Prenatal morphine exposure induces age-related changes in seizure susceptibility in male rats

The purpose of this study was to investigate the effects of prenatal exposure to morphine (5-10 mg/kg on days 11-18 of gestation) on flurothyl seizure susceptibility in adult and developing male rats. In adult rats, prenatal morphine exposure increased the threshold to clonic seizures but not to tonic-clonic seizures. The effects of prenatal morphine exposure on clonic seizures were age dependent. At postnatal day (PND) 15, prenatal drug exposure did not alter the seizure threshold. At PND 25, there was a reduction in the threshold but by PND 38, the clonic seizure threshold was increased and this increase persisted into adulthood. Prenatal exposure to morphine did not alter the tonic-clonic seizure threshold in any age group of intact male rats. A group of male rats prenatally exposed to morphine was gonadectomized in adulthood. In gonadectomized rats both clonic and tonic-clonic thresholds were increased. These results suggest that exposure to morphine during mid to late gestation induces age-dependent alterations in the susceptibility to clonic but not tonic-clonic seizures. In adult male rats the threshold to tonic-clonic seizures is influenced by prior gonadectomy in adulthood.     

Magnesium sulfate versus phenytoin for seizure prevention in amygdala-kindled rats

OBJECTIVE: Magnesium sulfate is widely used for seizure prophylaxis in preeclampsia-eclampsia. However, its anticonvulsant effects in other types of seizures have not been proved. Diphenylhydantoin has been widely characterized as the "gold standard" of anticonvulsants. In this study we compared the anticonvulsant effects of therapeutic blood levels of magnesium sulfate and phenytoin in seizures generated in amygdala-kindled rats. STUDY DESIGN: Eighteen male rats had a bipolar electrode stereotaxically implanted into the central nucleus of the amygdala. After recovery an electrical seizure threshold was determined for each rat. Rats were stimulated twice daily at their seizure thresholds (i.e., kindling) until three consecutive generalized tonic-clonic seizures occurred. Kindled rats randomly received one of the following intravenous injections in a volume of 1.5 ml/kg: saline solution, magnesium sulfate (30, 60, or 90 mg/kg), or phenytoin (12.5, 25, or 50 mg/kg). Fifteen minutes after injection rats were stimulated at their seizure thresholds, and electrical and behavioral seizure activity was assessed. Statistical comparisons were made by analysis of variance and post hoc comparisons when appropriate. RESULTS: Magnesium sulfate had no effect on any of the seizure parameters assessed. Phenytoin significantly reduced seizure duration (p < 0.01), duration of postictal depression (p < 0.01), and behavioral seizure stage (p < 0.01). CONCLUSION: Amygdala-kindled seizures are more potently inhibited by phenytoin than by magnesium sulfate.     

Health-related quality of life assessment in euthymic and depressed patients with bipolar disorder. Psychometric performance of four self-report measures

The aim of this study was to determine the interaction potential of the new antiepileptic drug felbamate (2-phenyl-1,3-propanediol dicarbamate) with three Ca2+ channel blockers (nicardipine, nifedipine, and flunarizine), one Ca2+ channel activator (Bay K 8644; 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridi ne carboxylic acid), and two methylxanthines (caffeine and aminophylline (theophylline2 . ethylenediamine)) which are all known to markedly change protective effects of conventional antiepileptic drugs. To do so, the maximal electroshock seizure test in mice (an experimental model predicting drug efficacy in the treatment of human generalized tonic-clonic seizures) was employed to (1) quantify changes in the protective efficacy and potency of felbamate produced by adjunct drugs and (2) assess the ability of aminophylline and caffeine to affect protective efficacy afforded by a submaximal protective dose of felbamate against maximal electroshock-induced seizures. Doses of adjunct drugs were selected based on their effects on the threshold for electroconvulsions and on appropriate literature. Nicardipine (10-30 mg/kg), nifedipine (5-20 mg/kg), flunarizine (2.5-10 mg/kg), Bay K 8644 (2.5-5 mg/kg), and aminophylline (50-75 mg/kg) did not change the protective efficacy and potency of felbamate against maximal electroshock-induced tonic convulsions. Aminophylline in the dose of 100 mg/kg, however, diminished the protective potency of felbamate as evidenced by a statistically significant increase in the protective ED50 value of felbamate (a dose, in mg/kg, predicted to protect 50% of mice against convulsive stimulus) from 79.6 to 118 mg/kg; P < 0.05). Aminophylline and caffeine only at high doses (100 and 161.7 mg/kg, respectively) significantly diminished the protective efficacy of felbamate (110 mg/kg) from 96% to 27% and 40% (P < 0.05), respectively. In conclusion, felbamate shows low interaction potential with Ca2+ channel modulators and methylxanthines. Such low interaction potential clearly differentiates felbamate from conventional antiepileptic drugs where protective effects are readily altered by the compounds tested in the present study.     

Rhabdomyolysis in transplant patients

In a retrospective analysis of all our patients with seizure onset prior to age 16 years, 25 patients with primary generalized tonic (n = 10) or tonic-clonic (n = 15) seizures were identified. These patients constituted 5.7% of the total seizure patient population in our institute between the ages of 1 month and 16 years. The natural history of generalized tonic-clonic seizures is known to be benign; however, that of isolated primary generalized tonic seizures is not clear. Therefore, an attempt was made to characterize the patients suffering from primary generalized tonic seizures and determine their outcome. Analysis of our patient population shows that both seizure types are characterized by early onset of generalized seizures that appear in normally developed children with a normal electroencephalographic background. The children usually respond quickly to antiepileptic drugs. A long-term follow-up (mean period of 7.6 years) was possible in 84% of the patients, and showed that 95% of them were seizure free at the end of the follow-up period. There was no significant difference between the two groups in regard to age of onset, family history, and seizures at follow-up. In conclusion, the natural history of patients with generalized tonic seizures is similar to the benign course of those with generalized tonic-clonic seizures.     

Anticonvulsant activity of felbamate in amygdala kindling model of temporal lobe epilepsy in rats

PURPOSE: Previous studies have demonstrated that felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate) at nontoxic doses exerts potent anticonvulsant activity in a variety of animal epilepsy or seizure models. We further characterized the anticonvulsant activity of FBM by using the kindling model of temporal lobe epilepsy (TLE). METHODS: The experiments were performed in fully kindled rats. The anticonvulsant effect of FBM was assessed by determining seizure severity, afterdischarge (AD) duration and seizure duration either at the focal seizure threshold, or after suprathreshold stimulation. In addition, the neurological performance of kindled rats after FBM administration was evaluated in the open field and by the rotorod test. RESULTS: FBM at doses of 12.5-50 mg/kg, given intraperitoneally (i.p.) 60 min before testing, dose-dependently increased the AD threshold (ADT). The maximal effect was achieved after the highest dose tested and reached almost 600% of the control ADT. This dose of FBM significantly diminished other seizure parameters, e.g., seizure severity, seizure duration, and AD duration. When the rats were stimulated with suprathreshold current (500 microA) seizure severity was moderately but significantly reduced. No behavioral abnormalities were noted in kindled rats after administration of either of the doses. CONCLUSIONS: FBM potently increases the threshold for focal seizures and reduces seizure severity, seizure duration, and AD duration at doses that produce no adverse behavioral effects in amygdala-kindled rats. These data are thus compatible with clinical experience with FBM in TLE and substantiate that kindling is a good predictor of anticonvulsant activity against TLE.     

Platelet glycoprotein Ia* is the processed form of multimerin--isolation and determination of N-terminal sequences of stored and released forms

The authors report on a patient who exhibited intractable epilepsy due to an inaccessible hypothalamic hamartoma and subsequently underwent stereotactic radiosurgery. This 25-year-old man had a 24-year history of intractable gelastic and tonic-clonic seizures. Magnetic resonance (MR) imaging performed at examination as well as that performed 30 months earlier demonstrated a nonenhancing and nonprogressive spherical mass, approximately 10 mm in diameter, located on the patient's right side at the floor of the third ventricle. Focal radiation treatment performed with a gamma knife unit administered 36 Gy to the center and 18 Gy to the periphery of the lesion. This treatment resulted in an improvement in seizure control. Before the patient underwent radiosurgery, he suffered from three to six generalized seizures per month in spite of attentive compliance with an anticonvulsant medication regimen. After irradiation of the harmatoma, the frequency of the seizures transiently increased and then subsided 3 months posttreatment. The patient has been free of seizures for the last 21 months, with no neurological or endocrinological complications. Magnetic resonance imaging performed 12 months posttreatment demonstrated complete disappearance of the lesion.     

Dynorphin and epilepsy

Studies on dynorphin involvement in epilepsy are summarised in this review. Electrophysiological, biochemical and pharmacological data support the hypothesis that dynorphin is implicated in specific types of seizures. There is clear evidence that this is true for complex partial (limbic) seizures, i.e. those characteristic of temporal lobe epilepsy, because; (1) dynorphin is highly expressed in various parts of the limbic system, and particularly in the granule cells of the hippocampus; (2) dynorphin appears to be released in the hippocampus (and in other brain areas) during complex partial seizures; (3) released dynorphin inhibits excitatory neurotransmission at multiple synapses in the hippocampus via activation of kappa opioid receptors; (4) kappa opioid receptor agonists are highly effective against limbic seizures. Data on generalised tonic-clonic seizures are less straightforward. Dynorphin release appears to occur after ECS seizures and kappa agonists exert a clear anticonvulsant effect in this model. However, more uncertain biochemical data and lack of efficacy of kappa agonists in other generalised tonic-clonic seizure models argue that the involvement of dynorphin in this seizure type may not be paramount. Finally, an involvement of dynorphin in generalised absence seizures appears unlikely on the basis of available data. This may not be surprising, given the presumed origin of absence seizures in alterations of the thalamo-cortical circuit and the low representation of dynorphin in the thalamus. In conclusion, it may be suggested that dynorphin plays a role as an endogenous anticonvulsant in complex partial seizures and in some cases of tonic-clonic seizures, but most likely not in generalised absence. This pattern of effects may coincide with the antiseizure spectrum of selective kappa agonists.     

Felbamate-associated fatal acute hepatic necrosis

Thirty-six cases of hepatic toxicity associated with felbamate therapy have been collected by the Food and Drug Administration. Five patients died. We describe a case of massive acute hepatic necrosis and death within 40 days of initiation of felbamate therapy for a generalized tonic-clonic seizure disorder. We describe the clinical and histopathologic features.     

Cloning and expression of the human galanin receptor GalR2

We have previously shown that the novel anticonvulsant levetiracetam exerts potent anticonvulsant activity against both focal and secondarily generalized seizures in fully amygdala-kindled rats, i.e. , a model of temporal lobe epilepsy. We examined whether levetiracetam also exhibits antiepileptogenic activity, i.e., prevents or retards acquisition or development of amygdala-kindling in rats. Before the experiments with chronic administration of levetiracetam at different doses, we determined the pharmacokinetics of the drug after i.p. injection. Levetiracetam had a relatively short half-life (about 2-3 hr) in rats, so that any lasting effects of the drug after chronic administration were certainly not due to drug accumulation. When rats were treated with levetiracetam during kindling acquisition at daily i.p. doses of 13, 27 or 54 mg/kg, the drug dose-dependently suppressed the increase in seizure severity and duration induced by repeated amygdala stimulation. After termination of daily treatment with 54 mg/kg, duration of behavioral seizures and of afterdischarges recorded from the amygdala remained to be significantly shorter compared to vehicle controls, although amygdala stimulations were continued in the absence of drug. These data thus indicate that levetiracetam not simply masked the expression of kindled seizures through an anticonvulsant action, but exerted a true antiepileptogenic effect. Adverse effects were not observed at any dose of levetiracetam tested in kindled rats. The powerful antiepileptogenic activity of levetiracetam in the kindling model indicates that levetiracetam is not only an interesting novel drug for symptomatic treatment of epilepsy but might be suited for pharmacological prevention of this disease in patients with a high prospective risk of the development of epilepsy.     

Idiopathic epilepsy with generalized seizures in early childhood]

Idiopathic epilepsies with generalized seizures of early childhood are based on a genetic predisposition. The onset takes place between the first and fifth years of age, boys are affected more often than girls. Dependent on the clinical symptomatology you have to distinguish: myoclonic seizures; atonic-astatic seizures; myoclonic-astatic seizures; absences; tonic-clonic seizures. In more than half of the cases a combination of these seizures can be observed. The differentiation of epilepsies with generalized seizures of multifocal origin (infantile spasms, Lennox-Gastaut syndrome and Pseudo-Lennox syndrome [atypical benign epilepsy]) may be difficult but is essential. Therapy of choice is valproate, often in combination with ethosuximide (in children with minor seizures) or with kaliumbromide or phenobarbital (in children with tonic-clonic seizures). Generally the prognosis is more unfavourable if epilepsy starts in the first year of life with afebrile and febrile generalized tonic-clonic or clonic seizures, if children are suffering from longlasting states of seizures and if development is disturbed before beginning of epilepsy.     

Gabapentin--a new antiepileptic agent

Gabapentin is a new antiepileptic drug. Its mechanism of action is not clearly understood, but it seems to differ from that of other antiepileptic drugs. The favourable pharmacokinetic properties of gabapentin make it simple to use. Our preliminary clinical observations with gabapentin at the National Center for Epilepsy are presented. 58 adult patients (mean age 28.9 years), mainly with refractory partial seizures, had gabapentin added to their existing medication. The follow-up period was 6.9 months on average. Only one patient experienced a reduction in seizures of more than 50%, while 25 patients experienced a moderate reduction in seizures (10-50%). The clinical effect was most favourable in patients with secondary generalized tonic-clonic seizures. Gabapentin was well tolerated, and no clinically significant interactions were encountered. Recent observations show that the doses of gabapentin used in our study may have been too low.     

Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971-1993

A series of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives were synthesized and evaluated for anticonvulsant activity. The compounds were assayed, intraperitoneally in mice and per os in rats, against seizures induced by maximal electroshock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The compounds were prepared to determine the relationship between the 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives' structures and anticonvulsant activity. Several of these compounds showed significant anticonvulsant activity. Compounds 43 and 45 were the most active of the series against MES-induced seizures with ED50 values of 8.7 and 7.6 mg/kg, respectively. Compound 45 displayed good protection against MES-induced seizures and low toxicity in rats with an oral ED50 of 18.6 mg/kg and a protective index (PI = TD50/ED50) of < 26.9. In vitro receptor binding studies revealed that compounds 43 and 45 bind to sigma 1 receptors with nanomolar affinities.     

Anti-viral effect of interferon-alpha on bovine viral diarrhea virus

PURPOSE: Lamotrigine (LTG) is recognised as effective add-on therapy for focal epilepsies, but this is the first double-blind, placebo-controlled, crossover study in treatment-resistant generalised epilepsy. METHODS: The study consisted of 2 x 8-week treatment periods followed by a 4-week washout period. Patients received doses of either 75 or 150 mg daily, depending on their concomitant antiepileptic drugs (AEDs). Long-term continuation was offered at the end of the study with open-label LTG. RESULTS: Five centres in Australia recruited 26 patients who were having absence, myoclonic, or generalized tonic-clonic seizures or a combination of these. Twenty-two patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 350% decrease in seizures was observed for tonic-clonic seizures in 50% of cases and for absence seizures in 33% of evaluable cases. Rash was the only adverse effect causing discontinuation. Twenty-three of 26 opted for open-label LTG, with 20 still receiving LTG for a mean of 26 months. In these 20, 80% had > or =50% seizure reduction and five (25%) were seizure free. CONCLUSIONS: This study shows that LTG is effective add-on therapy in patients with refractory generalised epilepsies. Statistically significant reduction in seizures in both absence and tonic-clonic seizure types was seen even with low doses of LTG.     

Pharmacokinetics and pharmacodynamics of valproate analogues in rats. IV. Anticonvulsant action and neurotoxicity of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid

We examined the pharmacodynamics of valproate (VPA) and three structural analogues, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA) in rats. A pentylenetetrazol (PTZ) infusion seizure model was used to determine threshold convulsive doses of PTZ; the increase in PTZ threshold dose after administration of test compound was taken as an index of anticonvulsant activity. Each of the compounds investigated antagonized PTZ-induced seizures, with MCCA evidencing the highest potency. Both CCA and MCCA appeared to have an approximate twofold advantage relative to VPA in protective index (i.e., the ratio of concentrations that produce toxicity to concentrations that produce anticonvulsant effect), based on a rotorod assay of neurotoxicity. Examination of the time course of PTZ antagonism indicated that there was significant dissociation between pharmacokinetics and pharmacodynamics of VPA, with a marked delay in production of maximal anticonvulsant activity. In contrast, only a slight delay in production of maximal protection against PTZ-induced seizures was observed for MCCA, and no delay was evident for CCA. The data indicate that the dynamics of anticonvulsant action differ between these low-molecular-weight carboxylic acids despite their similar chemical structures.     

Effect of dehydration on stimulation of ADH release by heterologous renin infusions in conscious dogs

The effect of acute administration of morphine on cerebral excitability was investigated in rats with two convulsant drugs: flurothyl (hexafluorodiethyl ether) and pentylenetetrazol (PTZ). In the flurothyl study, adult male Sprague-Dawley (S-D) rats were injected subcutaneously with morphine sulfate in doses ranging from 0.5 to 256 mg/kg. At 15, 30, 60 and 120 minutes after morphine injection, flurothyl was administered by inhalation and the seizure thresholds were determined. In the PTZ study, 64 mg/kg of morphine sulfate were injected subcutaneously into both S-D and CFN (Wistar-derived) rats. Thresholds to PTZ seizures were measured after administering the convulsant either by the intraperitoneal or intravenous route. The data revealed an anticonvulsant action of morphine on both flurothyl and PTZ. Peak time for this effect on flurothyl seizures was 30 minutes after subcutaneous administration of the opiate, with the maximal anticonvulsant activity appearing at the 64-mg/kg dose. The increase in seizure threshold in S-D rats at this dose was 36% with flurothyl, 94% with intravenous PTZ and 352% with i.p. PTZ. Morphine had a less dramatic influence on raising the latter seizure threshold in the CFN than in the S-D strain. The graded dose-related anticonvulsant action is independent of the respiratory depression associated with morphine administration and appears to be a reflection of an altered central nervous system excitability produced by the narcotic in rats.     

The long-term course of spike and wave complexes in the waking EEG of chronic schizophrenics

Nineteen chronic schizophrenics (8 males and 11 females) showed at least one spike and wave complex (SpW) in their rested-awake EEGs during long-term neuroleptic treatment. The age at the first appearance of the SpW ranged from 16 to 60 years, and the duration of neuroleptic medication preceding its appearance was from 1 to 35 years. Two types of SpW waveform were discriminated; one was a diffuse high voltage isolated 3.5-4 Hz SpW complex, and the other a diffuse moderate voltage 5-6 Hz SpW burst. In EEG studies repeated over the long-term, the presence of SpW was transient in 11 cases, intermittent in 5 cases, and continuous in 3 cases. Three patients had generalized tonic-clonic clinical seizures; two of their EEGs did not show SpW until after the onset of seizures. All three responded well to adjunctive anticonvulsant therapy. The other 16 patients exhibited SpW but did not have clinical seizures with or without prophylactic use of anticonvulsants. The SpW in the EEG of chronic schizophrenics might be an indicator of predisposition for seizure, but it is not a good predictor of seizure.     

Familial temporal lobe epilepsy: a clinically heterogeneous syndrome

We describe the clinical characteristics of a group of patients with familial temporal lobe epilepsy (TLE) in 11 kindreds with 36 affected individuals identified and investigated at the Montreal Neurological Hospital. Seizure types were simple partial (n = 20), complex partial (n = 29), and rare generalized tonic-clonic. Simple and complex partial seizures were infrequent or well controlled by anticonvulsant medication in 17 of 29 patients (59%) and without optimal response to medical therapy in 12 of 29 patients (41%). Pedigree analysis suggested autosomal dominant inheritance with incomplete penetrance. The syndrome of familial TLE has heterogeneous clinical manifestations and is not always benign.     

L-deprenyl (selegiline) exerts anticonvulsant effects against different seizure types in mice

L-Deprenyl (selegiline), a selective inhibitor of monoamine oxidase type B, has recently been shown to exert anticonvulsant and antiepileptogenic effects in the kindling model of partial (focal) epilepsy. In the present study, we examined if L-deprenyl exerts anticonvulsant effects in standard rodent models of generalized seizures. In addition to anticonvulsant activity, behavioral effects induced by L-deprenyl were monitored closely. To assess the stereoselectivity of anticonvulsant and behavioral effects of deprenyl, the D-enantiomer was included in the studies. Furthermore, the antiepileptic drug phenobarbital was used for comparison. The following tests were performed in mice: 1) the threshold for tonic electroconvulsions; 2) the maximal electroshock seizure test with fixed supramaximal (suprathreshold) stimulation; 3) the threshold for myoclonic, clonic and tonic seizures in response to i.v. infusion of pentylenetetrazole (PTZ); 4) the s.c. PTZ seizure test, with a fixed dose of PTZ (80 microgram/kg) for seizure induction; 5) the rotarod and chimney tests for determination of motor impairment. Furthermore, animals were observed in cage and open field for stereotyped behavior and other behavioral abnormalities. L-Deprenyl, tested at doses of 1 to 40 microgram/kg i.p., significantly increased myoclonic and clonic PTZ thresholds and the threshold for tonic electroconvulsions, whereas D-deprenyl was either ineffective or exhibited a lower anticonvulsant potency than L-deprenyl. Both drugs were ineffective in the maximal electroshock seizure and s.c. PTZ seizure tests. In contrast to the higher anticonvulsant potency of L-deprenyl in seizure threshold tests, D-deprenyl was more potent than L-deprenyl to induce behavioral abnormalities, such as hyperlocomotion. The data indicate that L-deprenyl exerts anticonvulsant activity against different seizure types. This anticonvulsant activity and the previously reported neuroprotective and cognition-enhancing action of L-deprenyl offer a unique combination of drug effects which might be of clinical benefit in patients with epilepsy.     

A crucial role of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptors in piriform and perirhinal cortex for the initiation and propagation of limbic motor seizures

The role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in the initiation and propagation of limbic motor seizures in rats was examined by the intracerebral and systemic administration of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (f) quinoxaline (NBQX), a selective antagonist of the AMPA subtype of glutamate receptor. Limbic motor seizures were evoked focally by the application of the gamma-aminobutyric acid receptor antagonist, bicuculline, into area tempestas, an epileptogenic site in the deep anterior piriform cortex. Before eliciting seizures, NBQX was applied focally into either 1) area tempestas or 2) perirhinal or posterior piriform cortex ipsilateral to the area tempestas from which seizures were evoked. In addition, pretreatment with i.p. NBQX was evaluated for anticonvulsant actions against area tempestas-evoked clonic or systemically evoked tonic seizures. In all conditions, a dose-dependent decrease in the severity of seizures was obtained with NBQX. With focal intracerebral administration, a dose of 500 pmol of NBQX consistently protected against limbic motor seizures, with partial protection achieved with 100 pmol. After i.p. administration, 2.5 and 5.0 mg/kg significantly protected the rats from both limbic motor seizures and tonic extensor seizures. No overt disturbance of spontaneous behavior was associated with the anticonvulsant doses of NBQX. Moreover, both forebrain substrates of limbic motor seizures and hindbrain substrates of tonic extensor seizures were highly susceptible to disruption by NBQX. The results indicate that AMPA subtype of glutamate receptors are crucial mediators of seizure propagation via perirhinal and piriform cortics.     

Applied research during fieldwork: interdisciplinary collaboration between universities and clinics

The anticonvulsant effects of levetiracetam were assessed in two genetic rat models. In the audiogenic-seizure prone rat, levetiracetam, 5.4 to 96 mg/kg i.p. dose-dependently inhibited both wild running and tonic-clonic convulsions. In the GAERS model of petit mal epilepsy, levetiracetam markedly suppressed spontaneous spike-and-wave discharge (SWD) but left the underlying EEG trace normal. The effects were already marked at 5.4 mg/kg and did not increase significantly up to 170 mg/kg although more animals were completely protected. Levetiracetam produced no observable effects on behaviour apart from slight reversible sedation at 170 mg/kg. In contrast, piracetam, a structural analogue of levetiracetam, significantly and consistently suppressed SWD in GAERS rats only at the high dose of 1000 mg/kg with some slight effects at lower doses. The effect of piracetam appeared to be due to increased sleeping rather than to a direct antiepileptic effect. The results with levetiracetam argue for a clinical application in both petit mal, absence epilepsy and in treating generalised tonic-clonic and partial seizures.