Phenobarbital treatment of status epilepticus in a rodent model

Although phenobarbital is frequently used in the treatment of status epilepticus, little has been published concerning the dose or serum concentration which effectively control adult status. We studied the efficacy of phenobarbital in controlling status in a rat model which induces generalized tonic-clonic seizures (GTCS) which respond to other drugs at serum concentrations similar to those reported to be effective in human status. We found that phenobarbital is rapidly absorbed following intraperitoneal injection, but entry into brain is delayed. Brain entry was facilitated during uncontrolled status epilepticus. The ED50 values for control of seizures in this model rose in a dose-dependent manner for increasing levels of seizure control, from 14.2 mg/kg for control of GTCS to 76.6 mg/kg for control of all motor and electrographic ictal activity. Raising serum concentrations above the 20 micrograms/ml required to control GTCS produced increasingly better control of the various types of ictal activity seen in this model.     

Epilepsy in Wolf-Hirschhorn syndrome (4p-)

PURPOSE: We investigated the evolution of epilepsy, seizure types, and effective drugs in Wolf-Hirschhorn syndrome, which is a malformation syndrome often with refractory seizures and status epilepticus. METHODS: We reviewed 11 cases of Wolf-Hirschhorn syndrome (age range, 2-25 years; SD, 7.2 years) and who were treated in Osaka University or Osaka Medical Center of Research Institute for Maternal and Child Health. RESULTS: In all patients, febrile or afebrile convulsions had developed. Epileptic seizures included alternative hemiconvulsions, generalized tonic-clonic seizures, focal clonic seizures, tonic seizures, and epileptic spasms. Seizures were often induced by a high fever or a hot bath. Status epilepticus occurred in all patients, including one patient who died at the first status epilepticus. In some cases, intratracheal intubation was needed because of respiratory insufficiency. The effective antiepileptic drugs for long-term use were sodium bromide (four of four), followed by clorazepate (CLP; one of two), and nitrazepam (NZP; two of four). Sodium bromide was particularly effective for preventing status epilepticus. The mean age of last status epilepticus in patients receiving sodium bromide (1 year 8 months) was significantly younger than that in those not treated with sodium bromide (3 year 4 months). CONCLUSIONS: We identified that, in most patients of Wolf-Hirschhorn syndrome, the frequency of both seizures and status epilepticus decreased gradually after age 5 years. However, during infancy, status epilepticus sometimes resulted in permanent disability or even death. We propose that sodium bromide should be used as the initial treatment for the prevention of the development of status epilepticus associated with Wolf-Hirschhorn syndrome.     

Effects of drugs on the initiation and maintenance of status epilepticus induced by administration of pilocarpine to lithium-pretreated rats

The ability of various drugs to prevent the onset of status epilepticus induced by administration of the muscarinic agonist, pilocarpine, to lithium-pretreated rats was determined. Motor limbic seizures and status epilepticus occurred in 100% of rats administered pilocarpine (30 mg/kg, s.c.) 20 h after pretreatment with lithium (3 meq/kg, i.p.). The latency to spike activity and to status epilepticus was 20 +/- 1 min and 24 +/- 1 min, respectively. Atropine, diazepam, phenytoin, carbamazepine, phenobarbital, paraldehyde, and L-phenylisopropyladenosine (L-PIA) prevented all phases of seizure activity induced by lithium/pilocarpine treatment. The initiation of status epilepticus was significantly prolonged by pretreatment with sodium valproate. These findings indicate that the seizures induced by administration of lithium and pilocarpine accurately model generalized tonic-clonic epilepsy. The anticonvulsant activity of L-PIA was prevented by prior treatment with the adenosine antagonist, theophylline. The latency to spike and seizure activity was decreased by theophylline, indicating that endogenous adenosine may have a tonic inhibitory influence on cholinergic neurons. Atropine, diazepam, phenobarbital, phenytoin, sodium valproate, L-PIA, and carbamazepine did not interrupt seizure activity when administered 60 min after pilocarpine (approximately 35 min after initiation of status epilepticus). When rats were administered paraldehyde at this time, status epilepticus was rapidly terminated and all rats survived. Thus, status epilepticus induced by lithium and pilocarpine provides a seizure model that is not responsive to conventional anticonvulsants.     

Electroclinical Features and Evolution of Grand mal Seizures in Infancy

Abstract: Seizures belonging to primary generalized epilepsy seem to be rare in infancy. Absence seizures are virtually non-existent, although atypical absence is infrequently observed. Most of the apparently generalized tonic-clonic seizures seem to be secondarily generalized partial seizures with initial subtle complex seizure manifestations characterized by motion arrest, staring or blank eyes. Among the generalized motor seizures in the first year, an extremely benign type of epilepsy exists, in which seizures stop before 3 years of age with normal psychomotor development. It is characterized by cryptogenic etiology, normal development before the onset, no neurological abnormality, no evolution into other types of seizures, a normal EEG course and no episodes of status epilepticus. However, it was difficult to differentiate this group from those developing normally but continuing to have seizures beyond 3 years.     

Role of endogenous adenosine in recurrent generalized seizures

We induced generalized seizures by cortical injection of penicillin in anesthetized, paralyzed cats. After they had developed recurrent ictal-interictal ECoG cycling and fictive tonic-clonic motor convulsions (status epilepticus), we studied the effect of systemically administered neuropharmacological agents on the seizure cycling. Antagonists of adenosine receptors, theophylline and 8-cyclopentyltheophylline, increased the cycle period due to marked prolongation of duration of ictal discharge, often to more than 30 min. Dipyridamole, an inhibitor of adenosine reuptake, lengthened the interictal phase of the seizure with no effect on ictal duration. Antagonists of gamma-aminobutyric acid and opioid peptides had no effect on either ictal or interictal phases nor did the nonspecific neural excitant, doxapram. These findings suggest that a major mechanism of ictal-interictal cycling during status epilepticus is the alternating accumulation during the ictal phase and clearance during the interictal phase of the inhibitory neurochemical, adenosine.     

États de mal épileptiques : épidémiologie, définitions et classifications

The annual incidence of status epilepticus based on the definitions of the International League Against Epilepsy (1993) ranges from 10.3 to 41 per 100,000 inhabitant. Half of the cases of status epilepticus concern epileptic patients. In all studies, incidence is higher in epileptic patients, young children and the elderly. It is estimated that 13% of patients with status epilepticus will experience recurrence during the two first years. The three leading etiologies are low-dose antiepileptic drugs, non-acute brain lesions and acute stroke. Seizures are generalized in 9 to 33% of patients and focal in 25 to 75%. Secondary generalized seizures can be observed in 19 to 66% of patients. Mortality ranges from 7.6 to 39% and varies as a function of inclusion of postanoxic encephalopathies and difference in initial care. The definition retained and the classification adopted for status epilepticus also affect mortality estimates. Status epilepticus is defined as the existence of a prolonged seizure or a series of seizures during which the patient does not recover, or incompletely recovers, consciousness. The duration parameter used to distinguish status epilepticus from a seizure remains controversial. At the present time, there is general agreement in the literature distinguishing two definitions based on different durations according to the clinical type of status epilepticus and its potential severity: (i) a status epilepticus is defined by a seizure lasting more than 30 minutes or recurrent seizures without recovery of consciousness over a period of 30 minutes; (ii) considering its severity, tonic-clonic status epilepticus has a specific definition leading to earlier therapeutic management. This operational definition is continuous, generalized, convulsive seizure lasting more than five minutes or two or more seizures during which the patient does not return to baseline consciousness. Several types of background can be used to establish a classification for status epilepticus: clinical manifestations, prognostic and therapeutic course, epidemiological data, pathophysiological mechanisms… At the present time, the classifications most commonly used in France for status epilepticus are derived from the syndromic epileptic classification, the seizure classification or the classification proposed by the French consensus workshop on status epilepticus. For routine clinical practice, an operational classification can be used to adopt therapeutic strategies adapted to probable prognosis: short-term life-threatening, mid-term life-threatening, not life-threatening.     

Self-sustaining limbic status epilepticus induced by 'continuous' hippocampal stimulation: electrographic and behavioral characteristics

A model of status epilepticus centered in the limbic system and elicited by 'continuous' focal electrical stimulation of the hippocampus is presented. Under appropriate conditions, the status epilepticus persisted for many hours after discontinuing the electrical stimulus. The critical determinant for the establishment of this self-sustaining limbic status epilepticus (SSLSE) was the length of stimulation, rather than the side (left vs. right) of stimulation or kindling before stimulation. Observations, obtained from stimulus-free intervals spaced regularly during the stimulus protocol and from the period after stimulation had been completed, revealed a distinct and stereotyped electrographic progression of SSLSE though several stages. Brief monitoring periods throughout the stimulus protocol yielded electrographic criteria that predicted which animals would experience experience SSLSE. The presence of synchronous, stimulus-independent seizure activity bilaterally in the hippocampi during stimulation was necessary to establish SSLSE. Intense motor seizure activity, like that seen with kindled motor seizures, occurred intermittently during SSLSE. However, 'limbic' behavioral seizures identical to those seen after low doses of kainic acid or during the early stages of kindling were nearly continuous. These studies indicate that there is a predictable course to limbic status epilepticus and point to the hippocampus as a key element involved in initiating and maintaining this syndrome.     

Symptomatology of Epileptic Seizures in the First Three Years of Life

PURPOSE: Few data are available concerning symptomatology of epileptic seizures in infants. METHODS: We reviewed 296 videotaped seizures from 76 patients aged 1-35 months (mean, 15.1 months) who underwent video-EEG monitoring at our institution from 1988 to 1998. Seizure symptomatology was first classified based on observable behavioral and motor manifestations and then correlated with ictal EEG. RESULTS: Four seizure types accounted for 81% of all seizures seen in this group: epileptic spasms (24%), clonic seizures (20%), tonic seizures (17%), and hypomotor seizures (20%; characterized by arrest or significant decrease of behavioral motor activity with indeterminate level of consciousness). The remaining seizures included small numbers of myoclonic, atonic, and versive seizures. All 12 focal motor seizures and all five versive seizures were associated with focal EEG seizure patterns, seen in the contralateral hemisphere in all but one patient with versive seizures. Generalized motor seizures (clinically generalized at onset) were accompanied either by focal (19 of 51; 37%) or generalized (32 of 51; 63%) EEG seizures. Hypomotor seizures also were associated with focal (14 of 20; 70%) or generalized (six of 20; 30%) EEG seizures. Four patients with generalized epileptic spasms had generalized EEG seizures in the setting of focal epilepsy based on neuroimaging, interictal EEG, and in two cases also on postresection seizure freedom. Seizure types not seen in this age group included auras, seizures with prominent automatisms (except in one case), and classic generalized tonic-clonic seizures. CONCLUSIONS: The repertoire of seizure manifestation in the first 3 years of life appears to be limited. In infants, focal motor seizures are reliably associated with focal EEG seizures in the contralateral hemisphere, whereas generalized motor and hypomotor clinical seizures may be either focal or generalized on EEG. Epileptic spasms may be seen in focal as well as generalized epilepsies. Video-EEG monitoring and neuroimaging may be critical for clarifying the focal or generalized nature of the epilepsy in infants.     

Kainic acid seizures in the developing brain: status epilepticus and spontaneous recurrent seizures.

Acute and chronic effects of seizures induced by intraperitoneal (i.p.) injection of kainic acid (KA) were studied in developing rats (postnatal days (P) 5, 10, 20, 30, and adult 60). For 3 months following KA-induced status epilepticus, spontaneous recurrent seizure (SRS) occurrence was quantified using intermittent video monitoring. Latency to generalized seizures was then tested using flurothyl, and brains were histologically analyzed for CA3 lesions. In P5-10 rats, KA caused generalized tonic-clonic ('swimming') seizures. SRS did not develop, and there was no significant difference between control and KA-treated rats in latency to flurothyl-induced seizures. In contrast, rats P20 and older exhibited limbic automatisms followed by limbic motor seizures which secondarily generalized. Incidence and frequency of SRS increased with age. P20-30 rats with SRS had shorter latencies to flurothyl seizures than did KA-treated P20-30 rats without SRS or controls. KA-treated P60 rats (with or without SRS) had shorter latencies than controls to flurothyl seizure onset. SRS in P60 rats occurred sooner after KA than in P20-30 rats. CA3 lesions were seen in P20-60 rats with and without SRS, but not in P5-10 rats. These data suggest that there are developmental differences in both acute and chronic responses to KA, with immature animals relatively protected from the long-term deleterious effects of this convulsant.     

Antiepileptic drugs combined with high‐frequency electrical stimulation in the ventral hippocampus modify pilocarpine‐induced status epilepticus in rats

Purpose: To evaluate the effects of high‐frequency electrical stimulation (HFS) in both ventral hippocampi, alone and combined with a subeffective dose of antiepileptic drugs, during the status epilepticus (SE) induced by lithium‐pilocarpine (LP). Methods: Male Wistar rats, stereotactically implanted in both ventral hippocampi, were injected with pilocarpine (30 mg/kg, i.p.) 24 h after lithium (3 mEq/kg) administration. One minute following pilocarpine injection, HFS (pulses of 60 μs width at 130 Hz at subthreshold intensities and applied during 3 h) was applied alone or combined with subeffective doses of antiepileptic drugs. Results: HFS alone reduced the incidence of severe generalized seizures. This effect was not evident when HFS was combined with phenytoin (33.3 mg/kg, i.p.). HFS combined with diazepam (0.41 mg/kg, i.p.) or phenobarbital (10 mg/kg, i.p.) reduced the incidence of severe generalized seizures and mortality rate, and augmented the latency to first forelimb clonus, generalized seizure, and status epilepticus (SE). When combined with gabapentin (46 mg/kg, i.p.), HFS reduced the incidence of severe generalized seizures, enhanced latency to SE, and decreased mortality rate. Discussion: Subeffective doses of antiepileptic drugs that increase the γ‐aminobutyric acid (GABA)ergic neurotransmission may represent a therapeutic tool to augment the HFS‐induced anticonvulsant effects.     

Can absence status epilepticus be of frontal lobe origin?

Five women with an unclassifiable nonconvulsive status epilepticus (NCSE) characterized by young age at onset, prolonged confusions, focal motor seizures, and both generalized spike-and-wave discharges and focal epileptic discharges on the EEG were studied with video-EEG monitoring. Electrographically, the NCSE originated from the left frontal lobe in 4 patients, and the left hemisphere with multifocal seizure discharges in 1 patient. Focal motor seizures seemed to originate from the left hemisphere in all 5 patients, particularly from its anterior part in 3 of them. Results show that the NCSE is complex partial status epilepticus of frontal lobe origin electroclinically mimicking absence status epilepticus once it reaches a full-blown phase.     

New insights from the use of pilocarpine and kainate models

Local or systemic administration of pilocarpine and kainate in rodents leads to a pattern of repetitive limbic seizures and status epilepticus, which can last for several hours. A latent period follows status epilepticus and precedes a chronic phase, which is characterized by the occurrence of spontaneous limbic seizures. These distinct features, in a single animal preparation, of an acute damage induced by status epilepticus, a silent interval between injury and the onset of spontaneous seizures, and a chronic epileptic state have allowed antiepileptic drug (AED) studies with different purposes, (a) in the acute phase, identification of compounds with efficacy against refractory status epilepticus and/or neuroprotection against damage induced by sustained seizures; (b) in the latent period, identification of agents with a potential for preventing epileptogenesis and/or against seizure-induced long-term behavioral deficits and (c) in the chronic phase, testing drugs effective against partial and secondarily generalized seizures. Studies on pilocarpine and kainate models have pointed out that some AEDs or other compounds exert an antiepileptogenic effect. The analogy of the latent phase of pilocarpine and kainate models with the acquisition of amygdala kindling should encourage testing of drugs that have proved to suppress the evolution of amygdala kindling. Drug testing in the chronic phase should not address only the suppression of secondarily generalized motor seizures. Most of current tools used to quantify spontaneous seizure events need to be coupled to electrophysiology and more sophisticated systems for recording and analyzing behavior.     

Strain differences affect the induction of status epilepticus and seizure-induced morphological changes

Genetic deficits have been discovered in human epilepsy, which lead to alteration of the balance between excitation and inhibition, and ultimately result in seizures. Rodents show similar genetic determinants of seizure induction. To test whether seizure‐prone phenotypes exhibit increased seizure‐related morphological changes, we compared two standard rat strains (Long–Evans hooded and Wistar) and two specially bred strains following status epilepticus. The special strains, namely the kindling‐prone (FAST) and kindling‐resistant (SLOW) strains, were selectively bred based on their amygdala kindling rate. Although the Wistar and Long–Evans hooded strains experienced similar amounts of seizure activity, Wistar rats showed greater mossy fiber sprouting and hilar neuronal loss than Long–Evans hooded rats. The mossy fiber system was affected differently in FAST and SLOW rats. FAST animals showed more mossy fiber granules in the naïve state, but were more resistant to seizure‐induced mossy fiber sprouting than SLOW rats. These properties of the FAST strain are consistent with those observed in juvenile animals, further supporting the hypothesis that the FAST strain shares circuit properties similar to those seen in immature animals. Furthermore, the extent of mossy fiber sprouting was not well correlated with sensitivity to status epilepticus, but was positively correlated with the frequency of spontaneous recurrent seizures in the FAST rats only, suggesting a possible role for axonal sprouting in the development of spontaneous seizures in these animals. We conclude that genetic factors clearly affect seizure development and related morphological changes in both standard laboratory strains and the selectively bred seizure‐prone and seizure‐resistant strains.     

Zonisamide: Electrophysiological and Metabolic Changes in Kainic Acid-Induced Limbic Seizures in Rats

Summary: We studied the pharmacological mechanism of zonisamide (ZNS) using an electrophysiological and autoradiographical method in a limbic seizure model in rats. Limbic seizure status epilepticus was induced by a unilateral microinjection of kainic acid (KA) into the amygdala. Initially, observed seizures were limited to the side of the injected amygdala and then propagated to bilateral sensorimotor cortex. Eighty minutes after injection, secondarily generalized seizure status epilepticus was induced, with each seizure lasting ∼30 s and recurring every 5 min. ZNS 100 mg/kg was administered intravenously (i.v.) during the generalized seizure. Forty minutes after ZNS administration, epileptic activity was observed only at the KA-injected amygdalar site and spikes were not observed in the bilateral sensorimotor cortex. We studied local cerebral glucose utilization (LCGU) after ZNS or saline administration using an autoradiographical method in the same limbic seizure preparation. In the ZNS group, LCGU decreased in the ipsilateral sensorimotor cortex and hippocampus, whereas in the controls LCGU increased in these structures. On the other hand, ZNS did not suppress the epileptic activity of the primary focus and no decrease in LCGU was observed in the KA-injected amygdala. ZNS inhibited seizure propagation from the epileptogenic focus but did not suppress the epileptic activity of the focus. Our results suggest that ZNS is effective for the treatment of secondarily generalized seizure.     

Valproate and Clonazepam Comedication in Patients with Intractable Epilepsy

The efficacy and the potential risk of inducing convulsive or nonconvulsive status epilepticus with the combination of valproate (VPA) and clonazepam (CZP), with or without other anticonvulsant drugs, in 55 patients with intractable epilepsy was evaluated. The patients were treated with VPA and CZP concomitantly for from 3 to 72 months (mean 21.7 months). Trough VPA serum levels ranged from 26 to 96 micrograms/ml). Trough CZP serum levels ranged from 5 to 63 ng/ml (mean 22.6 ng/ml). The treatment seizure frequency was compared with baseline values before combination treatment. Seizure improvement was obtained in 7 of 8 patients with absence seizures, 8 of 9 patients with myoclonic seizures, 19 of 39 patients with complex partial seizures, 3 of 14 patients with primary generalized tonic-clonic seizures, 8 of 23 patients with secondarily generalized tonic-clonic seizures, and 3 of 14 patients with atonic seizures. No single case of status epilepticus or exacerbation of seizures of any type was seen.     

Nonconvulsive Status Epilepticus: High Incidence of Complex Partial Status

Nonconvulsive status epilepticus may be subdivided into generalized (absence) status and complex partial status. The latter is regarded as a rarity, whereas the former constitutes the dominant part of the hitherto reported cases. We report 10 consecutive cases of adult patients with nonconvulsive status epilepticus, all documented by ictal electroencephalographic (EEG) recordings. Five had a complex partial status; the origin of the complex partial status appeared to be frontal in four of these patients. Three had recurrent complex partial seizures with incomplete recovery between seizures, and two had more continuous symptoms. One of the latter exhibited neither motor phenomena nor automatisms. The effect of diazepam or clonazepam was immediate in all 10 cases though transient in eight. A lasting control of the status was not achieved in six patients until i.v. phenytoin was added. The difficulties in the differentiation between complex partial status and absence status despite ictal EEG recordings are discussed, illustrated by a case with seizure discharges of a focal onset which rapidly generalized. The study indicates that complex partial status may be more common and the clinical expressions of absence status more variable than hitherto recognized.     

A comparative study of absence status epilepticus between children and adults

Based on the clinicoelectrographic data of 28 patients (14 children and 14 adults) with absence status epilepticus thoroughly documented by CCTV/EEG, it was found that there were significant differences between the children and adults. In childhood, absence status tended to occur in those who had experienced individual short-lived atypical absence seizures and also other types of generalized seizure. In contrast, there was a general tendency for absence status in adulthood to occur in females without individual absence seizure. With respect to the clinicoelectrographical manifestations, absence status with a decreased postural tone was prone to be associated with a more profound clouding of consciousness, whereas in those with myoclonic components there was a less profound clouding. The former was found solely in children while the latter was both in children and in adults. During absence status, the focal motor features with or without secondarily generalized convulsions were observed in 8 adult patients (57%). On the other hand, no focal motor manifestations were observed during absence status in children. Absence status is composed of two modalities: either a prolongation or repetition of absence seizures. It was demonstrated that, in children, either the prolongation or repetition of individual absence seizures developed into absence status. The short-lived absence was of an atypical nature, whereas in adults, absence status consisted of the prolongation of an absence seizure which occurred in patients with no experience of individual absence seizures. With respect to the drug treatment, antiabsence drugs had some effect in children, while none of the adult patients responded either to the antiabsence drugs or other antiepileptic drugs. The long-term seizure prognosis was not necessarily poor in children but invariably poor in adults. Four adult patients showed diffuse, but unilateral frontally accentuated asymmetrical paroxysmal activity during the status. Three of them showed initial localized spike-wave discharges in the unilateral frontal region followed by a generalized spike-wave rhythm. Furthermore, all of these 4 patients with focally accentuated ictal EEGs have shown partial motor seizures intermingled with absence status.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sex difference in susceptibility to epileptic seizures in rats: importance of estrous cycle.

Sex difference in seizure susceptibility is one of the unresolved issues of epilepsy. It is known that estrogen is excitatory and progesterone is inhibitory to the central nervous system. Therefore, it is to be expected that seizure susceptibility may be associated with the estrous cycle, which should be tested in epilepsy research. Otherwise, different results in epilepsy studies could be an artifact of the estrous cycle. Reports in the literature are inconsistent about testosterone effects on seizures. In light of these considerations, sex differences in seizure susceptibility were restudied in rats. There was no significant sex difference in mean latencies to picrotoxin-induced seizures; prestrous-females had the shortest latencies to epileptic seizures compared to males and estrousfemales. With testosterone-injected rats, there was either no sex difference in latencies (to akinetic and focal seizures) or females had significantly shorter latencies than males (to status epilepticus, generalized tonic-clonic seizures, and myoclonic seizures). Testosterone-treated male rats had a significantly longer mean latency than controls for status epilepticus only; otherwise, these males showed no significant differences between mean latencies before and after testosterone (to focal, myoclonic, or generalized tonic-clonic seizures). In females, mean latencies to myoclonic seizures and status epilepticus were significantly shorter after testosterone than before. It was concluded that there is a sex difference in susceptibility to epileptic seizures in rats, provided that the estrous cycle is taken into account. Testosterone may increase and decrease seizure susceptibility in females and males, respectively. These effects may be important for understanding the mechanisms of epileptic phenomena and may provide some important clues to epilepsy treatment.     

Limbic seizures without brain damage after injection of low doses of kainic acid into the amygdala of freely moving rats

Kainic acid (KA, 8-15 ng) was injected into the amygdala of conscious freely moving rats via chronically implanted fused silica cannulas. At 15-25 min after the injection, most rats suffered a limbic seizure attack of short duration, consisting of mastication, forelimb clonus, and raising on hind limbs, behaviorally indistinguishable from kindled seizures. Typically, the attack was followed by stereotypies, intense exploration, and by 1 or 2 more attacks. About 60 min after the injection, most rats appeared normal again and histopathological changes in their brains did not exceed those seen in vehicle-injected rats. In 3 cases, however, recurrent seizures culminated in behavioral status epilepticus 60-90 min after the injection. The status epilepticus was stopped by i.p. injection of diazepam (10 mg/kg) after a duration of 10 min (1 case) and 30 min (2 cases), respectively. After 10 min status epilepticus, we observed marginal neuronal damage with slight gliosis in both hippocampi (CA3 and CA1); after 30 min, hippocampal histopathology was more pronounced, with additional necrosis of the ipsilateral piriform cortex. After 0.8 microgram KA, a hundredfold higher dose, the incidence of limbic seizures during the first 40 min was not significantly higher (9/12) than after the lower KA doses (13/19). However, a significantly higher proportion of rats exhibited long-lasting seizure activity, associated with confluent destruction of CA3 pyramidal cells and additional seizure-related brain damage. Our results show that limbic motor seizures do not inevitably lead to histopathological changes in the brain, provided they do not culminate in a state of permanent seizure activity.