- Email: [email protected]
Levetiracetam treatment of idiopathic generalised epilepsy
Seizure 2003; 12: 617–620
doi:10.1016/S1059-1311(03)00139-0
Levetiracetam treatment of idiopathic generalised epilepsy GREGORY L. KRAUSS † , TIM BETTS ‡ , BASSEL ABOU-KHALIL § , GREGORY BERGEY † , HELEN YARROW ‡ & AKEMI MILLER † † Department
of Neurology, Johns Hopkins University, Baltimore, MD, USA; ‡ University of Birmingham, Birmingham, UK; § Department of Neurology, Vanderbilt University, Nashville-Davidson, TN, USA
Correspondence to: Dr Gregory L. Krauss, M.D., Meyer 2-147, 600 North Wolfe Street, Baltimore, MD 21287, USA. E-mail: [email protected]
Levetiracetam (LEV) is effective for treating localisation-related epilepsy, but it is uncertain whether it is effective for treating idiopathic generalised epilepsy. We compared 12-week baseline and LEV treatment periods for patients with generalised seizure types—myoclonic, tonic–clonic and absence seizures—who had failed other anticonvulsants. The majority of 55 patients (76%) had >50% seizure reduction with LEV therapy, 40% became seizure-free; 15% discontinued LEV due to adverse events, mostly sedation. This is preliminary evidence that LEV is effective for treating idiopathic generalised epilepsy. © 2003 BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved. Key words: levetiracetam; seizures; generalised epilepsy.
INTRODUCTION
METHODS
Levetiracetam (LEV) is an effective antiepilepsy drug for treating partial-onset seizures1–3 . Since LEV is currently available to patients outside of study protocols, it is difficult to perform placebo-controlled trials for treatment of generalised epilepsy. Reliable clinical data about efficacy of new antiepileptic drugs (AEDs) for generalised epilepsy is often derived from large treatment series in which patients’ seizures are carefully classified and treatment responses are compared to standard therapies4 . Preliminary reports suggest LEV may be beneficial for treating juvenile myoclonic epilepsy (JME) in patients who failed treatment with valproic acid5, 6 . LEV also blocks photic-induced generalised spikes in patients with photosensitive epilepsy in a dose-dependent manner7 . We report results from a large treatment series at three epilepsy centres for patients with frequent idiopathic generalised seizures—absence, myoclonic and tonic–clonic seizures—who began LEV treatment after failing treatment with valproic acid and other AEDs.
Patients with idiopathic generalised epilepsy from adult epilepsy clinics at Johns Hopkins University (Baltimore, USA), Vanderbilt University (Nashville, USA) and University of Birmingham (UK) received LEV treatment between 1997 and 2001. Patients were included if they had at least one seizure (absence, myoclonic or tonic–clonic8 ) per month during a 12-week baseline period and had previously failed treatment with valproic acid or a minimum of one other AED. Treatment failure was defined as persistent seizures despite a serum level in the ‘therapeutic range’. AED doses were nevertheless increased to maximum tolerated. We did not include patients who were seizure-free on their AED, but wished to switch because of adverse effects. Patients had normal MRIs and EEGs consistent with idiopathic generalised epilepsy, e.g. generalised spike-wave or polyspike-wave discharges and normal waking background. Patients with evidence of symptomatic epilepsy were excluded: those with tonic, atonic, or atypical absence seizure types, generalised or focal slowing on EEG or brain MRI abnormalities.
1059–1311/$30.00
© 2003 BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved.
618
G. L. Krauss et al.
Seizure frequencies were determined for the 12-week periods prior to and following LEV treatment using diaries. Patients with myoclonic and absence seizures documented all the seizures they were aware of. Occasional clusters of seizures that could not be counted were documented separately. Patients were treated with LEV 500–4000 mg divided BID as add-on therapy or were converted to monotherapy. The primary study endpoints were changes in seizure frequency, seizure responder rates (>50% seizure reduction) and LEV discontinuation rate. Patients with clusters of myoclonic or absence seizures had changes in frequency of cluster episodes measured. Patient-reported adverse events were recorded. Subject demographic data, MRI and EEG results, and seizure types were collected. Patients were grouped by generalised epileptic syndromes—childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), JME and epilepsy with tonic–clonic seizures (ETC)9 . ETC included patients with tonic–clonic seizures on awakening. Patients with unclear generalised syndromes were grouped separately.
The remaining patients had multiple seizure types. A total of 26 patients (47%) were diagnosed with JME; 18 patients (33%) had ETC; 11 (20%) had CAE or JAE. One JME-classified patient experienced only tonic–clonic seizures during baseline and treatment periods. Seven excluded patients had minor features of symptomatic epilepsy (low normal intelligence) or seizure patterns that were difficult to classify syndromically10 ; their treatment responses were assessed separately.
Previous and current AED treatment Forty patients (72.7%) previously failed treatment with VPA. A total of 29 patients (53%) previously failed treatment with three or more AEDs. Failed previous medications (in order of frequency) were valproic acid, carbamazepine, phenytoin, lamotrigine and gabapentin. A majority of patients (73%) were treated with up to two concomitant AEDs. The remaining patients were treated with three concomitant AEDs (including benzodiazepines).
RESULTS Seizure response
Subjects Demographic and EEG data for included patients (N = 55) are summarised in Table 1. Seizure types and epilepsy syndromes A total of 28 patients (51%) experienced only one seizure type during baseline and treatment periods.
Mean seizure frequencies and treatment responses are given in Table 2. Mean baseline monthly seizure frequencies varied considerably between the three seizure types: absence seizures 32.7 ± 62.7 SD, tonic–clonic 0.9 ± 1.3 SD and myoclonic seizures 24.7 ± 22.9 SD. Mean frequencies decreased for all seizure types during treatment with LEV: myoclonic seizures 84.6%, tonic–clonic seizures 62.5% and absence seizures 33.6%.
Table 1: Subject data. Patient total Gender, M/F Age, years, mean (range) Age at seizure onset, years, mean (range) EEG results Generalised spike-and-wave (SW) Generalised polyspike-and-wave (PSW) Generalised SW and PSW Normal
55 21/34 30.2 (16–67) 11.7 (1–47) 38 2 7 8
Response by generalised epilepsy syndromes Table 3 summarises results by epilepsy syndromes. Patients with JME had the highest responder rates to LEV (>50% seizure reduction)—88%, followed by patients with ETC—78%, and patients with absence epilepsy—46%. Overall, 42 patients (76.4%) experienced a 50% or greater decrease in the num-
Table 2: Monthly seizure frequency and response classified by seizure type. Seizure type
N
Baseline (mean ± SD)
LEV treatment (mean ± SD)
Percent reduction
Tonic–clonic Myoclonic Absence
43 21 22
2.4 ± 2.2 24.7 ± 22.9 32.7 ± 62.7
0.9 ± 1.3 3.8 ± 9.0 21.7 ± 63.0
62.5 84.6 33.6
Overall
55
24.4 ± 46.0
10.8 ± 41.2
55.7
Many patients had multiple seizure types.
Levetiracetam treatment of idiopathic generalised epilepsy
619
Table 3: Levetiracetam response by epilepsy syndrome. Syndrome
Number of patients
Discontinued due to SE
Responders (>50% seizure reduction)
Seizure free
JME ETC CAE or JAE
26 18 11
4 (15.3%) 1 (5.6%) 3 (27.3%)
23 (88.4%) 14 (77.8%) 5 (45.5%)
12 (46.2%) 7 (38.9%) 3 (27.3%)
Overall
55
8 (14.5%)
42 (76.4%)
22 (40%)
ber of seizures during LEV treatment, including 5 who were converted to LEV monotherapy. A total of 22 patients (40%) became seizure-free during treatment with LEV: 12 (46.2%) patients with JME, 7 (38.9%) patients with ETC and 3 (27.3%) patients with CAE/JAE.
LEV tolerability Patients tolerated LEV well—21 patients (38%) reported adverse events, none serious. Eight (15%) patients did not tolerate LEV and discontinued treatment. Adverse events reported by >5% of patients were (in order of frequency): sedation, nausea and irritability.
DISCUSSION Patients with idiopathic generalised seizures had marked seizure reduction with LEV treatment. A large number of patients (40%) became seizure-free or responded to LEV (76.4%) after previously failing treatment with valproic acid and other anticonvulsants. This is preliminary evidence that LEV is beneficial for treating generalised epilepsy. The responder rates, however, must be viewed cautiously. This is an uncontrolled treatment series and placebo-effects, lifestyle changes such as avoidance of sleep deprivation and other treatment factors might have reduced the frequency of generalised seizures. Some patients with absence epilepsy did not respond to LEV and one had his first tonic–clonic seizure during LEV treatment. Most patients with absence epilepsy with persisting seizures in adulthood, however, have tonic–clonic seizures. Drug-resistant absence epilepsy is an unusual syndrome and may not be representative of patients with more typical childhood and JAE syndromes. A small group of patients had mild cognitive impairment, but otherwise had features of idiopathic generalised epilepsy. These patients may represent a spectrum between symptomatic and idiopathic epilepsy4 . Nonetheless, most of these patients responded to LEV. Most patients were treated with LEV doses similar to that recommended for partial-onset epilepsy: 1000–3000 mg/day10 .
Our finding that LEV is effective for treating the generalised epilepsies is consistent with preliminary reports5–7 . There is also strong evidence from animal studies supporting a possible role for LEV for treating generalised seizures. LEV has an extremely high therapeutic index in blocking seizures in the GAERs absence seizure model11 and blocks startle-induced generalised seizures in the audiogenic mouse model of generalised epilepsy12 . The effect of LEV and structural analogues on blocking audiogenic seizures correlates with binding of the drug to a novel CNS neuronal receptor that has not been characterised13 . Patients in our series failed treatment with other AEDs used for generalised epilepsy—valproic acid, topiramate and lamotrigine—due to adverse events, poor seizure control, or a combination of both, and were therefore candidates for treatment with LEV. The long-term efficacy of LEV for treating generalised epilepsy remains to be determined. There is preliminary evidence, however, that the drug remains effective for treating JME for up to 5 years5 . Additional information is needed concerning the efficacy of LEV for treating generalised epilepsy in children and for treating severe symptomatic forms of epilepsy, such as Lennox–Gastaut Syndrome. Our preliminary findings need to be confirmed in controlled studies, but provide preliminary evidence that LEV may be effective for treating the generalised epilepsies in addition to partial-onset epilepsy.
REFERENCES 1. Betts, T., Waegemans, T. and Crawford, P. A multi-centre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure 2000; 9 (2): 80–87. 2. Cereghino, J. J., Biton, V., Abou-Khalil, B., Dreifuss, F., Gauer, L. J. and Leppik, I. Levetiracetam for partial seizures: results of a double-blind randomized clinical trial. Neurology 2000; 55 (2): 236–242. 3. Shorvon, S. D., Lowenthal, A., Janz, D., Bielen, E. and Loiseau, P. Multicenter double-blind, randomized, placebocontrolled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia 2000; 41 (9): 1179–1186. 4. Andermann, F. and Berkovic, S. F. Idiopathic generalized epilepsy with generalized and other seizures in adolescence. Epilepsia 2001; 42 (3): 317–320.
620 5. Greenhill, L., Betts, T. and Yarrow, H. Effect of levetiracetam on resistant juvenile myoclonic epilepsy. Seizure 2002; 11: 531. 6. Krauss, G. L., Abou-Khalil, B., Sheth, S. G. et al. Efficacy of levetiracetam for treatment of drug-resistant generalized epilepsy. Epilepsia 2001; 42 (Suppl. 7): 181. 7. Kasteleijn-Nolst Trenite, D. G., Marescaux, C., Stodieck, S., Edelbroek, P. M. and Oosting, J. Photosensitive epilepsy: a model to study the effects of antiepileptic drugs. Evaluation of the piracetam analogue, levetiracetam. Epilepsy Research 1996; 25 (3): 225–230. 8. Commission on the Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981; 22: 489–501. 9. Commission on the Classification and Terminology of the International League Against Epilepsy. Proposal for revised
G. L. Krauss et al.
10. 11.
12.
13.
classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30: 389–399. Levetiracetam Product Insert, UCB Pharma, Smyrna, GA. Gower, A. J., Hirsch, E., Boehrer, A., Noyer, M. and Marescaux, C. Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy. Epilepsy Research 1995; 22 (3): 207–213. Rigo, J. M., Hans, G., Nguyen, L. et al. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. British Journal of Pharmacology 2002; 136 (5): 659– 672. Klitgaard, H., Matagne, A., Gobert, J. and Wulfert, E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. European Journal of Pharmacology 1998; 353 (2/3): 191–206.
doi:10.1016/S1059-1311(03)00139-0
Levetiracetam treatment of idiopathic generalised epilepsy GREGORY L. KRAUSS † , TIM BETTS ‡ , BASSEL ABOU-KHALIL § , GREGORY BERGEY † , HELEN YARROW ‡ & AKEMI MILLER † † Department
of Neurology, Johns Hopkins University, Baltimore, MD, USA; ‡ University of Birmingham, Birmingham, UK; § Department of Neurology, Vanderbilt University, Nashville-Davidson, TN, USA
Correspondence to: Dr Gregory L. Krauss, M.D., Meyer 2-147, 600 North Wolfe Street, Baltimore, MD 21287, USA. E-mail: [email protected]
Levetiracetam (LEV) is effective for treating localisation-related epilepsy, but it is uncertain whether it is effective for treating idiopathic generalised epilepsy. We compared 12-week baseline and LEV treatment periods for patients with generalised seizure types—myoclonic, tonic–clonic and absence seizures—who had failed other anticonvulsants. The majority of 55 patients (76%) had >50% seizure reduction with LEV therapy, 40% became seizure-free; 15% discontinued LEV due to adverse events, mostly sedation. This is preliminary evidence that LEV is effective for treating idiopathic generalised epilepsy. © 2003 BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved. Key words: levetiracetam; seizures; generalised epilepsy.
INTRODUCTION
METHODS
Levetiracetam (LEV) is an effective antiepilepsy drug for treating partial-onset seizures1–3 . Since LEV is currently available to patients outside of study protocols, it is difficult to perform placebo-controlled trials for treatment of generalised epilepsy. Reliable clinical data about efficacy of new antiepileptic drugs (AEDs) for generalised epilepsy is often derived from large treatment series in which patients’ seizures are carefully classified and treatment responses are compared to standard therapies4 . Preliminary reports suggest LEV may be beneficial for treating juvenile myoclonic epilepsy (JME) in patients who failed treatment with valproic acid5, 6 . LEV also blocks photic-induced generalised spikes in patients with photosensitive epilepsy in a dose-dependent manner7 . We report results from a large treatment series at three epilepsy centres for patients with frequent idiopathic generalised seizures—absence, myoclonic and tonic–clonic seizures—who began LEV treatment after failing treatment with valproic acid and other AEDs.
Patients with idiopathic generalised epilepsy from adult epilepsy clinics at Johns Hopkins University (Baltimore, USA), Vanderbilt University (Nashville, USA) and University of Birmingham (UK) received LEV treatment between 1997 and 2001. Patients were included if they had at least one seizure (absence, myoclonic or tonic–clonic8 ) per month during a 12-week baseline period and had previously failed treatment with valproic acid or a minimum of one other AED. Treatment failure was defined as persistent seizures despite a serum level in the ‘therapeutic range’. AED doses were nevertheless increased to maximum tolerated. We did not include patients who were seizure-free on their AED, but wished to switch because of adverse effects. Patients had normal MRIs and EEGs consistent with idiopathic generalised epilepsy, e.g. generalised spike-wave or polyspike-wave discharges and normal waking background. Patients with evidence of symptomatic epilepsy were excluded: those with tonic, atonic, or atypical absence seizure types, generalised or focal slowing on EEG or brain MRI abnormalities.
1059–1311/$30.00
© 2003 BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved.
618
G. L. Krauss et al.
Seizure frequencies were determined for the 12-week periods prior to and following LEV treatment using diaries. Patients with myoclonic and absence seizures documented all the seizures they were aware of. Occasional clusters of seizures that could not be counted were documented separately. Patients were treated with LEV 500–4000 mg divided BID as add-on therapy or were converted to monotherapy. The primary study endpoints were changes in seizure frequency, seizure responder rates (>50% seizure reduction) and LEV discontinuation rate. Patients with clusters of myoclonic or absence seizures had changes in frequency of cluster episodes measured. Patient-reported adverse events were recorded. Subject demographic data, MRI and EEG results, and seizure types were collected. Patients were grouped by generalised epileptic syndromes—childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), JME and epilepsy with tonic–clonic seizures (ETC)9 . ETC included patients with tonic–clonic seizures on awakening. Patients with unclear generalised syndromes were grouped separately.
The remaining patients had multiple seizure types. A total of 26 patients (47%) were diagnosed with JME; 18 patients (33%) had ETC; 11 (20%) had CAE or JAE. One JME-classified patient experienced only tonic–clonic seizures during baseline and treatment periods. Seven excluded patients had minor features of symptomatic epilepsy (low normal intelligence) or seizure patterns that were difficult to classify syndromically10 ; their treatment responses were assessed separately.
Previous and current AED treatment Forty patients (72.7%) previously failed treatment with VPA. A total of 29 patients (53%) previously failed treatment with three or more AEDs. Failed previous medications (in order of frequency) were valproic acid, carbamazepine, phenytoin, lamotrigine and gabapentin. A majority of patients (73%) were treated with up to two concomitant AEDs. The remaining patients were treated with three concomitant AEDs (including benzodiazepines).
RESULTS Seizure response
Subjects Demographic and EEG data for included patients (N = 55) are summarised in Table 1. Seizure types and epilepsy syndromes A total of 28 patients (51%) experienced only one seizure type during baseline and treatment periods.
Mean seizure frequencies and treatment responses are given in Table 2. Mean baseline monthly seizure frequencies varied considerably between the three seizure types: absence seizures 32.7 ± 62.7 SD, tonic–clonic 0.9 ± 1.3 SD and myoclonic seizures 24.7 ± 22.9 SD. Mean frequencies decreased for all seizure types during treatment with LEV: myoclonic seizures 84.6%, tonic–clonic seizures 62.5% and absence seizures 33.6%.
Table 1: Subject data. Patient total Gender, M/F Age, years, mean (range) Age at seizure onset, years, mean (range) EEG results Generalised spike-and-wave (SW) Generalised polyspike-and-wave (PSW) Generalised SW and PSW Normal
55 21/34 30.2 (16–67) 11.7 (1–47) 38 2 7 8
Response by generalised epilepsy syndromes Table 3 summarises results by epilepsy syndromes. Patients with JME had the highest responder rates to LEV (>50% seizure reduction)—88%, followed by patients with ETC—78%, and patients with absence epilepsy—46%. Overall, 42 patients (76.4%) experienced a 50% or greater decrease in the num-
Table 2: Monthly seizure frequency and response classified by seizure type. Seizure type
N
Baseline (mean ± SD)
LEV treatment (mean ± SD)
Percent reduction
Tonic–clonic Myoclonic Absence
43 21 22
2.4 ± 2.2 24.7 ± 22.9 32.7 ± 62.7
0.9 ± 1.3 3.8 ± 9.0 21.7 ± 63.0
62.5 84.6 33.6
Overall
55
24.4 ± 46.0
10.8 ± 41.2
55.7
Many patients had multiple seizure types.
Levetiracetam treatment of idiopathic generalised epilepsy
619
Table 3: Levetiracetam response by epilepsy syndrome. Syndrome
Number of patients
Discontinued due to SE
Responders (>50% seizure reduction)
Seizure free
JME ETC CAE or JAE
26 18 11
4 (15.3%) 1 (5.6%) 3 (27.3%)
23 (88.4%) 14 (77.8%) 5 (45.5%)
12 (46.2%) 7 (38.9%) 3 (27.3%)
Overall
55
8 (14.5%)
42 (76.4%)
22 (40%)
ber of seizures during LEV treatment, including 5 who were converted to LEV monotherapy. A total of 22 patients (40%) became seizure-free during treatment with LEV: 12 (46.2%) patients with JME, 7 (38.9%) patients with ETC and 3 (27.3%) patients with CAE/JAE.
LEV tolerability Patients tolerated LEV well—21 patients (38%) reported adverse events, none serious. Eight (15%) patients did not tolerate LEV and discontinued treatment. Adverse events reported by >5% of patients were (in order of frequency): sedation, nausea and irritability.
DISCUSSION Patients with idiopathic generalised seizures had marked seizure reduction with LEV treatment. A large number of patients (40%) became seizure-free or responded to LEV (76.4%) after previously failing treatment with valproic acid and other anticonvulsants. This is preliminary evidence that LEV is beneficial for treating generalised epilepsy. The responder rates, however, must be viewed cautiously. This is an uncontrolled treatment series and placebo-effects, lifestyle changes such as avoidance of sleep deprivation and other treatment factors might have reduced the frequency of generalised seizures. Some patients with absence epilepsy did not respond to LEV and one had his first tonic–clonic seizure during LEV treatment. Most patients with absence epilepsy with persisting seizures in adulthood, however, have tonic–clonic seizures. Drug-resistant absence epilepsy is an unusual syndrome and may not be representative of patients with more typical childhood and JAE syndromes. A small group of patients had mild cognitive impairment, but otherwise had features of idiopathic generalised epilepsy. These patients may represent a spectrum between symptomatic and idiopathic epilepsy4 . Nonetheless, most of these patients responded to LEV. Most patients were treated with LEV doses similar to that recommended for partial-onset epilepsy: 1000–3000 mg/day10 .
Our finding that LEV is effective for treating the generalised epilepsies is consistent with preliminary reports5–7 . There is also strong evidence from animal studies supporting a possible role for LEV for treating generalised seizures. LEV has an extremely high therapeutic index in blocking seizures in the GAERs absence seizure model11 and blocks startle-induced generalised seizures in the audiogenic mouse model of generalised epilepsy12 . The effect of LEV and structural analogues on blocking audiogenic seizures correlates with binding of the drug to a novel CNS neuronal receptor that has not been characterised13 . Patients in our series failed treatment with other AEDs used for generalised epilepsy—valproic acid, topiramate and lamotrigine—due to adverse events, poor seizure control, or a combination of both, and were therefore candidates for treatment with LEV. The long-term efficacy of LEV for treating generalised epilepsy remains to be determined. There is preliminary evidence, however, that the drug remains effective for treating JME for up to 5 years5 . Additional information is needed concerning the efficacy of LEV for treating generalised epilepsy in children and for treating severe symptomatic forms of epilepsy, such as Lennox–Gastaut Syndrome. Our preliminary findings need to be confirmed in controlled studies, but provide preliminary evidence that LEV may be effective for treating the generalised epilepsies in addition to partial-onset epilepsy.
REFERENCES 1. Betts, T., Waegemans, T. and Crawford, P. A multi-centre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure 2000; 9 (2): 80–87. 2. Cereghino, J. J., Biton, V., Abou-Khalil, B., Dreifuss, F., Gauer, L. J. and Leppik, I. Levetiracetam for partial seizures: results of a double-blind randomized clinical trial. Neurology 2000; 55 (2): 236–242. 3. Shorvon, S. D., Lowenthal, A., Janz, D., Bielen, E. and Loiseau, P. Multicenter double-blind, randomized, placebocontrolled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia 2000; 41 (9): 1179–1186. 4. Andermann, F. and Berkovic, S. F. Idiopathic generalized epilepsy with generalized and other seizures in adolescence. Epilepsia 2001; 42 (3): 317–320.
620 5. Greenhill, L., Betts, T. and Yarrow, H. Effect of levetiracetam on resistant juvenile myoclonic epilepsy. Seizure 2002; 11: 531. 6. Krauss, G. L., Abou-Khalil, B., Sheth, S. G. et al. Efficacy of levetiracetam for treatment of drug-resistant generalized epilepsy. Epilepsia 2001; 42 (Suppl. 7): 181. 7. Kasteleijn-Nolst Trenite, D. G., Marescaux, C., Stodieck, S., Edelbroek, P. M. and Oosting, J. Photosensitive epilepsy: a model to study the effects of antiepileptic drugs. Evaluation of the piracetam analogue, levetiracetam. Epilepsy Research 1996; 25 (3): 225–230. 8. Commission on the Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981; 22: 489–501. 9. Commission on the Classification and Terminology of the International League Against Epilepsy. Proposal for revised
G. L. Krauss et al.
10. 11.
12.
13.
classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30: 389–399. Levetiracetam Product Insert, UCB Pharma, Smyrna, GA. Gower, A. J., Hirsch, E., Boehrer, A., Noyer, M. and Marescaux, C. Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy. Epilepsy Research 1995; 22 (3): 207–213. Rigo, J. M., Hans, G., Nguyen, L. et al. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. British Journal of Pharmacology 2002; 136 (5): 659– 672. Klitgaard, H., Matagne, A., Gobert, J. and Wulfert, E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. European Journal of Pharmacology 1998; 353 (2/3): 191–206.