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PubMed1999

Pertussis toxin decreases absence seizures and GABA(B) receptor binding in thalamus of a genetically prone rat (GAERS).

Postsynaptic GABA(B) receptor-mediated events have previously been shown to be reduced by prior treatment with pertussis toxin in rat brain. In the present study genetic absence epilepsy rats from Strasbourg (GAERS) were given single bilateral injections of pertussis toxin (PTx 0.4 microg), denatured-PTx or vehicle saline into the relay nuclei of the thalamus under anaesthesia. After recovery the spike and wave discharge duration (SWD) was monitored for up to 6 days following which the brains were removed and GABA(B) or GABA(A) receptor autoradiography performed on 10 microm transverse sections. By 6 days the SWD of the rats treated with PTx was suppressed by 96% compared with vehicle-injected rats with a significant (62%) reduction even after 1 day. Denatured toxin had no effect at any time. After 6 days GABA(B), but not GABA(A), receptor binding was significantly reduced by 70-80% in the ventrolateral and ventral posteriolateral thalamic nuclei. No changes in other brain regions were detected and denatured toxin failed to alter GABA(A) or GABA(B) receptor binding in any brain region. These data implicate G-protein mechanisms in the generation of SWD in GAERS and support the role of GABA(B) receptors in their induction within the thalamus.

Animals↗
PubMed1999

On the putative contribution of GABA(B) receptors to the electrical events occurring during spontaneous spike and wave discharges.

Cortical and thalamic neurones play a major role in the generation/expression of spike and wave discharges (SWDs), the main electroencephalographic (EEG) feature of absence seizures. The detailed mechanisms leading to this paroxysmal EEG activity, however, are still poorly understood. We have now made in vivo intracellular recordings from layer V cortical neurones of the facial motor cortex and from thalamocortical (TC) neurones of the ventroposteromedial and ventroposterolateral nuclei in a well established model of this disease: the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). The main feature of the intracellularly recorded activity of TC neurones during spontaneous SWDs was the presence of rhythmic sequences of synaptic potentials consisting of an EPSP closely followed by 2-6 IPSPs. These rhythmic sequences were superimposed on a small tonic hyperpolarization that lasted for the whole duration of the SWD and was still present at potentials close to -85 mV. The rhythmic IPSPs, on the other hand, had a reversal potential of -68 mV, and always appeared as depolarizing events when recording with KCl-filled electrodes at -55 mV. Low frequency electrical stimulation of the corresponding cortical area evoked in TC neurones a short and a long lasting IPSP, whose waveforms were reminiscent of a GABA(A) and a GABA(B) IPSP, respectively. The main feature of the intracellular activity recorded in cortical neurones during spontaneous SWDs was the presence of rhythmic depolarizations. Their frequency was similar to the one of SWDs in the EEG, and was not affected by DC injection. The amplitude of the rhythmic depolarizations, however, increased following steady hyperpolarization of the neurone by DC injection. An increase in the apparent input resistance of cortical neurones was observed during SWDs compared to the inter-SWDs periods. Low frequency electrical stimulation of the contralateral striatum evoked in cortical neurones a short and a long lasting IPSP, whose waveforms were reminiscent of a GABA(A) and a GABA(B) IPSP, respectively. Our data indicate that there are no rhythmic GABA(B) IPSPs and low threshold Ca2+ potentials in GAERS TC neurones during SWDs, but rhythmic sequences of EPSP/IPSPs superimposed on a tonic hyperpolarization that might represent a long lasting GABA(B) IPSP. Further experiments are required to clarify the nature of the voltage waveform and the increase in input resistance observed in cortical neurones during spontaneous SWDs in GAERS.

Animals↗
PubMed2006

[Reintroduction of treatment with lamotrigine in combination with valproate after an initial allergic skin reaction].

INTRODUCTION: Lamotrigine (LTG) is effective for a variety of seizure types especially against absence seizures in cotherapy with valproate (VPA). Skin rash is the most frequent side effect leading to LTG discontinuation. OBSERVATIONS: We report two patients with refractory absence epilepsy and a previous history of allergic reaction to LTG in which LTG was rechallenged. LTG was effective in both cases without incident. DISCUSSION: High initial dose and rapid dose escalation is associated with increased rash rate. LTG is contraindicated in patients who have demonstrated hypersensitivity to the drug. However, because the initial dose and the dose titration play a crucial role, LTG was reintroduced with a very low initial dose and very slow titration schedule without recurrence of skin rash. CONCLUSION: Patients who have experienced a previous mild skin allergy may be reconsidered for a rechallenge with LTG if the expected therapeutic response to the drug is high. Patients must be warned about the risks.

Adult↗
PubMed2003

Ictal stimulus processing during spike-wave discharges in genetic epileptic rats.

In the present experiment it was investigated whether and to what extent auditory information processing is possible during the presence of spike-wave discharges in rats. To that end, WAG/Rij rats which are an animal model for absence epilepsy, were provided with cortical electrodes for the registration of the electroencephalogram (EEG). The animals were first trained in an appetitively motivated conditioning paradigm to learn to discriminate between two auditory stimuli with equal duration and frequency but with different intensities. Next, the stimuli were presented in the test phase in pseudorandom order during spike-wave discharges. The reactivity of the ongoing EEG was analysed. It was found that the presentation of the reinforced stimulus induced a larger number of aborted spike-wave discharges than the non-reinforced stimulus, regardless of the intensity of the stimuli. This implies that during generalised spike-wave discharges the brain is still capable of evaluating the meaning of an ictally presented stimulus. It also shows that sensory, attentional and mnemonic processes are at least partially intact during the occurrence of a spike-wave discharge. The results of the present study are largely in agreement with results on human spike-wave activity-related cognitive disturbances. Moreover, they may lead to a refinement of the concept of epileptic consciousness and may emphasise the heuristic value of rodent models for studying both ictal and interictal information processing.

Acoustic Stimulation↗
PubMed2001

Modulation of absence seizures by branched-chain amino acids: correlation with brain amino acid concentrations.

The occurrence of absence seizures might be due to a disturbance of the balance between excitatory and inhibitory neurotransmissions in the thalamo-cortical loop. In this study, we explored the consequences of buffering the glutamate content of brain cells on the occurrence and duration of seizures in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a genetic model of generalized non-convulsive epilepsy. Branched-chain amino acids (BCAAs) and alpha-ketoisocaproate (alpha-KIC), the ketoacid of leucine were repeatedly shown to have a critical role in brain glutamate metabolism. Thus, GAERS were injected by intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) route with these compounds, then the effects on seizures were evaluated on the electroencephalographic recording. We also measured the concentration of amino acids in thalamus and cortex after an i.p. injection of leucine or alpha-KIC. Intracerebroventricular injections of leucine or alpha-KIC did not influence the occurrence of seizures, possibly because the substances reached only the cortex. BCAAs and alpha-KIC, injected intraperitoneally, increased the number of seizures whereas they had only a slight effect on their duration. Leucine and alpha-KIC decreased the concentration of glutamate in thalamus and cortex without affecting GABA concentrations. Thus, BCAAs and alpha-KIC, by decreasing the effects of glutamatergic neurotransmission could facilitate those of GABAergic neurotransmission, which is known to increase the occurrence of seizures in GAERS.

Action Potentials↗
PubMed2002

Decreased gene expression of calretinin and ryanodine receptor type 1 in tottering mice.

Tottering mice are a spontaneously occurring animal model of human absence epilepsy. They carry a mutation in the P/Q-type calcium channel alpha1A subunit gene which is highly expressed by cerebellar Purkinje cells. In this study, we investigated the role of calretinin and ryanodine receptor type 1 (RyR1) gene expression in the cerebellum of tottering mice. Cerebellar tissue specimens from four experimental groups were processed for in situ hybridization histochemistry (ISHH): (1) wild-type (+/+); (2) heterozygous (tg/+) and two homozygous groups; either (3) without occurrence of an episode of paroxysmal dyskinesia (tg/tg-N); or (4) after an episode of paroxysmal dyskinesia (tg/tg-P) that lasted about 45 min on average. Quantitative analysis showed a statistically significant decrease (p = 0.0001, ANOVA) of calretinin gene expression at the level of the simple lobule of the cerebellum in both homozygous groups compared to the wild-type and heterozygous groups. RyR1 was decreased in the flocculus of the cerebellum in both the tg/tg-N and tg/tg-P groups compared to wild type (p = 0.0174, ANOVA). These results suggest that calretinin gene expression, as well as other genes involved in regulation of calcium homeostasis, such as RyR1, may play a role in the biochemical functional alterations present in tottering mice.

Animals↗
PubMed2000

EEG frequency profiles of idiopathic generalised epilepsy syndromes.

UNLABELLED: The objective of this study was to investigate EEG frequency profiles (topographic distribution of spectral power data) in well-defined idiopathic generalised epilepsy (IGE) syndromes: juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), epilepsy with grand mal seizures on awakening (EGMA), and in the unified 'common IGE' (CIGE) group of these patients. METHODS: Absolute and relative (percent) power values were computed from waking EEG activity by Fast Fourier Transform (FFT). Each patient group was compared to an age-matched group of healthy control persons. RESULTS: There was a general tendency for diffuse (absolute and relative) delta-theta-alpha power excess and relative beta power deficit in all IGE groups as compared to controls. Statistically significant (P</=0.05) bilateral absolute power differences were: fronto-parietal delta and diffuse theta (in JAE), frontal delta (in JME) and frontal alpha (in EGMA). Statistically significant (P</=0. 05) relative power differences were: frontal delta, diffuse theta, fronto-centro-parietal beta (in JAE), frontal delta and beta (in JME) and fronto-central alpha (in EGMA). The CIGE group showed power alterations of the same type but differences were statistically more significant than in the other patient groups. CONCLUSION: Absolute power findings were interpreted as enhanced neuronal synchrony in the 0.5-12.0 Hz frequency range together with the tendency of decreasing synchrony in faster (12.5-32.0 Hz) frequencies. Corresponding shifts in relative power were interpreted as reflecting dysfunction of cortical regions. The authors hypothesise that these IGE frequency profiles reflect widespread cortical dysfunction essentially common to all the investigated IGE syndromes.

Adolescent↗
PubMed2001

Alteration of GLUR2 expression in the rat brain following absence seizures induced by gamma-hydroxybutyric acid.

We explored the involvement of the glutamate receptor subunit B (GluR2) in the mechanism of absence seizures induced by gamma-hydroxybutyric acid (GHB). The expression and distribution of GluR2 protein in rat brain were examined during and after GHB-induced absence seizures. The data indicate that GluR2 protein expression significantly decreases following the onset of absence seizures. The suppression of GluR2 expression was prolonged and it outlasted the duration of the continuous absence seizure activity. The alteration of GluR2 protein levels was accompanied by a re-distribution of GluR2 expression from laminae V to IV in cerebral cortex. We also analyzed the duration and latency of absence seizures induced by GHB 72 h following an initial GHB-induced absence seizure, a time when suppression of GluR2 protein was maximal. The second absence seizure was significantly more prolonged than the first. These data may indicate that the putative down-regulation of GluR2 following GHB-induced absence seizure could have contributed to the potentiation of subsequent seizures in animals. A related hypothesis posed by the data is that down-regulation of GluR2 is involved in the mechanisms of the maintenance of recurrent absence seizure activity once it is initiated and therefore, may contribute to the chronicity of seizures in absence epilepsy.

Animals↗
PubMed1996

Cortical versus thalamic mechanisms underlying spike and wave discharges in GAERS.

Genetic absence epilepsy rats from Strasbourg (GAERS) have non-convulsive generalized seizures associated with spike-wave (SW) discharges, which are due to a hyperexcitable state of the thalamo-cortico circuits involving the reticular thalamic nucleus (nRt). Investigation of the primary genetically-determined defect responsible for GAERS epilepsy revealed the following abnormalities: (1) increased effectiveness of AMPA receptors dependent glutamate-mediated transmission; (2) impairment of GABA-mediated transmission in the neocortex; (3) increased amplitude of the voltage-dependent low-threshold Ca2(+)-current (I(T)) in the nRt. The maturational profile of these abnormalities supports the conclusion that the abnormality in the I(T) current in the nRt is the primary genetically-determined defect, which may secondarily induce the other changes found in the neocortex and thalamus of GAERS.

2-Amino-5-phosphonovalerate↗
PubMed1999

Effects of neurosteroids on spike-wave discharges in the genetic epileptic WAG/Rij rat.

Effects of i.p. administration of the neurosteroids, allopregnanolone and pregnenolone sulfate, were studied in WAG/Rij rats, a genetic model for generalized absence epilepsy. EEG recordings showed that allopregnanolone, a positive modulator of the GABA(A) receptor, in doses ranging from 5 to 20 mg/kg, increased dose-dependently the number- and total duration of spike-wave discharges. Pregnenolone sulfate, a positive modulator of NMDA receptors, also increased those parameters, though only at the highest dose used (100 mg/kg). Significant changes in spike-wave discharges occurred during the first hour post-injection and were not accompanied with behavioral alterations. The obtained data indicate that both these neurosteroids aggravate the spike-wave activity. This finding contrasts with the anti-convulsant effects of some neurosteroids and they point to a different pharmacological profile of epilepsy with convulsive or non-convulsive seizures.

Animals↗
PubMed1999

Cardiovascular effects of intracerebroventricular bicuculline in rats with absence seizures.

Gamma-aminobutyric acid (GABA) plays an important role in both central cardiovascular homeostasis and pathogenesis of epileptic seizures. Previous studies have indicated a critical role of the amygdala in the spread of seizures from brainstem to forebrain and in the regulation of autonomic responses such as blood pressure and heart rate. The purpose of the present study was to examine blood pressure and heart rate effects of bicuculline, a GABA(A) antagonist, and the effect of lesions of the central or the basolateral nuclei of the amygdala on bicuculline-induced cardiovascular responses in conscious WAG/Rij rats with absence epilepsy. Intracerebroventricular administration of 0.3 and 0.5 nmol of bicuculline produces an increase in blood pressure and a slight bradycardia in non-epileptic Wistar rats. The blood pressure response to intracerebroventricular bicuculline is significantly potentiated in epileptic WAG/Rij rats. Bilateral lesions of the basolateral nucleus of the amygdala of WAG/Rij rats completely prevent the pressor response to 0.5 nmol of bicuculline, whereas unilateral lesion of the basolateral nucleus does not affect blood pressure changes in epileptic WAG/Rij rats. Additionally, the pressor effect of 0.5 nmol of bicuculline is not attenuated by bilateral electrolytic ablation of the central nucleus of the amygdala in WAG/Rij rats. Heart rate response to bicuculline is not significantly changed in the lesioned groups. These findings indicate (a) altered GABAergic function in blood pressure regulation; and (b) a critical role of the basolateral nucleus in GABA(A)-mediated blood pressure control in epileptic WAG/Rij rats.

Amygdala↗
PubMed2003

The health-related quality of life of childhood epilepsy syndromes.

OBJECTIVE: There is increasing awareness of the importance of assessing physical, psychological, social and behavioural well-being in chronic disease. The aim of this study was to examine the health-related quality of life (HRQoL) of children with common epilepsy syndromes and to explore if there are HRQoL differences between those syndromes. METHODS: Each child had their epilepsy syndrome defined according to the International League Against Epilepsy classification. Epilepsy syndromes included symptomatic frontal, temporal, parietal/occipital lobe and partial unlocalized epilepsy, and two idiopathic epilepsies, childhood absence epilepsy (CAE) and benign rolandic epilepsy (BRE). Seizure semiology and ictal/interictal electroencephalogram (EEG) were determined for symptomatic partial epilepsy syndromes by video-EEG monitoring. HRQoL was evaluated with an epilepsy-specific instrument, the Quality of Life in Childhood Epilepsy Questionnaire, and two generic instruments, the Child Health Questionnaire and Child Behavior Checklist. RESULTS: Children with symptomatic partial epilepsy syndromes were affected by epilepsy in a similar way and did not have unique HRQoL profiles. However, these children had significantly lower HRQoL scores compared to those with CAE or BRE. All children with epilepsy regardless of syndrome had a higher frequency of behavioural problems compared to normative data. CONCLUSION: These results indicate that children with epilepsy regardless of syndrome require evaluation of the psychosocial implications. There is a greater impact on HRQoL in symptomatic epilepsy compared to idiopathic epilepsy. Specific symptomatic partial syndromes did not differ in the degree they affect HRQoL. These findings have important implications for clinicians caring for children with epilepsy.

Adolescent↗
PubMed1999

Can GABAA conductances explain the fast oscillation frequency of absence seizures in rodents?

Rodent models of absence epilepsy generate spike-and-wave oscillations at relatively fast frequency (5-10 Hz) compared with humans ( approximately 3 Hz). Possible mechanisms for these oscillations were investigated by computational models that included the complex intrinsic firing properties of thalamic and cortical neurons, as well as the multiple types of synaptic receptors mediating their interactions. The model indicates that oscillations with spike-and-wave field potentials can be generated by thalamocortical circuits. The frequency of these oscillations critically depended on GABAergic conductances in thalamic relay cells, ranging from 2-4 Hz for strong GABAB conductances to 5-10 Hz when GABAA conductances were dominant. This model therefore suggests that thalamocortical circuits can generate two types of spike-and-wave oscillations, whose frequency is determined by the receptor type mediating inhibition in thalamic relay cells. Experiments are proposed to test this mechanism.

Animals↗
PubMed2002

Topiramate monotherapy for childhood absence seizures: an open label pilot study.

This open-label, single-site, pilot study evaluated the therapeutic usefulness of topiramate in five children with typical absence seizures defined as loss of awareness associated with 3 Hz spike-wave activity on 24 hour ambulatory electroencephalogram (EEG). The children were previously untreated or treated unsuccessfully using other antiepileptic medication. Topiramate was initiated at a dose of 1 mg x kg (-1)day (-1), titrated twice weekly in 1 mg x kg (-1)day (-1)increments to 12 mg x kg (-1)day (-1)or individual maximally tolerated dose. Response was assessed after 6 weeks with ambulatory EEG monitoring and patient/parent record of seizure counts. All children completed the study. One previously untreated child became seizure-free on 5 mg x kg (-1)day(-1) topiramate, with no residual spike-wave activity at the final visit. In two patients, the frequency of seizures decreased in the early phases of titration, but rose to baseline levels as the topiramate dose was increased. With a reduction in dose to 6 mg x kg (-1)day (-1), seizure control improved, with substantial reductions in spike-wave activity. Seizure counts were not improved in the two remaining patients. Transient mood changes were noted in two patients. No child was withdrawn secondary to adverse effects. The results suggest that topiramate may be effective in childhood absence epilepsy. Controlled studies are now required to identify the clinically optimal dose.

Anticonvulsants↗
PubMed1985

Petit mal-absences of childhood onset: familial prevalences of migraine and seizures.

Seventy-seven patients suffering from childhood onset absence epilepsy as well as their families were investigated for familial prevalences of epileptic seizures and migraine. Proceeding from the whole sample, epileptic seizures seemed to occur more often in the families of female propositi, though maternal relatives of females and paternal relatives of males were more often affected than the respective opposite groups. - Migraine was more often diagnosed in female family members, which might be due to biased reports. Remarkably though, migraine prevalence was significantly higher in the mothers of female as compared to male propositi. These findings are discussed in context to others supporting a model of polygenic inheritance of epilepsy with sex-related thresholds of manifestation.

Child↗
PubMed2003

Sleep oscillations developing into seizures in corticothalamic systems.

PURPOSE: The aim of this article is to discuss the neuronal substrates of sleep oscillations leading to seizures consisting of spike-wave (SW) complexes at 2-4 Hz, mimicking those seen in absence epilepsy, or SW and polyspike-wave (PSW) complexes at 1.5-2.5 Hz, often associated with fast runs at 10-15 Hz, as in the Lennox-Gastaut syndrome. METHODS: Extracellular recordings were done in permanently implanted animals during the natural waking-sleep cycle. Single and dual simultaneous recordings from cortical neurons, cortical and thalamic neurons, or cortical neurons and glial cells were performed in cats under ketamine-xylazine anesthesia. RESULTS: (a) The minimal substrate of SW seizures is the neocortex because such seizures may occur in thalamectomized animals, in which spindles are absent. In intact-brain animals, SW seizures are initiated in neocortex and spread to the thalamus after a few seconds. The majority of thalamocortical (TC) neurons are steadily hyperpolarized throughout the cortical SW seizures. (b) In the Lennox-Gastaut syndrome, the paroxysmal depolarizing shifts (PDSs) associated with the EEG "spike" of SW/PSW complexes contain an important inhibitory component, whereas the hyperpolarization during the EEG "wave" component is not due to gamma-aminobutryic acid (GABA)ergic inhibitory postsynaptic potentials (IPSPs) but is ascribed to a mixture of disfacilitation and K+ currents. As is also the case with seizures consisting of pure SW complexes, the majority of TC neurons are hyperpolarized during the cortical paroxysms and disinhibited after the cessation of cortical seizures. CONCLUSIONS: Seizures with SW complexes and of the Lennox-Gastaut type preferentially evolve from sleep oscillations. They are initiated in neocortex and spread to the thalamus after a few seconds. The majority of TC neurons are inhibited during these seizures.

Animals↗
PubMed2005

Genetics of idiopathic epilepsies.

PURPOSE: To search for clues to molecular genetics of common idiopathic epilepsy syndromes. Genetic defects have been identified recently in certain inherited epilepsy syndromes in which the phenotypes are similar to those of common idiopathic epilepsies. METHODS: Mutations identified as the causes of inherited idiopathic epilepsies were reviewed. RESULTS: Mutations of the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor were found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of two K(+)-channel genes were identified in benign familial neonatal convulsions. Mutations of the genes encoding several subunits of the voltage-gated Na(+)-channel and gamma-aminobutyric acid (GABA)(A) receptor also were identified as the underlying causes of various epilepsy syndromes, such as autosomal dominant epilepsy with febrile seizures plus, benign familial neonatal infantile seizures, and autosomal dominant juvenile myoclonic epilepsy. Mutations within the same gene may result in different epilepsy phenotypes. Thus, the Na(+) channel, GABA(A) receptor, and their auxiliaries may be involved in the pathogenesis of various types of epilepsy. Some forms of juvenile myoclonic epilepsy, idiopathic generalized epilepsy, and absence epilepsy may result from mutations of Ca(2+) channels. Mutations of the Cl(-) channel have been recently found to be associated with a certain type of epilepsy. The recent discovery that mutations of LGI1, a gene encoding a nonchannel molecule, are associated with autosomal partial epilepsy with auditory features may provide a new insight into our understanding of the genetics of idiopathic epilepsy. CONCLUSIONS: These findings suggest the involvement of brain channelopathies in the pathogenesis of certain types of idiopathic epilepsy.

Codon, Nonsense↗
PubMed1984

Monodose versus 3 daily doses of sodium valproate: a controlled trial.

12 patients with absence epilepsy were treated with alternatively 1 or 3 daily doses of sodium valproate (VPA) in a double-blind cross-over design. Seizure frequency, EEG paroxysmal activity, clinical side-effects and laboratory findings were assessed for both treatment periods. There was no statistically significant difference between the 2 dosage schedules, and the simplicity of monodose treatment is an important factor in good patient compliance. The apparent discrepancy between plasma half-life and biological action of VPA is discussed.

Clinical Trials as Topic↗