Control Of Absence Seizures Research Articles

Pathophysiological mechanisms of genetic absence epilepsy in the rat

Generalized non-convulsive absence seizures are characterized by the occurrence of synchronous and bilateral spike and wave discharges (SWDs) on the electroencephalogram, that are concomitant with a behavioral arrest. Many similarities between rodent and human absence seizures support the use of genetic rodent models, in which spontaneous SWDs occur. This review summarizes data obtained on the neurophysiological and neurochemical mechanisms of absence seizures with special emphasis on the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). EEG recordings from various brain regions and lesion experiments showed that the cortex, the reticular nucleus and the relay nuclei of the thalamus play a predominant role in the development of SWDs. Neither the cortex, nor the thalamus alone can sustain SWDs, indicating that both structures are intimely involved in the genesis of SWDs. Pharmacological data confirmed that both inhibitory and excitatory neurotransmissions are involved in the genesis and control of absence seizures. Whether the generation of SWDs is the result of an excessive cortical excitability, due to an unbalance between inhibition and excitation, or excessive thalamic oscillations, due to abnormal intrinsic neuronal properties under the control of inhibitory GABAergic mechanisms, remains controversial. The thalamo-cortical activity is regulated by several monoaminergic and cholinergic projections. An alteration of the activity of these different ascending inputs may induce a temporary inadequation of the functional state between the cortex and the thalamus and thus promote SWDs. The experimental data are discussed in view of these possible pathophysiological mechanisms.

Thalamic NMDA transmission in a genetic model of absence epilepsy in rats.

In the selected strain of GAERS Wistar rats (Genétic Absence Epilepsy Rats from Strasbourg), all animals present spontaneously recurrent absence seizures characterized by bilateral and synchronous generalized spike-and-wave discharges (SWD) accompanied by behavioural arrest. SWD depend on a thalamo-cortical network connecting the reticular and relay nuclei of the thalamus and their cortical projection areas. This loop involves both GABAergic and glutamatergic synapses. In the present study, we investigated the implication of NMDA transmission in the genesis of absence seizures in GAERS. Intra-peritoneal or intra-cerebroventricular injections of NMDA, the competitive NMDA antagonist CGP 40116, the non-competitive NMDA antagonist (+)-MK 801 and the antagonist of the glycine modulatory site 5,7-dichlorokynurenic acid dose-dependently suppressed SWD. Bilateral infusions of the same drugs in the lateral relay nuclei of the thalamus had similar suppressive effects. Intra-cerebroventricular or intrathalamic administration of D-serine, an agonist of the glycine modulatory site, had no effect on SWD. These data show that NMDA neurotransmission, especially within the thalamus, plays a major role in the control of absence seizures in GAERs. Disregulation of NMDA-mediated transmission by NMDA or antagonists, interacting with various sites of the receptor complex, may suppress the thalamo-cortical oscillatory activity which underlies SWD.

Nucleus basalis lesions suppress spike and wave discharges in rats with spontaneous absence-epilepsy

Cholinergic drugs were shown to affect spike and wave discharges in a selected strain of Wistar rats with generalized non-convulsive absence epilepsy, named GAERS (Genetic Absence Epilepsy Rats from Strasbourg). The involvement of cholinergic transmission from the nucleus basalis in the control of absence seizures in GAERS was investigated in the present study, by examining the effects of unilateral excitotoxic lesions of this nucleus on the occurrence of spike-wave discharges. Ibotenate (0.01 M) and quisqualate (0.03 and 0.06 M)-induced lesions of the nucleus basalis suppressed spike-wave discharges in the cortex ipsilateral to the lesion. The suppression was associated with a disappearance of both acetylcholinesterase-fibres in the cerebral cortex and choline acetyltransferase immunopositive neurons within the nucleus basalis. Concomitantly, the background electroencephalographic activity was slowed. These results suggest that cholinergic innervation of the cerebral cortex by the nucleus basalis is involved in the occurrence of generalized non-convulsive seizures, in relation to the control of cortical activation.

Involvement of intrathalamic GABA b neurotransmission in the control of absence seizures in the rat

The role of intrathalamic GABA b neurotransmission in the control of absence seizures was investigated. In rats with genetic absence epilepsy, bilateral injections of R-baclofen (50, 100 and 200 ng/side), a selective GABA b receptor agonist, into the specific relay nuclei and the reticular nuclei of the thalamus increased spontaneous spike and wave discharges in a dose-dependent fashion, whereas injections of a GABA b antagonist CGP 35 348 (1, 2.5 and 5 μg/side) into the same sites decreased these seizures dose-dependently. The effect of R-baclofen (200 ng/side) on spike and wave discharges could be blocked by a subsequent injection of CGP 35 348 (1 μg/side) at the same site. Injections of R-baclofen (200 ng) or CGP 35 348 (5 μg) into the midline thalamus had no effect on these seizures. In non-epileptic rats, bilateral injections of R-baclofen (1 μg/side) into the specific relay nuclei induced synchronized rhythmic oscillations on the cortical electroencephalogram. The results suggest that GABA b receptors in the ventrolateral thalamus and in the reticular nuclei are involved in an oscillatory activity which underlies the rhythmic spike and wave discharges recorded during spontaneous generalized non-convulsive seizures.

Evidence for a critical role of GABAergic transmission within the thalamus in the genesis and control of absence seizures in the rat.

The involvement of GABAergic transmission within the thalamus in the generation and control of spike and wave discharges (SWD) in generalized non-convulsive or absence epilepsy was studied in rats with spontaneous SWD and in non-epileptic rats. In epileptic rats, bilateral injections of gamma-vinyl GABA (GVG, 10 micrograms/side) or muscimol (10 ng/side) into the medial part of the ventral lateral thalamus, i.e. the specific relay nuclei, significantly increased spontaneous cortical SWD whereas similar injections into the most lateral part of the thalamus, i.e. the area of the reticular nuclei, significantly suppressed these seizures. Injections of GVG (20 micrograms) or muscimol (20 ng) into the midline thalamus had no direct effect on the spontaneous SWD. In non-epileptic rats, injections of GVG (25 micrograms/side) or muscimol (100 ng/side) into the thalamic relay nuclei produced short SWD on the cortical EEG. These results suggest that GABAergic neurons in the reticular nuclei and their projections to the specific relay nuclei of the thalamus are involved in the elicitation and control of generalized non-convulsive seizures.

Treatment of the nonconvulsive epilepsies.

Eliminating seizures should be the first goal of therapy for nonconvulsive epilepsies, but preventing seizures, i.e., guarding against head injuries and immunizing against agents that attack the nervous system, is the second goal. An accurate diagnosis of seizure type helps ensure that the appropriate medication for that particular form of epilepsy will be prescribed. Drug decisions should also be based on the risk: benefit ratio to the individual patient, and drug interactions should be considered when more than one drug is required. Frequent monitoring of drug serum levels is necessary in the case of multiple drug therapy or until seizures are controlled. Ethosuximide is considered the drug of choice in absence seizures, but valproic acid is equally effective. Although effective in controlling absence seizures, clonazepam is not favored in this indication because of a high incidence of side effects and the development of tolerance. Atonic seizures are generally refractory to treatment, but valproate, clonazepam, and occasionally carbamazepine represent the drugs of choice in management. Phenytoin continues to be a very popular drug for most types of seizures, but carbamazepine, used adjunctively until recently, is effective as monotherapy for the control of partial seizures, particularly those of the complex partial variety.

The role of cholinergic mechanisms in the corticofugal inhibition of the spinal trigeminal nucleus

A conditioning stimulus to the contralateral coronal gyrus of cats inhibits the response of certain neurons in the spinal trigeminal nucleus to maxillary nerve stimulation. This corticofugal inhibition (CFI) is markedly increased by eserine. The subsequent administration of atropine reverses the effect of eserine. However, atropine has a variable effect when it is given as the initial drug. On the other hand, the simultaneous injection of atropine and D-amphetamine consistently decreases the CFI, even though D-amphetamine alone also has a variable effect. The magnitude of the effect of the combined administration of atropine and D-amphetamine is directly proportional to the magnitude of the CFI prior to the injection. These results indicate that the CFI is modulated by a cholinergic facilitatory and an adrenergic inhibitory pathway. Furthermore, there appears to be a close reciprocal relationship between the cholinergic and adrenergic mechanisms in our experimental model, such that the CFI is consistently decreased only when an anticholinergic and an adrenergic effect are exerted simultaneously. These observations are discussed in relation to the neurotransmitters that may be involved in the production and control of absence seizures, since we have previously found that anti-absence drugs depress the CFI.