O. Carter Snead

Evidence for GABAB-mediated mechanisms in experimental generalized absence seizures

Experimental absence seizures are characterized by the fact that they are exacerbated by both direct and indirect GABA agonists. To date most of the studies that have examined this phenomenon have utilized GABAA agonists. We assessed the effect of a GABAB agonist, baclofen and a specific GABAB antagonist in two pharmacological models of absence seizures in rodent after using either gamma-hydroxybutyrate or pentylenetetrazole to induce the bilaterally synchronous spike wave discharges that typify absence seizures in rodent. Baclofen markedly prolonged and the GABAB antagonist attenuated or blocked the experimental absence seizures in both models. These data suggest a role for GABAB-related mechanisms in the pathogenesis of generalized absence seizures and raise the possibility that GABAB antagonists may have therapeutic potential as antiabsence drugs.

Pharmacological models of generalized absence seizures in rodents

A number of animal models of generalized absence seizures in rodents are described. These include absence seizures induced by γ-hydroxybutyrate (GHB), low dose pentylenetetrazole, penicillin, THIP and AY-9944. All of these models share behavioral and EEG similarity to human absence seizures and show pharmacologic specificity for antiabsence drugs such as ethosuximide and trimethadione. Moreover, the absence seizures induced by these agents are exacerbated by GABAergic agonists, a property unique to experimental absence seizures. These models are predictable, reproducible, and easy to standardize. They are useful both in studying mechanisms of pathogenesis of absence seizures as well as in screening for antiabsence activity of potential antiepileptic drugs.

The ontogeny of [3H]γ-hydroxybutyrate and [3H]GABAB binding sites: relation to the development of experimental absence seizures

gamma-Hydroxybutyric acid (GHB) is a naturally occurring compound which has the ability to induce generalized absence seizures when given to animals. There is growing evidence that both gamma-aminobutyric acid (GABA)B- and GHB-mediated mechanisms are involved in the pathogenesis of this phenomenon. Because of the fact that absence seizures are a disorder of children the ontogeny of [3H]GHB and [3H]GABAB binding and the developmental appearance of absence seizures in the GHB model of absence was ascertained and compared in developing rats. [3H]GABAB binding was present within the first 3 days of postnatal life and rose to levels which exceeded those found in adults, peaking between the 3rd and 5th postnatal week. [3H]GHB binding on the other hand did not appear until postnatal day 17 when it was detectable in the CA1 region of the hippocampus. There was a steady increase in [3H]GHB binding until adult levels were reached by postnatal day 40. Comparison of [3H]GABAB and [3H]GHB binding revealed that both sites were common to layer I-III of cortex, but otherwise differed in their regional distribution. There was an absolute concordance of the ontogeny of GHB-induced absence seizures with the developmental appearance of [3H]GHB binding in the superficial laminae of cortex; both appeared at postnatal day 18. These data support the hypotheses that the [3H]GHB and [3H]GABAB binding sites are separate from one another and suggest that maturational events in thalamus and cortex in the 3rd postnatal week are involved in the expression of GHB-induced absence seizures.

Clinical utility of video-EEG monitoring

This study investigated the efficiency of simultaneous video-electroencephalography (EEG) monitoring in documenting paroxysmal events, the value in clinical diagnosis, and the effect on treatment. In this retrospective review, 230 children underwent this procedure between January, 1990 and December, 1992. The data demonstrated that video-EEG monitoring can be used as a daytime procedure with a high success rate (80%) in detecting and differentiating the nature of recurrent paroxysmal behaviors that have occurred on a daily basis. Video-EEG monitoring has a high diagnostic rate in differentiating seizure versus nonseizure events (70%), in classifying seizure types (88%), and in evaluating the candidacy for epilepsy surgery (64%). Video-EEG diagnosis resulted in an alteration of clinical management in 45% of patients. Continuous video-EEG monitoring is an efficient and valuable procedure in the diagnosis and management of paroxysmal disorders in children.

Relation of the [3H]γ-hydroxybutyric acid (ghb) binding site to the γ-aminobutyric acidb (gabab) receptor in rat brain

Abstract Hydroxybutyric acid (GHB) is a naturally occurring compound that has the ability to induce generalized absence seizures when given to animals. GHB has been hypothesized to induce this effect via the postsynaptic γ-aminobutyric acid B (GABA B ) receptor. We sought to test this hypothesis by examining the affinity of GABA B agonists and antagonists for the [ 3 H]GHB binding site, the affinity of GHB and a GHB antagonist for the [ 3 H]GABA B binding site, and the effect of guanine nucleotides and pertussis toxin on both, using autoradiographic binding assays. GHB and its antagonist, NCS 382, did not compete for [ 3 H]GABA B binding, nor did (-)-baclofen or the [ 3 H]GABA B antagonists, CGP 35348 or SCH 50911, compete for [ 3 H]GHB binding; however, the GABA B agonist 3-amino-propylphosphinic acid (3-APPA), and the GABA B antagonists phaclofen and 2-hydroxysaclofen (2-OH saclofen) did show a weak affinity for [ 3 H]GHB binding in frontal cortex. GTP and the nonhydrolyzable GTP analogues, GTPγS and Gpp(NH)p, depressed [ 3 H]GABA B binding throughout the brain, but increased [ 3 H]GHB binding in frontal cortex and thalamus, those regions involved in GHB-induced absence seizures. Pertussis toxin significantly depressed [ 3 H]GABA B binding throughout the brain, but attenuated [ 3 H]GHB binding only in frontal cortex, and to a lesser degree than [ 3 H]GABA B binding. The guanine nucleotide-induced changes in [ 3 H]GHB and [ 3 H]GABA B binding were due to a change in K D for both. Moreover, GTPγS reversed the ability of 3-APPA, phaclofen, and 2-OH saclofen to compete for [ 3 H]GHB binding. These data do not support the hypothesis that GHB acts through the postsynaptic GABA B receptor to produce absence seizures. Rather, they raise the possibility either that the [ 3 H]GHB binding site may be an isoform of the presynaptic GABA B receptor or that an independent GHB site is operative in the GHB model of absence seizures.

Bicuculline induced seizures in infant rats: ontogeny of behavioral and electrocortical phenomena

The effects of bicuculline, a gamma-aminobutyric acid (GABA) antagonist, were investigated in 258 immature rats between the third and 22nd postnatal days. Behavioral and electrocorticographic events were correlated. Bicuculline induced both behavioral and electrographic seizures as early as the third postnatal day, an age when the CD50 for bicuculline was lowest, and therefore the sensitivity to it was the greatest. Bicuculline may thus be a suitable convulsant for epilepsy studies involving rats during the first postnatal week.

Thalamic mediodorsal and intralaminar nuclear lesions disrupt the generation of experimentally induced generalized absence-like seizures in rats

The effect of bilateral electrolytic lesions of various thalamic sites on the generation of bilaterally synchronous spike and wave discharges (SWD) was studied in two experimental rat models of absence-like seizures. SWD induced by both pentylenetetrazole (20 mg/kg, i.p.) and gamma-hydroxybutyric acid (gamma-butyrolactone, 100 mg/kg, i.p.) were recorded simultaneously from the thalamus and cortex. In both models generation of SWD from the mediodorsal, intralaminar (central lateral and paracentral), ventroposterolateral (VPL) and the reticular thalamic (RT) nucleus was synchronous with that of frontoparietal cortex. Bilateral lesions in mediodorsal and intralaminar thalamic nuclei abolished SWD from both cortex and thalamus in both models. Similar lesions in VPL did not abolish, but attenuated the duration of pentylenetetrazole- and gamma-hydroxybutyric acid-induced SWD, more significantly from the thalamus than from the cortex. RT lesions were associated with more pronounced suppression of pentylenetetrazole-, but not gamma-hydroxybutyric acid-induced SWD in the thalamus. These findings suggest a potential role for mediodorsal and intralaminar thalamic nuclei in the generation of experimental absence-like seizures in rats.

GABAA receptor function in the γ-hydroxybutyrate model of generalized absence seizures

γ-Hydroxybutyric acid (GHB) produces absence-like seizures when given to animals. One of the distinguishing characteristics of experimental generalized absence seizures is that they are exacerbated by GABAA agonists. Therefore, the hypothesis that GHB-induced absence seizures result from an interaction between GHB and the GABAA receptor complex was tested. The effect of GHB on the function of various components of the GABAA receptor complex in the cortex of the rat, was determined in a series of in vitro experiments. Similar studies were carried out at various times following systemic administration of the prodrug of GHB, γ-butyrolactone (GBL) and changes in the GABAA receptor were correlated with electrographic and behavioral changes. γ-Hydroxybutyric acid had no effect on the binding of [3H]muscimol, [3H]flunitrazepam and [35S]t-butyl-bicyclophosphorothionate (TBPS) or on the uptake of 36Cl− into synaptoneurosomes in the in vitro studies. Nor were changes observed after the administration of GBL before the onesetof GHB-induced absence seizures. However, at the onset of GHB-induced spike wave discharge, there was a significant (P < 0.04) decrease in the binding of [35S]TBPS, associated with a significant decrease in muscimol-stimulated uptake of 36Cl− with no other biochemical change. One minute after onset of GHB-induced absence seizure, a significant (P < 0.05) increase in the binding of [3H]muscimol was noted. Ten minutes later the decrease in muscimol-stimulated uptake of 36Cl− had normalized, while the changes in binding of [3H]muscimol and [35S]TBPS persisted. Because GABAA function remained unchanged in the in vitro studies, as well as prior to the onset of GHB-induced absence seizures in the in vivo experiments, these studies do not support the hypothesis that GHB interacts directly with the GABAA receptor complex to produce absence-like seizures.

Usefulness of [18F]Fluorodeoxyglucose positron emission tomography in pediatric epilepsy surgery

We sought to analyze our experience with pediatric epilepsy surgery patients to determine the place of [18F]fluorodeoxyglucose (FDG) positron emission tomography (FDG-PET) in the preoperative evaluation of such children relative to chronic invasive intracranial monitoring. Fifty-six children who received an interictal FDG-PET as part of a phase 1 epilepsy surgery evaluation were compared with 44 children who did not have this study in a retrospective analysis of 100 patients accrued over a 4-year period. There was no significant difference between the two groups of children in terms of age or follow-up or was there a significant difference between the FDG-PET group and the no-FDG-PET group in regard to the numbers of children who had surgery, the type of procedure done, whether chronic invasive intracranial monitoring was performed, or outcome. The hypometabolic area demonstrated on interictal FDG-PET was concordant with that of the epileptogenic zone as mapped out with ictal recordings from subdural electrodes in 2 of 13 patients in whom a complete data set was available for comparison. In the other 11 children there was either poor agreement between interictal FDG-PET and ictal electrocorticographic data or the interictal FDG-PET was normal in the face of an epileptogenic focus which was successfully mapped by invasive electrophysiologic techniques and excised. We conclude that one cannot exclude a child with intractable partial seizures from surgical consideration because the interictal FDG-PET is normal; nor is there sufficient correlation between the interictal hypometabolic area on FDG-PET and the epileptogenic zone in terms of anatomic location and size to justify forgoing chronic invasive intracranial monitoring in children with intractable partial seizures being evaluated for epilepsy surgery unless there is absolute concordance between all neuroimaging, clinical, and video-electroencephalographic data.

Increased γ-hydroxybutyric acid receptors in thalamus of a genetic animal model of petit mal epilepsy

The distribution and kinetics of specific binding sites for gamma-hydroxybutyrate (GHB), a naturally occurring compound known to produce absence-like seizures, was studied in the brains of Wistar rats with spontaneous, bilaterally synchronous spike wave discharges (SWDs), a model of petit mal epilepsy, and non-epileptic controls using [3H]GHB autoradiography. [3H]GHB receptor binding was increased 40-60% in lateral thalamic nuclei of the epileptic animals. Kinetic analysis showed that the increase in the binding was due to an increase in density of low affinity GHB binding sites in the epileptic animals. Given the ability of GHB to produce petit mal-like seizures when administered to animals, and the fact that the SWDs in the Wistar rat model seem to emanate from lateral thalamus, these data raise the possibility that GHB-mediated mechanisms may play a role in the pathogenesis of petit mal seizures.