Absence seizures are the most pure form of generalized epilepsy. They are characterized in the electroencephalogram by widespread bilaterally synchronous spike-wave discharges (SWDs), which are the reflections of highly synchronized oscillations in thalamocortical networks. To reveal network mechanisms responsible for the initiation and generalization of the discharges, we studied the interrelationships between multisite cortical and thalamic field potentials recorded during spontaneous SWDs in the freely moving WAG/Rij rat, a genetic model of absence epilepsy. Nonlinear association analysis revealed a consistent cortical "focus" within the peri-oral region of the somatosensory cortex. The SWDs recorded at other cortical sites consistently lagged this focal site, with time delays that increased with electrode distance (corresponding to a mean propagation velocity of 1.4 m/sec). Intra-thalamic relationships were more complex and could not account for the observed cortical propagation pattern. Cortical and thalamic sites interacted bi-directionally, whereas the direction of this coupling could vary throughout one seizure. However, during the first 500 msec, the cortical focus was consistently found to lead the thalamus. These findings argue against the existence of one common subcortical pacemaker for the generation of generalized spike-wave discharges characteristic for absence seizures in the rat. Instead, the results suggest that a cortical focus is the dominant factor in initiating the paroxysmal oscillation within the corticothalamic loops, and that the large-scale synchronization is mediated by ways of an extremely fast intracortical spread of seizure activity. Analogous mechanisms may underlie the pathophysiology of human absence epilepsy.

https://www.jneurosci.org/content/jneuro/22/4/1480.full.pdf

Cortical Focus Drives Widespread Corticothalamic Networks during Spontaneous Absence Seizures in Rats

Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations

Summary: Purpose: Properties of oscillations with frequencies >100 Hz were studied in kainic acid (KA)-treated rats and compared with those recorded in normal and kindled rats as well as in patients with epilepsy to determine differences associated with epilepsy.

Methods: Prolonged in vivo wideband recordings of electrical activity were made in hippocampus and entorhinal cortex (EC) of (a) normal rats, (b) kindled rats, (c) rats having chronic recurrent spontaneous seizures after intrahippocampal KA injections, and (d) patients with epilepsy undergoing depth electrode evaluation in preparation for surgical treatment.

Results: Intermittent oscillatory activity ranging from 100 to 200 Hz in frequency and 50–150 ms in duration was recorded in CA1 and EC of all three animal groups, and in epileptic human hippocampus and EC. This activity had the same characteristics in all groups, resembled previously observed “ripples” described by Buzsaki et al., and appeared to represent field potentials of inhibitory postsynaptic potentials (IPSPs) on principal cells. Unexpectedly, higher frequency intermittent oscillatory activity ranging from 200 to 500 Hz and 10–100 ms in duration was encountered only in KA-treated rats and patients with epilepsy. These oscillations, termed fast ripples (FRs), were found only adjacent to the epileptogenic lesion in hippocampus, EC, and dentate gyrus, and appeared to represent field potential population spikes. Their local origin was indicated by correspondence with the negative phase of burst discharges of putative pyramidal cells.

Conclusions: The persistence of normal-appearing ripples in epileptic brain support the view that inhibitory processes are preserved. FRs appear to be field potentials reflecting hypersynchronous bursting of excitatory neurons and provide an opportunity to study the role of this pathophysiologic phenomenon in epilepsy and seizure initiation. Furthermore, if FR activity is unique to brain areas capable of generating spontaneous seizures, its identification could be a powerful functional indicator of the epileptic region in patients evaluated for surgical treatment.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1157.1999.tb02065.x

Hippocampal and Entorhinal Cortex High-Frequency Oscillations (100-500 Hz) in Human Epileptic Brain and in Kainic Acid-Treated Rats with Chronic Seizures

Animal models of the epilepsies

Pathophysiological mechanisms of genetic absence epilepsy in the rat

Spontaneous paroxysmal electroclinical patterns in rat: A model of generalized non-convulsive epilepsy

Summary: Of 100 randomly chosen, adult male Wistar rats in the breeding colony at the Centre de Neurochimie, Strasbourg, 31 presented spontaneous, nonconvulsive epileptic seizures: wave-and-spike discharges, 7–11 cy-cles/s, 200–600 μV, accompanied by behavioral arrest and myoclony of the vibrissae and of the facial and cervical muscles. Pentylenetetrazol (PTZ) 10 and 20 mg/kg increased the duration and number of seizures by 100–150% in these spontaneously epileptic animals, and caused identical seizures in apparently normal rats. Sodium valproate, diazepam, trimethadione, and ethosux-imide suppressed the spontaneous seizures and protected against PTZ-induced seizures in a dose-dependent fashion. Carbamazepine and diphenylhydantoin were inefficacious or aggravative in the two cases. The clinical, EEG, and pharmacological observations suggest that the Wistar rats displaying spontaneous seizures constitute a valid physiological and pharmacological model of petit mal absences, presenting advantages compared to the usual models in which seizures are induced byinjected epileptogenic drugs.



RESUME

Sur 100 rats Wistar, mâles, adultes, preleves au hasard dans Ľe1evage du Centre de Neurochimie de Strasbourg, 31 ont presente spontanement des crises epileptiques nonconvulsives (de-charges de pointes-ondes de 7–11 c/s et de 200–600 μ V accom-pagnees ďun arret de Ľactivite et de myoclonies des vibrisses et de la musculature faciale et cervicale). Le pentylenetetrazol a 10 et 20 mg/kg augmente de 100–150% la duree et le nombre des crises chez les animaux spontanement epileptiques; aux memes doses, le pentylenetetrazol fait apparaitre des crises iden-tiques chez les animaux apparemment indemnes. Le valproate de sodium, le diazepam, la trimethadione, et Ľethosuximide sup-priment les crises spontanees et protegent contre les crises induces par 20 mg/kg de PTZ de facon dose-dependante. La car-bamazepine et la diphenylhydantoine sont inefficaces ou aggravates sur les deux types de crises. Ľensemble des resultats cliniques, electroencephalographiques, et pharmacologiques permettent de penser que les crises spontanees du rat Wistar constituent un bon modele physiologique et pharmacologique ďabsences. Ce modele semble presenter quelques avantages par rapport aux modeles usuels induits par des injections de drogues epileptogenes.



RESUMEN

De las 100 ratas Wistar machos y adultos, seleccionadas al azar de la colonia de crias del Centro de Neuroqui'mica en Es-trasburgo, 31 presentaron ataques epilepticos no convulsivos: descargas punta-onda de 7 a 11 ciclos por segundo y 200 a 600 μ.V, acompanadas de interrupcion del comportamiento y mio-clonias de las vibrisas y de los musculos faciales y cervicales. La administracion de 10 a 20 mg/kg de pentilentetrazol (PTZ) incrementaron en un 100 a 150% la duracion y el numero de los ataques en estos animales espontaneamente epilepticos y causo ataques identicos en ratas aparentemente normales. El valproato sodico, el diazepan, la trimetadiona y la etosuximida suprimieron los ataques espontaneos y protegieron a las ratas de las crisis inducidas por el PTZ. La carbamazepina y la difenilhidantoina fueron ineficaces o perjudiciales en dos casos. Las observa-ciones clinicas, electroencefalograficas y farmacologicas sugi-eren que las ratas Wistar que muestran ataques espontaneos con-stituyen un valido modelo fisiologico y farmacologico de las au-sencias petit-mal. Este modelo presenta ventajas con respecto a modelos comunes en los que los ataques se inducen inyectando drogas epileptogenicas.



ZUSAMMENFASSUNG

Von 100 zufallig ausgewahlten mannlichen erwachsenen Wistar-Ratten aus der Zuchtkolonie am Centre de Neurochimie, Strasburg zeigten 31 spontane, nicht konvulsive epileptische Anfalle: wave and spike Entladungen von 7 bis 11 c/s und 200 bis 600 uV, die von einem Verharren und Myokloni der Schnau-zhaare sowie der facialen und cervikalen Muskeln begleitet waren. Pentylentetrazol (PTZ) in einer Dosis von 10 und 20 mg/ kg verlangerte bei diesen spontan epileptischen Tieren die Dauer und erhohte die Anzahl der Anfalle um 100 bis 150%. Daruber hinaus verursachte diese Dosis identische Anfalle bei scheinbar normalen Ratten. Natrium Valproat, Diazepam, Trimethadion und Ethosuximid unterdruckten die spontanen Anfalle und schutzten, in Abhangigkeit von der Dosis, vor PTZ-induzierten Anfallen. Carbamazepin und Diphenylhydantoin waren wir-kungslos; in 2 Fallen verstarkten sie die Anfalle. Die klinischen, EEG, und pharmakologischen Beobachtungen legen nahe, daβ die Wistar-Ratten mit spontanen Anfallen ein gutes physiolo-gisches und pharmakologisches Modell der Petit Mai Absencen darstellen, das Vorteile gegenuber den ubrigen Modellen bietet, bei denen epileptogene Medikamente injiziert werden mussen.

A Model of Chronic Spontaneous Petit Mal‐like Seizures in the Rat: Comparison with Pentylenetetrazol‐Induced Seizures

Enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mallike epilepsy

Of 13 patients with complex partial seizures who experienced stuporous states during treatment with sodium valproate (VPA), 4 received VPA only, 4 VPA and phenobarbital (PB) and 5 VPA, PB, and a third anticonvulsant. Seven cases were described in detail. Side effects-stupor or confusion-appeared a few days after efficacious drug plasma levels were attained, persisted until therapy was readjusted, and disappeared 24 to 72 h after VPA withdrawal. Therapeutic trials established the role of VPA in the onset of stuporous states. The adverse effects of VPA were potentiated by the concomitant administration of other anticonvulsants. Stupor was not due to VPA overdoses, and plasma concentration of the drugs were not correlated with the electroclinical signs. The EEG showed spike and wave discharges or continuous sharp theta and delta waves persisting during VPA treatment. The fact that all 13 stuporous, VPA-treated patients were subjected to partial seizures with complex symptomatology, and none were cases of generalized epilepsy, together with the observations that the disturbances of consciousness started with focal symptoms and EEG signs resembling those of spontaneously occurring partial seizures, suggest that VPA given alone or in association with other antiepileptics has a paradoxical epileptogenic effect in certain forms of epilepsy.

L. Rumbach

Papers

Spontaneous paroxysmal electroclinical patterns in rat: A model of generalized non-convulsive epilepsy

A Model of Chronic Spontaneous Petit Mal‐like Seizures in the Rat: Comparison with Pentylenetetrazol‐Induced Seizures

Enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mallike epilepsy

Stuporous episodes during treatment with sodium valproate: report of seven cases.