges (SWD). Peripheral administration of U50,488H (10 and 30 mg/kg s.c.) also attenuated the seizure activity in this model. The specific kappa opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 10 micrograms/5 microliters i.c.v., 18 h before EEG registration) moderately increased the number of SWD, which suggests that endogenous opioids acting through kappa receptors may tonically inhibit the seizure activity in these rats. In addition, the enhancement of an absence-like seizure activity induced by the specific mu opioid receptor agonist D-Ala2-N-methyl-Phe4-Gly5-ol-enkephalin (DAMGO, 0.7 microgram/5 microliters i.c.v.) was also attenuated in rats pretreated with U50,488H, U69,593 or PD117,302. These data indicate that activation of the kappa opioid receptor exerts an inhibitory effect on absence-like seizure activity in WAG/Rij rats.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2006

The mechanism of carbamazepine aggravation of absence seizures.

Carbamazepine (CBZ) aggravates many generalized seizures types, particularly absence seizures, but the mechanisms underlying this are poorly understood. GABA signaling within the reticular nucleus (Rt) and the ventrobasal complex (VB) of the thalamus is critical to the neurophysiology of absence seizures. The hypothesis that CBZ aggravates absence seizures by acting at the VB thalamus via a GABA(A) receptor-mediated mechanism was investigated in a genetic rat model, generalized absence epilepsy rats from Strasbourg (GAERS). Seizure activity was quantified by a 90-min electroencephalogram recording postdrug injection. Intracerebroventricular injections of CBZ (15 microg in 4 microl) resulted in seizure aggravation versus vehicle treatment, with a mean increase in seizure time of 40%. This indicates that CBZ acts directly, rather than via a metabolite, on the brain to aggravate seizures. Seizure aggravation also occurred following bilateral microinjection of CBZ (0.75 microg in 0.2 microl) into the VB (53%) but not following injection into the Rt (-9%). However, seizure aggravation was blocked when the GABA(A) receptor antagonist, bicuculline (BIC, 0.04 microg in 0.2 microl), was coinjected with CBZ into the VB. Injection of BIC alone (versus vehicle) into the VB also blocked seizure aggravation following systemic administration of CBZ (15 mg/kg i.p.). In vitro studies in Xenopus oocytes expressing recombinant GABA(A) receptors demonstrated that CBZ produced a dose-dependent potentiation of the GABA current at a physiological relevant concentration range (1-100 microM). These data demonstrate that CBZ acts at the VB thalamus to aggravate absence seizures in GAERS and that activation of GABA(A) receptors is critical to this effect.

Animals↗