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Levetiracetam monotherapy for adults with localization-related epilepsy
Epilepsy & Behavior Epilepsy & Behavior 3 (2002) 471–474 www.academicpress.com
Levetiracetam monotherapy for adults with localization-related epilepsy Taoufik M. Alsaadi,a,* Catherine Thieman,b and Edie E. Zusman a
Department of Neurology, Comprehensive Epilepsy Program, University of California, Davis, 4860 Y Street, Suite 3700, Sacramento, CA 95817, USA b Department of Neurological Surgery, Comprehensive Epilepsy Program, University of California, Davis, 4860 Y Street, Suite 3700, Sacramento, CA 95817, USA Received 18 June 2002; received in revised form 12 August 2002; accepted 13 August 2002
Abstract We identified 37 patients with a history of partial seizures, with and without secondarily generalization, who received levetiracetam (LEV) (Keppra) monotherapy. Patients began LEV either as first line therapy (n ¼ 9) or were converted to LEV monotherapy (n ¼ 28) after failing prior antiepileptic medications (AEDs). Thirty-four patients continued on LEV for at least six months; of these, 13 patients became seizure free and 15 patients had >50% reduction in their seizures. Three patients discontinued LEV because of adverse effects. LEV monotherapy can be effective and well tolerated in adults with new onset and difficult-to-control partial epilepsy. A prospective, large, double blind monotherapy study is needed to confirm this finding. Ó 2002 Elsevier Science (USA). All rights reserved. Keywords: Partial seizures; Monotherapy; Levetiracetam
1. Introduction Levetiracetam is a novel antiepileptic drug (AED) that has been approved as adjunctive treatment for adults with partial onset seizures. Its effectiveness was established in three multicenter, well-controlled pivotal trials [1–3]. In addition, LEV is well tolerated with a favorable pharmacokinetic profile that includes minimal protein binding, lack of hepatic metabolism, and twice a day dosing [4]. These features and others make it ideal for use as monotherapy. In order to determine the ‘‘proof of principal’’ that LEV can be used as a single agent in patients who had refractory seizures despite treatment with multiple classical AEDs, an earlier European multicenter placebo-controlled, responder-selected monotherapy study was conducted [3]. The results indicated that conversion to LEV monotherapy can be successful in patients with refractory partial epilepsy with and without secondarily generalization. In this study, we evaluated our experi*
Corresponding author. Fax: 1-916-734-6525. E-mail address: taoufi[email protected] (T.M. Alsaadi).
ence with levetiracetam as monotherapy in newly diagnosed na€ıve epilepsy patients as well as in patients with difficult-to-control seizures.
2. Methods We retrospectively reviewed the charts of our patients who were diagnosed with epilepsy after having two unprovoked seizures during the years 2000–2002. We identified patients who received LEV as monotherapy either as a first line or add-on agent with subsequent conversion to LEV monotherapy. We reviewed patientsÕ demographic data, diagnostic evaluation for epilepsy, seizure types, and seizure frequency prior to and following initiation of LEV monotherapy. All patients had follow-up visits at regular intervals every two months, or at shorter intervals if medically necessary. No patients failed to follow-up while on LEV. All patients had their LEV dose titrated up to maximal tolerated dose or up to 5000 mg/day, and for elderly patients the dose was titrated up to 2000 mg/day or up to seizure freedom. We compared seizure counts for the previous six months as baseline, prior to initiation of LEV treatment, to seizure
1525-5050/02/$ - see front matter Ó 2002 Elsevier Science (USA). All rights reserved. PII: S 1 5 2 5 - 5 0 5 0 ( 0 2 ) 0 0 5 1 6 - 4
472
T.M. Alsaadi et al. / Epilepsy & Behavior 3 (2002) 471–474
counts at six months of follow-up after LEV was started and maintained as therapy. Seizure frequency was determined using a seizure diary completed by each patient or their caregivers, which is standard practice in our clinic. Adverse events (AEs) while on LEV were also noted at each clinic visit. This information was kept in a computerized data system that was maintained up-todate by one of the co-authors (CT).
3. Results We identified 37 patients (27 females, 10 males), ages 18–91, (mean 41.4) with a history of partial seizures with and without secondarily generalization. The duration of epilepsy prior to LEV treatment ranged from 1–30 years, (mean 12.3 years). Nine of these patients began LEV as first line therapy with seizure duration of 1–52 years (median 2 years, mean 7.2 years). One patient had undiagnosed seizures for 52 years. Three of the nine patients had liver disease, and the remaining six patients chose to start LEV because of its favorable pharmacokinetic and side effect profile. Twenty-eight patients converted to LEV monotherapy after they failed several trials of AEDs, which included phenytoin (Dilantin), phenobarbital, carbamazepine (Tegretol), divalproex sodium (Depakote) lamotrigine (Lamictal), and topiramate (Topamax), (mean 2.5 AEDs). Characteristics and demographics of our two groups of patients are summarized in Tables 1 and 2. Table 1 Demographics and characteristics of the conversion to LEV monotherapy group Variable
LEV (n ¼ 28)
Mean age (years) (SD) Gender (% male/female) Age at epilepsy onset (years) (SD) Mean duration of epilepsy (years) (SD) Cause of epilepsy (% unknown) Cause of epilepsy (% with MTS on MRI) Mean number of previous AEDs (SD) Mean seizures frequency (n/week) Mean LEV dosages (mg/day)
39.17 (15) 35/65 27.19 (21.73) 13.67 (11.28) 16/28 (57%) 7/28 (21.4%) 2.5 (1.42) 2.29 2446.4
MTS, mesial temporal sclerosis. Table 2 Demographics and characteristics of the naive LEV monotherapy group Variable
LEV (n ¼ 9)
Mean age (years) (SD) Gender (% male/female) Age at epilepsy onset (years) (SD) Mean duration of epilepsy (years) (SD) Cause of epilepsy (% unknown) Mean seizures frequency (n/month) Mean LEV dosages (mg/day)
47 (17.8) 0/100 41.8 (20.3) 7.2 (16.8) 66% 1.6 1777.7
Of the 37 patients, 34 (92%) continued on LEV monotherapy for at least 6 months. Three patients discontinued therapy within two weeks after LEV was started at dosages less than 500 mg/day because of side effects, two of whom were started on LEV as a first line agent. Of the seven patients who were maintained on LEV as first line therapy for at least six months, four became seizure free and three patients had >75% reduction in their seizures. Twenty-eight patients converted to LEV after failing several AEDs. Nine patients became seizure free within six months; three of whom had failed more than one AED before trying LEV. Seven patients had >50% reduction of seizures; all of whom had failed more than one AED before being converted to LEV. Five patients reported >75% reduction of seizures; three of whom failed more than one AED. Six patients had no change in their seizures frequency. None of the patients reported worsening of any seizure type after LEV was started. No patient developed a new seizure type during treatment with LEV (Figs. 1 and 2). Five patients reported being nervous (irritable) within two weeks after starting on LEV, either as a single agent (n ¼ 4) or as add-on treatment (n ¼ 1). Three patients discontinued LEV, while the other two patients were able to continue on LEV when their complaints decreased after the first month of therapy. Two patients reported being dizzy within days after starting LEV but were able to continue on LEV. No other major AEs were reported.
4. Discussion This study suggests that LEV monotherapy can be effective in na€ıve epilepsy patients who were never tried on AEDs, as well as in patients with difficult-to-control epilepsy. Forty-four percent of our naive patients became seizure free after starting LEV, while 33% had more than 75% reduction of their seizures. This finding is consistent with earlier studies using old and new generation AEDs [5,6]. Still, 22% (2 of 9) of these patients discontinued LEV because of agitation occurring within the first few days of LEV at small doses (500 mg a day in two divided doses). Interestingly, all of the patients who complained of agitation were women, which raise the question of a sex-specific side effect in this group of patients. A previous study of 470 patients attending tertiary epilepsy clinics demonstrated that 16% of patients became seizure free after they failed their first AED at adequate doses when a second AED was tried [6,7]. In the previously mentioned study, 19.9% of patients receiving LEV were able to discontinue their previous AEDs and maintain LEV monotherapy for 12 weeks [3]. In the present study, 75% of our patients were success-
T.M. Alsaadi et al. / Epilepsy & Behavior 3 (2002) 471–474
473
Fig. 1. Patient disposition throughout the study.
Fig. 2. Effect of LEV monotherapy on seizure frequency. Each bar represents the percentage of patients achieving no significant changes, 75%, 50% seizure reduction, and the seizure free patients when converted to LEV monotherapy.
fully converted to LEV monotherapy, achieving more than 50% reduction of seizures, of whom 32% were seizure free on LEV monotherapy. Most of these patients (60.7%) had failed more than one AED, while 32% of patients were on duotherapy at the time of conversion. Our higher than previously reported success rate with conversion to LEV may be related to the small sampling of patients studied, differences in the severity of underlying disease, selection bias, as well as the lack of double blind randomization. Four of our patients were converted to LEV with rapid titration (within a few days) while in the hospital for video-EEG monitoring. These four patients tolerated this rapid titration without
side effects, except for one patient who complained of dizziness when the drug was initiated. Behavioral symptoms associated with levetiracetam have been observed in 13.3% of patients in placebocontrolled epilepsy trials and to a lesser extent in nonepilepsy trials utilizing LEV monotherapy [8]. Reports of behavioral problems during LEV treatment were associated with a pre-study history of psychiatric problems, or with use of Dilantin. All of the patients who reported nervousness in our study had this problem within the first two weeks of LEV therapy at smaller than the recommended starting dosages. Only two of our patients had a history of depression prior to starting LEV treatment. Our observations, in agreement with the others, suggest that these (AEs) do not appear to be dose related [8,9]. What makes a minority of patients susceptible to LEV-related behavioral side effects remains to be determined. In summary, we found that LEV can be effective as monotherapy in patients with newly diagnosed epilepsy as well as in patients with difficult-to-control seizures. In addition, it is very well tolerated, with only a small number of patients discontinuing the drug due to side effects. A larger, double blind study is needed to confirm our findings.
Acknowledgments The authors thank Dr. Andrew Wilner for his comments and suggestions.
References [1] Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double blind randomized clinical trial. Neurology 2000;35:236–42. [2] Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on
474
T.M. Alsaadi et al. / Epilepsy & Behavior 3 (2002) 471–474
therapy in patients with refractory partial seizures. Epilepsia 2000;41:1179–86. [3] Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000;41:1276–83. [4] Patsalos PN. Pharmacokinetic profile of LEV: toward ideal characteristics. Pharmacol Ther 2000;85:77–85. [5] Mattson R, Cramer J, Collins J, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and
[6] [7] [8] [9]
secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313:145–51. Kwan P, Brodie M. Early identification of refractory epilepsy. N Engl J Med 2000;342(5):314–9. Kwan P, Brodie M. Epilepsy after the first drug: substitution or add-on? Seizure 2000;9:464–8. French J. A systemic review of the safety profiles of Levetiracetam: a new antiepileptic drug. Epilepsy Res 2001;47:77–90. Kossoff E, Bergey G, Freeman J, et al. levetiracetam psychosis in children with epilepsy. Epilepsia 2001;42:1611–3.
Levetiracetam monotherapy for adults with localization-related epilepsy Taoufik M. Alsaadi,a,* Catherine Thieman,b and Edie E. Zusman a
Department of Neurology, Comprehensive Epilepsy Program, University of California, Davis, 4860 Y Street, Suite 3700, Sacramento, CA 95817, USA b Department of Neurological Surgery, Comprehensive Epilepsy Program, University of California, Davis, 4860 Y Street, Suite 3700, Sacramento, CA 95817, USA Received 18 June 2002; received in revised form 12 August 2002; accepted 13 August 2002
Abstract We identified 37 patients with a history of partial seizures, with and without secondarily generalization, who received levetiracetam (LEV) (Keppra) monotherapy. Patients began LEV either as first line therapy (n ¼ 9) or were converted to LEV monotherapy (n ¼ 28) after failing prior antiepileptic medications (AEDs). Thirty-four patients continued on LEV for at least six months; of these, 13 patients became seizure free and 15 patients had >50% reduction in their seizures. Three patients discontinued LEV because of adverse effects. LEV monotherapy can be effective and well tolerated in adults with new onset and difficult-to-control partial epilepsy. A prospective, large, double blind monotherapy study is needed to confirm this finding. Ó 2002 Elsevier Science (USA). All rights reserved. Keywords: Partial seizures; Monotherapy; Levetiracetam
1. Introduction Levetiracetam is a novel antiepileptic drug (AED) that has been approved as adjunctive treatment for adults with partial onset seizures. Its effectiveness was established in three multicenter, well-controlled pivotal trials [1–3]. In addition, LEV is well tolerated with a favorable pharmacokinetic profile that includes minimal protein binding, lack of hepatic metabolism, and twice a day dosing [4]. These features and others make it ideal for use as monotherapy. In order to determine the ‘‘proof of principal’’ that LEV can be used as a single agent in patients who had refractory seizures despite treatment with multiple classical AEDs, an earlier European multicenter placebo-controlled, responder-selected monotherapy study was conducted [3]. The results indicated that conversion to LEV monotherapy can be successful in patients with refractory partial epilepsy with and without secondarily generalization. In this study, we evaluated our experi*
Corresponding author. Fax: 1-916-734-6525. E-mail address: taoufi[email protected] (T.M. Alsaadi).
ence with levetiracetam as monotherapy in newly diagnosed na€ıve epilepsy patients as well as in patients with difficult-to-control seizures.
2. Methods We retrospectively reviewed the charts of our patients who were diagnosed with epilepsy after having two unprovoked seizures during the years 2000–2002. We identified patients who received LEV as monotherapy either as a first line or add-on agent with subsequent conversion to LEV monotherapy. We reviewed patientsÕ demographic data, diagnostic evaluation for epilepsy, seizure types, and seizure frequency prior to and following initiation of LEV monotherapy. All patients had follow-up visits at regular intervals every two months, or at shorter intervals if medically necessary. No patients failed to follow-up while on LEV. All patients had their LEV dose titrated up to maximal tolerated dose or up to 5000 mg/day, and for elderly patients the dose was titrated up to 2000 mg/day or up to seizure freedom. We compared seizure counts for the previous six months as baseline, prior to initiation of LEV treatment, to seizure
1525-5050/02/$ - see front matter Ó 2002 Elsevier Science (USA). All rights reserved. PII: S 1 5 2 5 - 5 0 5 0 ( 0 2 ) 0 0 5 1 6 - 4
472
T.M. Alsaadi et al. / Epilepsy & Behavior 3 (2002) 471–474
counts at six months of follow-up after LEV was started and maintained as therapy. Seizure frequency was determined using a seizure diary completed by each patient or their caregivers, which is standard practice in our clinic. Adverse events (AEs) while on LEV were also noted at each clinic visit. This information was kept in a computerized data system that was maintained up-todate by one of the co-authors (CT).
3. Results We identified 37 patients (27 females, 10 males), ages 18–91, (mean 41.4) with a history of partial seizures with and without secondarily generalization. The duration of epilepsy prior to LEV treatment ranged from 1–30 years, (mean 12.3 years). Nine of these patients began LEV as first line therapy with seizure duration of 1–52 years (median 2 years, mean 7.2 years). One patient had undiagnosed seizures for 52 years. Three of the nine patients had liver disease, and the remaining six patients chose to start LEV because of its favorable pharmacokinetic and side effect profile. Twenty-eight patients converted to LEV monotherapy after they failed several trials of AEDs, which included phenytoin (Dilantin), phenobarbital, carbamazepine (Tegretol), divalproex sodium (Depakote) lamotrigine (Lamictal), and topiramate (Topamax), (mean 2.5 AEDs). Characteristics and demographics of our two groups of patients are summarized in Tables 1 and 2. Table 1 Demographics and characteristics of the conversion to LEV monotherapy group Variable
LEV (n ¼ 28)
Mean age (years) (SD) Gender (% male/female) Age at epilepsy onset (years) (SD) Mean duration of epilepsy (years) (SD) Cause of epilepsy (% unknown) Cause of epilepsy (% with MTS on MRI) Mean number of previous AEDs (SD) Mean seizures frequency (n/week) Mean LEV dosages (mg/day)
39.17 (15) 35/65 27.19 (21.73) 13.67 (11.28) 16/28 (57%) 7/28 (21.4%) 2.5 (1.42) 2.29 2446.4
MTS, mesial temporal sclerosis. Table 2 Demographics and characteristics of the naive LEV monotherapy group Variable
LEV (n ¼ 9)
Mean age (years) (SD) Gender (% male/female) Age at epilepsy onset (years) (SD) Mean duration of epilepsy (years) (SD) Cause of epilepsy (% unknown) Mean seizures frequency (n/month) Mean LEV dosages (mg/day)
47 (17.8) 0/100 41.8 (20.3) 7.2 (16.8) 66% 1.6 1777.7
Of the 37 patients, 34 (92%) continued on LEV monotherapy for at least 6 months. Three patients discontinued therapy within two weeks after LEV was started at dosages less than 500 mg/day because of side effects, two of whom were started on LEV as a first line agent. Of the seven patients who were maintained on LEV as first line therapy for at least six months, four became seizure free and three patients had >75% reduction in their seizures. Twenty-eight patients converted to LEV after failing several AEDs. Nine patients became seizure free within six months; three of whom had failed more than one AED before trying LEV. Seven patients had >50% reduction of seizures; all of whom had failed more than one AED before being converted to LEV. Five patients reported >75% reduction of seizures; three of whom failed more than one AED. Six patients had no change in their seizures frequency. None of the patients reported worsening of any seizure type after LEV was started. No patient developed a new seizure type during treatment with LEV (Figs. 1 and 2). Five patients reported being nervous (irritable) within two weeks after starting on LEV, either as a single agent (n ¼ 4) or as add-on treatment (n ¼ 1). Three patients discontinued LEV, while the other two patients were able to continue on LEV when their complaints decreased after the first month of therapy. Two patients reported being dizzy within days after starting LEV but were able to continue on LEV. No other major AEs were reported.
4. Discussion This study suggests that LEV monotherapy can be effective in na€ıve epilepsy patients who were never tried on AEDs, as well as in patients with difficult-to-control epilepsy. Forty-four percent of our naive patients became seizure free after starting LEV, while 33% had more than 75% reduction of their seizures. This finding is consistent with earlier studies using old and new generation AEDs [5,6]. Still, 22% (2 of 9) of these patients discontinued LEV because of agitation occurring within the first few days of LEV at small doses (500 mg a day in two divided doses). Interestingly, all of the patients who complained of agitation were women, which raise the question of a sex-specific side effect in this group of patients. A previous study of 470 patients attending tertiary epilepsy clinics demonstrated that 16% of patients became seizure free after they failed their first AED at adequate doses when a second AED was tried [6,7]. In the previously mentioned study, 19.9% of patients receiving LEV were able to discontinue their previous AEDs and maintain LEV monotherapy for 12 weeks [3]. In the present study, 75% of our patients were success-
T.M. Alsaadi et al. / Epilepsy & Behavior 3 (2002) 471–474
473
Fig. 1. Patient disposition throughout the study.
Fig. 2. Effect of LEV monotherapy on seizure frequency. Each bar represents the percentage of patients achieving no significant changes, 75%, 50% seizure reduction, and the seizure free patients when converted to LEV monotherapy.
fully converted to LEV monotherapy, achieving more than 50% reduction of seizures, of whom 32% were seizure free on LEV monotherapy. Most of these patients (60.7%) had failed more than one AED, while 32% of patients were on duotherapy at the time of conversion. Our higher than previously reported success rate with conversion to LEV may be related to the small sampling of patients studied, differences in the severity of underlying disease, selection bias, as well as the lack of double blind randomization. Four of our patients were converted to LEV with rapid titration (within a few days) while in the hospital for video-EEG monitoring. These four patients tolerated this rapid titration without
side effects, except for one patient who complained of dizziness when the drug was initiated. Behavioral symptoms associated with levetiracetam have been observed in 13.3% of patients in placebocontrolled epilepsy trials and to a lesser extent in nonepilepsy trials utilizing LEV monotherapy [8]. Reports of behavioral problems during LEV treatment were associated with a pre-study history of psychiatric problems, or with use of Dilantin. All of the patients who reported nervousness in our study had this problem within the first two weeks of LEV therapy at smaller than the recommended starting dosages. Only two of our patients had a history of depression prior to starting LEV treatment. Our observations, in agreement with the others, suggest that these (AEs) do not appear to be dose related [8,9]. What makes a minority of patients susceptible to LEV-related behavioral side effects remains to be determined. In summary, we found that LEV can be effective as monotherapy in patients with newly diagnosed epilepsy as well as in patients with difficult-to-control seizures. In addition, it is very well tolerated, with only a small number of patients discontinuing the drug due to side effects. A larger, double blind study is needed to confirm our findings.
Acknowledgments The authors thank Dr. Andrew Wilner for his comments and suggestions.
References [1] Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double blind randomized clinical trial. Neurology 2000;35:236–42. [2] Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on
474
T.M. Alsaadi et al. / Epilepsy & Behavior 3 (2002) 471–474
therapy in patients with refractory partial seizures. Epilepsia 2000;41:1179–86. [3] Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000;41:1276–83. [4] Patsalos PN. Pharmacokinetic profile of LEV: toward ideal characteristics. Pharmacol Ther 2000;85:77–85. [5] Mattson R, Cramer J, Collins J, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and
[6] [7] [8] [9]
secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313:145–51. Kwan P, Brodie M. Early identification of refractory epilepsy. N Engl J Med 2000;342(5):314–9. Kwan P, Brodie M. Epilepsy after the first drug: substitution or add-on? Seizure 2000;9:464–8. French J. A systemic review of the safety profiles of Levetiracetam: a new antiepileptic drug. Epilepsy Res 2001;47:77–90. Kossoff E, Bergey G, Freeman J, et al. levetiracetam psychosis in children with epilepsy. Epilepsia 2001;42:1611–3.