Lamotrigine adjunctive therapy among children and adolescents with primary generalized tonic-clonic seizures.
CONTEXT AND OBJECTIVE: Primary generalized tonic-clonic seizures are relatively more common among children than among adults. Primary generalized tonic-clonic seizures are associated with increased risk of injury and death. Therefore, effective control of primary generalized tonic-clonic seizures is necessary to reduce epilepsy-related morbidity and mortality. Lamotrigine has demonstrated efficacy from published randomized clinical trials for childhood partial seizures, absence seizures, and for the generalized seizures associated with Lennox-Gastaut syndrome. A randomized, blinded, placebo-controlled study was conducted to assess the efficacy and tolerability of adjunctive therapy with lamotrigine in the treatment of primary generalized tonic-clonic seizures among patients > or = 2 years of age; we report the data from children and adolescents 2 to 20 years of age from this randomized clinical trial. This is the first published analysis of data from a randomized, double-blind, controlled clinical trial of primary generalized tonic-clonic seizures focusing on children and adolescents. PATIENTS AND METHODS: We randomly assigned (1:1) 117 patients, aged 2 to 55 years, with primary generalized tonic-clonic seizures inadequately controlled on 1 to 2 current antiepileptic drugs and with evidence of primary generalized tonic-clonic seizures on electroencephalogram and no historical or electroencephalogram evidence of partial seizures to either lamotrigine or placebo in a double-blind parallel group clinical trial from 2001 through 2004. We analyzed the subgroup of children and adolescents, aged 2 to 20 years (n = 45), from this randomized clinical trial. Patients having > or = 3 primary generalized tonic-clonic seizures over an 8-week baseline were randomly assigned (1:1) to receive either lamotrigine or placebo. The treatment period consisted of an escalation phase (12 weeks for patients 2-12 years; 7 weeks for patients > 12 years) and a maintenance phase (12 weeks). The study had 4 phases: screening phase, baseline phase, escalation phase, and maintenance phase. During the screening phase, baseline medical examinations and seizure type and seizure frequency assessments were performed. During the 8-week baseline phase, the number and dosages of concomitant antiepileptic drugs were maintained while seizure frequency was assessed. The assessment of primary generalized tonic-clonic seizure frequency was determined during the 8-week baseline phase. Patients eligible for random assignment experienced > or =3 primary generalized tonic-clonic seizures during the baseline phase and > or = 1 primary generalized tonic-clonic seizure in the 8 weeks before the baseline phase. Lamotrigine was introduced and titrated using a schedule based on the patients' age and concurrent antiepileptic drug regimen. During the escalation phase, the number and doses of concomitant antiepileptic drugs were not changed. The escalation phase was followed by a 12-week maintenance phase during which time the lamotrigine dose was maintained at a specific dose defined by the patients' age and concomitant antiepileptic drugs, whereas the doses of concurrent antiepileptic drugs were maintained at a constant dose. Concurrent antiepileptic drugs could not be discontinued or added during the maintenance phase. The primary efficacy end point measure was the median reduction in the frequency of primary generalized tonic-clonic seizures from baseline; seizure counts were recorded prospectively in standardized daily seizure diaries. Other efficacy end point data for analysis were as follows: the median seizure counts, the median percentage change from the baseline phase in average monthly seizure frequency for other generalized seizure types, and the percentage of patients with a reduction of > or = 25%, > or = 50%, > or = 75%, or 100% in frequencies of primary generalized tonic-clonic seizures and all generalized seizures during the escalation phase and/or maintenance phase relative to the baseline phase. Accurate counts of absence seizure frequency require electroencephalogram-video monitoring; absence seizure frequency was not an outcome measure for this analysis. RESULTS: Forty-five (21 lamotrigine and 24 placebo) patients 2 to 19 years of age were randomly assigned and received study drug. Eight patients (3 lamotrigine and 5 placebo) had a combination of clinical (myoclonus and/or absence seizures) and electroencephalogram findings that were consistent with juvenile myoclonic epilepsy. Among the 45 children randomly assigned, 74% had generalized spike, polyspike, and/or generalized spike and wave discharges on routine electroencephalogram recordings; the remaining 26% of children had no electroencephalogram findings suggestive of partial epilepsy and a clear history consistent with primary generalized tonic-clonic seizures. Electroencephalogram findings were not significantly different between the lamotrigine and the placebo treatment groups. The median percentage decrease from baseline in primary generalized tonic-clonic seizures during the entire treatment period was 77% in the lamotrigine group and 40% in the placebo group (P = .044). The median primary generalized tonic-clonic seizure counts per month were 0.7 in the lamotrigine group and 3.6 in the placebo group during escalation (P = .008), 0.3 in the lamotrigine group and 2.0 in the placebo group during maintenance (P = .005), and 0.4 in the lamotrigine group and 2.5 in the placebo group during the entire treatment period (P = .007). Trends were noted during escalation and maintenance with a median percentage decrease in primary generalized tonic-clonic seizures during escalation of 72% in the lamotrigine group and 30% in the placebo group (P = .059), and 83% in the lamotrigine group and 42% in the placebo group during maintenance (P = .058). During the maintenance phase, 48% of lamotrigine patients were seizure free compared with 17% treated with placebo (P = .051). One patient from each treatment group discontinued from the study because of an adverse event; 1 patient who received lamotrigine experienced "disorientation"; and 1 patient who received placebo had a convulsion with apnea. No rashes occurred among patients taking lamotrigine or placebo. No patient experienced worsening of the intensity or frequency of myoclonus. CONCLUSIONS: Adjunctive lamotrigine therapy seems effective in controlling primary generalized tonic-clonic seizures among patients 2 to 20 years of age.