- Email: [email protected]
Levetiracetam monotherapy for children and adolescents with benign rolandic seizures
Seizure (2007) 16, 271—275
www.elsevier.com/locate/yseiz
CASE REPORT
Levetiracetam monotherapy for children and adolescents with benign rolandic seizures A. Verrotti a,*, G. Coppola b, R. Manco a, G. Ciambra c, P. Iannetti c, S. Grosso d, P. Balestri d, E. Franzoni e, F. Chiarelli a a
Department of Pediatrics, University of Chieti, Policlinico Universitario, Via dei Vestini 5, 66100 Chieti, Italy b Department of Child Neuropsychiatry, University of Naples, Italy c Department of Pediatrics, University of Roma, Italy d Department of Pediatrics, University of Siena, Italy e Department of Child Neuropsychiatry, University of Bologna, Italy Received 29 September 2006; accepted 4 December 2006
KEYWORDS Benign epilepsy with centrotemporal spikes; Levetiracetam; Antiepileptic drugs
Summary To assess the efficacy, tolerability and safety of Levetiracetam (LEV) therapy, we identified 21 (15 male; 6 female) patients with a history of benign epilepsy with centrotemporal spikes (BECTS), with and without secondarily generalization in children and adolescents aged between 5.0 and 12.1 years. LEV was administered as a first drug (number of patients = 9) or converted after previous treatment with other AEDs (number of patients = 12). The patients were subdivided into two groups: ‘‘newly diagnosed’’ patients and ‘‘converted’’ patients. Patients were followed up for 12 months and all patients were able to continue on LEV treatment. At the end of follow-up (12 months), all patients were seizure free or showed a reduction of seizures >50%. LEV dosage ranged from 1000 to 2500 mg/daily. Overall, 100% of patients completed the 12 months study, without any important side effect. Somnolence and irritability occurred in two (9.5%) patients. Our results support findings that LEV monotherapy is effective and well tolerated in children with BECTS. Prospective, large, long-term double-blind studies are needed to confirm these findings. # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Introduction Benign epilepsy with centrotemporal spikes (BECTS), known as benign Rolandic epilepsy (BRE), is a benign * Corresponding author. Tel.: +39 0871358015; fax: +39 0871574831. E-mail address: [email protected] (A. Verrotti).
partial idiopathic epilepsy, characterized by partial motor seizures, usually brief and infrequent, with or without generalization recurring mostly during sleep, with onset during childhood. The patients have absence of neurological and mental deficits,1 although some authors have suggested that part of these patients can show intellectual impairments.2 The EEG criteria are: normal background activity and
1059-1311/$ — see front matter # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2006.12.006
272 sleep organization; peculiar focal or multifocal centrotemporal spikes (CTS), increasing in frequency during sleep.3,4 This type of epilepsy generally tends to follow a benign course and the treatment is often not required. However, treatment decision requires clinical judgment and observations over time. In fact, treatment is started in subjects with frequent seizures and/or seizures that recur during wakefulness, or when the ictal events are disruptive to the patient or family.5,6 Once assumed the treatment option, it may be suitable to choose the best tolerated antiepileptic drug (AED), possibly at the minimal effective dosage. Valproic acid and Carbamazepine are the most frequently prescribed AED in this type of epilepsy.1,5 More recently, based on the particularly favourable pharmacokinetic profile and the good tolerability, Levetiracetam (LEV) has been successfully considered as monotherapy option; the pharmacokinetic profile of LEV makes this AED a good option for the treatment of pediatric patients.7 LEV is a novel AED which has been approved as adjunctive treatment for adults with partial onset seizures. Its mechanisms of action appear different from other AEDs.8 LEV binds to a specific membrane-binding site in the brain.9 It neither affects glutamate or gamma aminobutyric acidmediated synaptic transmission,10,11 nor does it modulate voltage dependent sodium or T-type calcium currents.12 LEV is well tolerated and its effectiveness was established in multicenter, wellcontrolled pivotal trials.13—15 The safety profile is consistent with that observed in many epilepsy trials.16—18 Moreover, LEV has proven efficacy in the treatment of partial seizures with or without secondary generalization and refractory epilepsies;19—21 but preliminary observations are favourable for a broader use. Therefore, LEV is widely used but the experience in BECTS is limited, in fact, only Bello-Espinoza.22 have reported three cases of young children with typical BECTS treated with LEV. The objective of this study was to generate information on LEV monotherapy in a group of children and adolescents with BECTS.
Patients and methods Twenty-one subjects (15 male; 6 female) with BECTS were enrolled in this prospective study from five centers of Italy. All patients have been diagnosed with this type of epilepsy, according to the International League Against Epilepsy (ILAE)3. The age of seizures onset ranged from 5.0 to 12.1 years, with a peak of frequency at mean S.D. 7.7 4.4 years.
A. Verrotti et al. All patients showed typical rolandic seizures. The typical seizures were hemifacial, characterized by clonic manifestations involving the hemiface, sometimes preceded by unilateral paresthesia involving toungue, lips, gums and cheek; the jerks were often associated with a lateral tonic deviation of the mouth involving lips and toungue, and result drooling due to sialorrhoea. The seizures lasted from less than a minute to 3 min, and spreaded to the homolateral arm and rarely to the leg. No permanent deficits were observed in all cases. Exclusion criteria were: neurological disorders or intellectual impairment, history or presence of pseudoseizures, history of recurrent psychotic or major effective disorder, the use of CNS-influencing medication, unless patients had been stabilized on such medication for >1 months before the study, metabolic disorders, active infection or neoplasm, any clinically relevant progressive or serious illness expected to interfere with the patient completing the trial, previous treatment with LEV discontinued due to adverse events. In all cases, computed tomography or magnetic resonance imaging before the trial confirmed the absence of neoplasia or progressive cerebral or neurodegenerative diseases. In all patients, electroencephalograms (EEG) were recorded during wakefulness with hyperventilation and photic stimulation and during drowsiness and sleep (stages 1—4); all patients show a normal, well-organized and symmetrical background activity. We recorded only interictal EEGs: in all patients we found typical CTS, clearly localized in the central regions; the main spikes component was diphasic with a maximum surface, negative, rounded peak followed by a smaller positive peak; this was followed by a negative or negative-positive slow wave. A relatively minute positive spike often preceded this spike-slow wave complex. The spikes significantly increased in frequency during drowsiness and through all sleep stages. LEV was administered as a first drug (number of patients = 9) or converted after previous treatment with other AEDs (number of patients = 12). Therefore, the 21 patients were subdivided into two groups: ‘‘newly diagnosed’’ (AED naı¨ve) group and ‘‘converted’’ group. In this second group of patients, different AEDs were tried before introducing TPM treatment: Valproate (4 patients), Carbamazepine (6 patients), Oxcarbazepine (1 patient), Lamotrigine (1 patient). All patients received these AEDs monotherapy. In these 12 patients preexisting AED treatment was gradually tapered during titration phase of LEV. All patients began LEV 250 mg each evening and dosing was escalated gradually; after titration, LEV
Levetiracetam monotherapy for children and adolescents with benign rolandic seizures
273
Efficacy
was administered, the range of prescribed LEV dosages ranged from 1000 to 2500 mg/daily. All patients were carefully followed at 6 and 12 months after the beginning of LEV therapy. At each visit, the investigator assessed the number and type of seizures, adverse events, with their severity, relationship to LEV treatment, and outcome. Each treatment-emergent physical and neurological abnormality was recorded as adverse event, as was any condition worsening or requiring initiation of medication. Height and weight were monitored throughout the trial. Physical and neurologic examinations, laboratory assessment and electrocardiography were performed, and vital signs were recorded; during the baseline and the treatment periods and at study completion, detailed records of adverse events were documented. During the follow-up, in all patients were performed the following laboratorial examinations: complete peripheral blood counts, urinary analysis and measurement of blood creatinine, alanine and aspartate aminotransferase levels, erythrocyte and leukocyte count, amylase, transaminase, BUN. Compared with baseline seizures frequency and severity, the response to LEV treatment was classified as: seizures free (100% seizures control); responders (>50% reduction) or marginal effect (<50% reduction) in monthly seizures frequency. The evaluation of the patients started after the end of LEV titration. The efficacy of LEV therapy was calculated by counting mean seizures frequency/ months; in particular, baseline period was 6 months before LEV treatment; visit 6 months: mean seizures frequency for the period ‘‘after the end of tritation’’ 6 months; visit 12 months: mean seizures frequency for the period 6—12 months. Data of the patients are reported as mean S.D.
Table 1 illustrates changes in seizures frequency at 6 months and 12 months of follow-up. During the first 6 months of the study 8 (30.1%) patients of the naı¨ve group and 9 (42.8%) patients of second group became seizure free. At the end of follow-up, 9 (42.8%) ‘‘newly diagnosed patients’’ and 8 (30.1%) ‘‘converted patients’’ showed complete cessation of seizures. One patient of the second group has been controlled for 6 months, but than relapsed and at the end, was classified as ‘‘responder’’.
Tolerability Adverse reactions occurred in 2 (9.5%) patients; in these two patients drowsiness and irritability was reported during the initial phase (2 weeks) of treatment and than disappeared. No other important adverse effects were observed during the therapy. No findings of major clinical significance were noted regarding the effects of study medication on laboratory test results, vital signs, electrocardiographic recordings, physical and neurologic examinations, and phychiatric and mental status.
Discussion Considering the spontaneous benign course of BECTS a continuous treatment should be considered only in subjects with frequent seizures. Moreover, patients with frequent seizures and secondarily generalized tonic-clonic seizures may need medication.1,4 LEV has proven efficacy in this type of epilepsy as has been recently reported by Bello-Espinoza.22 Also our study has evaluated the efficacy and the safety of LEV in the treatment of BECTS. This study suggests that LEV monotherapy can be effective and very well tolerated in BECTS at the onset of disease as well as far who failed other AEDs prior to LEV treatment. In addition, this study shows a high retention rate of LEV with all patients able to continue on LEV for 12 months. We treated two different types of patients:
Results No patients were lost during follow-up. All patients remained on LEV therapy during the 12 months.
Table 1 Effects of LEV on seizures frequency in the 21 patients at 6 and 12 months 6 Months, newly diagnosed patients
6 Months, converted patients
12 Months, newly diagnosed patients
12 Months, converted patients
Seizures free Responders Marginal effect
8 1 0
9 2 1
9 0 0
8 4 0
Total
9
12
9
12
274 naive patients and converted patients and the response was significantly better in naive patients. Recently, it has been underlined that this epilepsy is a challenge in terminology and classification,23 because BECTS is a heterogeneous condition which includes a large spectrum of clinical features;2,24,25 the atypical features could influence the response to treatment.1,26 Although efficacy as measured by seizure frequency is the principal outcome evaluated in studies, of great importance to the patient is the change in quality of life made possible by a new treatment. With regard to safety, LEV has been reported to be a well-tolerated drug. Adverse reactions, mainly represented by headache, infection, somnolence and anorexia, have been reported, with the incidence varying from 10 to 19%.27,28 Acute psychosis has also been reported.29—32 In our experience, LEV has shown to be well tolerated, in fact, only two patients reported transient somnolence and irritability. Somnolence, dizziness, and headache were three most frequent events also in the large study performed by Tsai and Yen.18 We confirm that these side effects are transient, in fact, previous studies showed that somnolence occurs predominantly during the initial phase of treatment with LEV.16,18 Generally, adverse events of LEV were typically of a non-serious nature, mild-to-moderate in intensity, and only slightly more frequent than in placebo-treated patients.33 This study provides further support for the LEV safety: no discontinuation due to adverse events was reported in our study, confirming that LEV is a drug with a safe profile. The small number of patients studied, as well as the nature of this study and the short-term followup, along with lack of randomization may not allow us to make firm conclusions. However, our preliminary data suggest that LEV may be an acceptable choice as monotherapy for BECTS.
References 1. Panayiotopoulos CP. Benign childhood partial seizures and related epileptic syndromes. London: John Libbey and Company Ltd.; 1999. 2. Verrotti A, Latini G, Trotta D, Giannuzzi R, Cutarella R, Morgese G, et al. Typical an atypical rolandic epilepsy in childhood: a follow-up study. Pediatric Neurol 2002;26: 26—9. 3. Commission, on Classification and Terminology of the International League Against Epilepsy: Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30:389—99. 4. Panayiotopoulos CP. Benign childhood epilepsy with centrotemporal spikes. In: Panayiotopoulos CP, editor. The epilepsies. Seizures, syndromes and management. Chipping Norton: Bladon Medical Publishing; 2005. p. 224—34.
A. Verrotti et al. 5. Hamada Y, Okuno T, Hattori H, Mikawa H. Indication for antiepileptic drug treatment of benign childhood epilepsy with centro-temporal spikes. Brain Dev 1994;16:159—61. 6. Galanopoulou AS, Bojko A, Lado F, Moshe ` SL. The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep. Brain Dev 2000;22: 279—95. 7. Pellock JM, Glauser TA, Bebin EM, Fountain NB, Ritter FJ, Coupez RM, et al. Pharmacokinetic study of Levetiracetam in children. Epilepsia 2001;42:1574—9. 8. Klitgaard H, Pitkanen A. Antiepileptogenesis, neuroprotection and disease modification in the treatment of epilepsy: focus on Levetiracetam. Epileptic Disord 2003;5(Suppl. 1):S9—16. 9. Noyer M, Gillard M, Matagne A. The novel antiepileptic drug Levetiracetam (UCB L059) appears to act via a specific binding site in CNS membranes. Eur J Pharmacol 1995;286:137—46. 10. Birnstiel S, Wulfert E, Beck SG. Levetiracetam (UCB L059) affects in vitro models of epilepsy in CA3 pyramidal neurons without altering normal synaptic transmission. Naunyn Schmiedebergs Arch Pharmacol 1997;356:611—8. 11. Rigo JM, Hans G, Nguyer L. The antiepileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA-and glycine-gated currents. Br J Pharmacol 2002;136:659—72. 12. Zona C, Niespodziany I, Marchetti C, Klitgaard H, Bernardi G, Margineanu DG. Levetiracetam does not modulate neuronal voltage-gated Na + and T-type Ca2 + currents. Seizures 2001;10:279—86. 13. Cereghino JJ, Biton V, Abou-khalil B, Dreifuss F, Ganer LJ, Leppik I. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000;55:236—42. 14. Ben-Menachem E, Falter U. Efficacy and tolerability of Levetiracetam 3000 mg in patients with refractorial partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia 2000;41:1276—83. 15. Shorvon SD, van Rijckevorsel K. A new antiepileptic drug. J Neurol Neurosurg Psychiatr 2002;72:426—8. 16. French J, Edrich P, Cramer JA. A systematic review of the safety profile of Levetiracetam: a new antiepileptic drug. Epilepsy 2001;47:77—90. 17. Marson AG, Hutton JL, Leach JP, Castillo S, Schmidt D, White S, et al. Levetiracetam, oxocarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review. Epilepsy Res 2001;46:259—70. 18. Tsai JJ, Yen DJ, Hsih MS, Chen SS, Hiersemenzel R, Edrich P, et al. Efficacy and Safety or Levetiracetam (up to 2000 mg/ day) in Taiwanese Patients with Refractory Partial Seizures: a multicenter, randomized, double-blind, placebo-controlled study. Epilepsia 2006;47:72—81. 19. Shorvon SD, Lowenthal A, Janz D, Bielen E, Loislan P. Multicenter double-blind, randomized, placebo-controlled trial of Levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000;41:1179—86. 20. Grosso S, Franzoni E, Coppola G, Iannetti P, Verrotti A, Cordelli DM, et al. Efficacy and safety of Levetiracetam: an add-on trial in children with refractory epilepsy. Seizures 2005;14:248—53. 21. Mohanraj R, Parker PG, Stephen LJ, Brodie MJ. Levetiracetam in refractory epilepsy: a prospective observational study. Seizures 2005;14:23—7. 22. Bello-Espinoza LE, Roberts SL. Levetiracetam for benign epilepsy of childhood with centrotemporal spikes-three cases. Seizure 2003;12:157—9.
Levetiracetam monotherapy for children and adolescents with benign rolandic seizures 23. Lundberg S, Eeg Olofsson. Rolandic epilepsy: a challenge in terminology and classification. Eur J Paediatr Neurol 2003;7:239—41. 24. Lage L, Buyse G, Deconinck A, Ceulemans B. Effect of levetiracetam in refractory childhood epilepsy syndromes. Eur J Paediatr Neurol 2003;7:123—8. 25. Kossoff EH, Boatman D, Freeman JM. Landau-Kleffner syndrome responsive to levetiracetam. Epilepsy Behav 2003;4:571—5. 26. Al Twajri WA, Shevell MI. Atypical benign epilepsy of childhood with rolandic spikes: features of a subset requiring more than one medication for seizure control. J Child Neurol 2002;17:901—4. 27. Glauser TA, Pellock JM, Bebin EM, Fountain NB, Ritter FJ, Jensen CM, et al. Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial. Epilepsia 2002;43:518—24.
275
28. Glauser TA, Dulac O. Preliminary efficacy of levetiracetam in children. Epileptic Disord 2003;5(Suppl. 1):S45—50. 29. Herranz JL. Levetiracetam in children and adolescents with epilepsy. Revue Neurologie 2003;37:558—60. 30. Kossoff EH, Bergey GK, Freeman JM, Vining EP. Levetiracetam psychosis in children with epilepsy. Epilepsia 2001;42: 1611—3. 31. Mula M, Trimble MR, Sander JW. Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam. Seizures 2004;13:55—7. 32. Mula M, Trimble MR, Yuen A, Liu RS, Sander JW. Psychiatric adverse events during levetiracetam therapy. Neurology 2003;63:704—6. 33. Morrell MJ, Leppik I, French J, Ferrendelli J, Han J, Maqnus L. The Keeper trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study. Epilepsy Res 2003;54:153—61.
www.elsevier.com/locate/yseiz
CASE REPORT
Levetiracetam monotherapy for children and adolescents with benign rolandic seizures A. Verrotti a,*, G. Coppola b, R. Manco a, G. Ciambra c, P. Iannetti c, S. Grosso d, P. Balestri d, E. Franzoni e, F. Chiarelli a a
Department of Pediatrics, University of Chieti, Policlinico Universitario, Via dei Vestini 5, 66100 Chieti, Italy b Department of Child Neuropsychiatry, University of Naples, Italy c Department of Pediatrics, University of Roma, Italy d Department of Pediatrics, University of Siena, Italy e Department of Child Neuropsychiatry, University of Bologna, Italy Received 29 September 2006; accepted 4 December 2006
KEYWORDS Benign epilepsy with centrotemporal spikes; Levetiracetam; Antiepileptic drugs
Summary To assess the efficacy, tolerability and safety of Levetiracetam (LEV) therapy, we identified 21 (15 male; 6 female) patients with a history of benign epilepsy with centrotemporal spikes (BECTS), with and without secondarily generalization in children and adolescents aged between 5.0 and 12.1 years. LEV was administered as a first drug (number of patients = 9) or converted after previous treatment with other AEDs (number of patients = 12). The patients were subdivided into two groups: ‘‘newly diagnosed’’ patients and ‘‘converted’’ patients. Patients were followed up for 12 months and all patients were able to continue on LEV treatment. At the end of follow-up (12 months), all patients were seizure free or showed a reduction of seizures >50%. LEV dosage ranged from 1000 to 2500 mg/daily. Overall, 100% of patients completed the 12 months study, without any important side effect. Somnolence and irritability occurred in two (9.5%) patients. Our results support findings that LEV monotherapy is effective and well tolerated in children with BECTS. Prospective, large, long-term double-blind studies are needed to confirm these findings. # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Introduction Benign epilepsy with centrotemporal spikes (BECTS), known as benign Rolandic epilepsy (BRE), is a benign * Corresponding author. Tel.: +39 0871358015; fax: +39 0871574831. E-mail address: [email protected] (A. Verrotti).
partial idiopathic epilepsy, characterized by partial motor seizures, usually brief and infrequent, with or without generalization recurring mostly during sleep, with onset during childhood. The patients have absence of neurological and mental deficits,1 although some authors have suggested that part of these patients can show intellectual impairments.2 The EEG criteria are: normal background activity and
1059-1311/$ — see front matter # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2006.12.006
272 sleep organization; peculiar focal or multifocal centrotemporal spikes (CTS), increasing in frequency during sleep.3,4 This type of epilepsy generally tends to follow a benign course and the treatment is often not required. However, treatment decision requires clinical judgment and observations over time. In fact, treatment is started in subjects with frequent seizures and/or seizures that recur during wakefulness, or when the ictal events are disruptive to the patient or family.5,6 Once assumed the treatment option, it may be suitable to choose the best tolerated antiepileptic drug (AED), possibly at the minimal effective dosage. Valproic acid and Carbamazepine are the most frequently prescribed AED in this type of epilepsy.1,5 More recently, based on the particularly favourable pharmacokinetic profile and the good tolerability, Levetiracetam (LEV) has been successfully considered as monotherapy option; the pharmacokinetic profile of LEV makes this AED a good option for the treatment of pediatric patients.7 LEV is a novel AED which has been approved as adjunctive treatment for adults with partial onset seizures. Its mechanisms of action appear different from other AEDs.8 LEV binds to a specific membrane-binding site in the brain.9 It neither affects glutamate or gamma aminobutyric acidmediated synaptic transmission,10,11 nor does it modulate voltage dependent sodium or T-type calcium currents.12 LEV is well tolerated and its effectiveness was established in multicenter, wellcontrolled pivotal trials.13—15 The safety profile is consistent with that observed in many epilepsy trials.16—18 Moreover, LEV has proven efficacy in the treatment of partial seizures with or without secondary generalization and refractory epilepsies;19—21 but preliminary observations are favourable for a broader use. Therefore, LEV is widely used but the experience in BECTS is limited, in fact, only Bello-Espinoza.22 have reported three cases of young children with typical BECTS treated with LEV. The objective of this study was to generate information on LEV monotherapy in a group of children and adolescents with BECTS.
Patients and methods Twenty-one subjects (15 male; 6 female) with BECTS were enrolled in this prospective study from five centers of Italy. All patients have been diagnosed with this type of epilepsy, according to the International League Against Epilepsy (ILAE)3. The age of seizures onset ranged from 5.0 to 12.1 years, with a peak of frequency at mean S.D. 7.7 4.4 years.
A. Verrotti et al. All patients showed typical rolandic seizures. The typical seizures were hemifacial, characterized by clonic manifestations involving the hemiface, sometimes preceded by unilateral paresthesia involving toungue, lips, gums and cheek; the jerks were often associated with a lateral tonic deviation of the mouth involving lips and toungue, and result drooling due to sialorrhoea. The seizures lasted from less than a minute to 3 min, and spreaded to the homolateral arm and rarely to the leg. No permanent deficits were observed in all cases. Exclusion criteria were: neurological disorders or intellectual impairment, history or presence of pseudoseizures, history of recurrent psychotic or major effective disorder, the use of CNS-influencing medication, unless patients had been stabilized on such medication for >1 months before the study, metabolic disorders, active infection or neoplasm, any clinically relevant progressive or serious illness expected to interfere with the patient completing the trial, previous treatment with LEV discontinued due to adverse events. In all cases, computed tomography or magnetic resonance imaging before the trial confirmed the absence of neoplasia or progressive cerebral or neurodegenerative diseases. In all patients, electroencephalograms (EEG) were recorded during wakefulness with hyperventilation and photic stimulation and during drowsiness and sleep (stages 1—4); all patients show a normal, well-organized and symmetrical background activity. We recorded only interictal EEGs: in all patients we found typical CTS, clearly localized in the central regions; the main spikes component was diphasic with a maximum surface, negative, rounded peak followed by a smaller positive peak; this was followed by a negative or negative-positive slow wave. A relatively minute positive spike often preceded this spike-slow wave complex. The spikes significantly increased in frequency during drowsiness and through all sleep stages. LEV was administered as a first drug (number of patients = 9) or converted after previous treatment with other AEDs (number of patients = 12). Therefore, the 21 patients were subdivided into two groups: ‘‘newly diagnosed’’ (AED naı¨ve) group and ‘‘converted’’ group. In this second group of patients, different AEDs were tried before introducing TPM treatment: Valproate (4 patients), Carbamazepine (6 patients), Oxcarbazepine (1 patient), Lamotrigine (1 patient). All patients received these AEDs monotherapy. In these 12 patients preexisting AED treatment was gradually tapered during titration phase of LEV. All patients began LEV 250 mg each evening and dosing was escalated gradually; after titration, LEV
Levetiracetam monotherapy for children and adolescents with benign rolandic seizures
273
Efficacy
was administered, the range of prescribed LEV dosages ranged from 1000 to 2500 mg/daily. All patients were carefully followed at 6 and 12 months after the beginning of LEV therapy. At each visit, the investigator assessed the number and type of seizures, adverse events, with their severity, relationship to LEV treatment, and outcome. Each treatment-emergent physical and neurological abnormality was recorded as adverse event, as was any condition worsening or requiring initiation of medication. Height and weight were monitored throughout the trial. Physical and neurologic examinations, laboratory assessment and electrocardiography were performed, and vital signs were recorded; during the baseline and the treatment periods and at study completion, detailed records of adverse events were documented. During the follow-up, in all patients were performed the following laboratorial examinations: complete peripheral blood counts, urinary analysis and measurement of blood creatinine, alanine and aspartate aminotransferase levels, erythrocyte and leukocyte count, amylase, transaminase, BUN. Compared with baseline seizures frequency and severity, the response to LEV treatment was classified as: seizures free (100% seizures control); responders (>50% reduction) or marginal effect (<50% reduction) in monthly seizures frequency. The evaluation of the patients started after the end of LEV titration. The efficacy of LEV therapy was calculated by counting mean seizures frequency/ months; in particular, baseline period was 6 months before LEV treatment; visit 6 months: mean seizures frequency for the period ‘‘after the end of tritation’’ 6 months; visit 12 months: mean seizures frequency for the period 6—12 months. Data of the patients are reported as mean S.D.
Table 1 illustrates changes in seizures frequency at 6 months and 12 months of follow-up. During the first 6 months of the study 8 (30.1%) patients of the naı¨ve group and 9 (42.8%) patients of second group became seizure free. At the end of follow-up, 9 (42.8%) ‘‘newly diagnosed patients’’ and 8 (30.1%) ‘‘converted patients’’ showed complete cessation of seizures. One patient of the second group has been controlled for 6 months, but than relapsed and at the end, was classified as ‘‘responder’’.
Tolerability Adverse reactions occurred in 2 (9.5%) patients; in these two patients drowsiness and irritability was reported during the initial phase (2 weeks) of treatment and than disappeared. No other important adverse effects were observed during the therapy. No findings of major clinical significance were noted regarding the effects of study medication on laboratory test results, vital signs, electrocardiographic recordings, physical and neurologic examinations, and phychiatric and mental status.
Discussion Considering the spontaneous benign course of BECTS a continuous treatment should be considered only in subjects with frequent seizures. Moreover, patients with frequent seizures and secondarily generalized tonic-clonic seizures may need medication.1,4 LEV has proven efficacy in this type of epilepsy as has been recently reported by Bello-Espinoza.22 Also our study has evaluated the efficacy and the safety of LEV in the treatment of BECTS. This study suggests that LEV monotherapy can be effective and very well tolerated in BECTS at the onset of disease as well as far who failed other AEDs prior to LEV treatment. In addition, this study shows a high retention rate of LEV with all patients able to continue on LEV for 12 months. We treated two different types of patients:
Results No patients were lost during follow-up. All patients remained on LEV therapy during the 12 months.
Table 1 Effects of LEV on seizures frequency in the 21 patients at 6 and 12 months 6 Months, newly diagnosed patients
6 Months, converted patients
12 Months, newly diagnosed patients
12 Months, converted patients
Seizures free Responders Marginal effect
8 1 0
9 2 1
9 0 0
8 4 0
Total
9
12
9
12
274 naive patients and converted patients and the response was significantly better in naive patients. Recently, it has been underlined that this epilepsy is a challenge in terminology and classification,23 because BECTS is a heterogeneous condition which includes a large spectrum of clinical features;2,24,25 the atypical features could influence the response to treatment.1,26 Although efficacy as measured by seizure frequency is the principal outcome evaluated in studies, of great importance to the patient is the change in quality of life made possible by a new treatment. With regard to safety, LEV has been reported to be a well-tolerated drug. Adverse reactions, mainly represented by headache, infection, somnolence and anorexia, have been reported, with the incidence varying from 10 to 19%.27,28 Acute psychosis has also been reported.29—32 In our experience, LEV has shown to be well tolerated, in fact, only two patients reported transient somnolence and irritability. Somnolence, dizziness, and headache were three most frequent events also in the large study performed by Tsai and Yen.18 We confirm that these side effects are transient, in fact, previous studies showed that somnolence occurs predominantly during the initial phase of treatment with LEV.16,18 Generally, adverse events of LEV were typically of a non-serious nature, mild-to-moderate in intensity, and only slightly more frequent than in placebo-treated patients.33 This study provides further support for the LEV safety: no discontinuation due to adverse events was reported in our study, confirming that LEV is a drug with a safe profile. The small number of patients studied, as well as the nature of this study and the short-term followup, along with lack of randomization may not allow us to make firm conclusions. However, our preliminary data suggest that LEV may be an acceptable choice as monotherapy for BECTS.
References 1. Panayiotopoulos CP. Benign childhood partial seizures and related epileptic syndromes. London: John Libbey and Company Ltd.; 1999. 2. Verrotti A, Latini G, Trotta D, Giannuzzi R, Cutarella R, Morgese G, et al. Typical an atypical rolandic epilepsy in childhood: a follow-up study. Pediatric Neurol 2002;26: 26—9. 3. Commission, on Classification and Terminology of the International League Against Epilepsy: Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30:389—99. 4. Panayiotopoulos CP. Benign childhood epilepsy with centrotemporal spikes. In: Panayiotopoulos CP, editor. The epilepsies. Seizures, syndromes and management. Chipping Norton: Bladon Medical Publishing; 2005. p. 224—34.
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