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How Effective Is Lamotrigine in Primary Generalized Tonic-Clonic Seizures?

Further evidence favors lamotrigine as an add-on drug for this seizure type.

The authors present a randomized, double-blind trial comparing lamotrigine with placebo as adjunctive therapy for recurrent primary generalized tonic-clonic (PGTC) seizures in 117 patients (age 2 years) already receiving one or two antiepileptic drugs (AEDs). Eighty-seven patients (74%) completed this manufacturer-funded study. After an 8-week baseline phase during which seizure frequency was assessed, participants underwent a 7- or 12-week dose-escalation phase, followed by a 12-week dose-maintenance phase. Patient age and use of concomitant AEDs determined the rate of drug escalation and target dose. The primary endpoint was the change from baseline in average monthly PGTC seizure frequency. An important secondary endpoint was seizure reduction for all generalized seizure types.

Seizure frequency decreased more in the lamotrigine group than in the placebo group for PGTC (by 66.5% vs. 34.2%; P=0.006) as well as for all generalized seizures (by 46.8% vs. 15.9%; P=0.004). The result was similar in pediatric (age 2–12) and older (age >12) patients, although the small sample sizes precluded statistically significant results. No aggravation of other seizure types, particularly myoclonic seizures, was seen. Side effects were minor in the treatment group, with only one non-serious rash reported.

Comment: Because most patients with idiopathic generalized epilepsies have adequate seizure control, few randomized clinical trials of PGTC have been conducted. Previous studies have been hampered by the difficulty in distinguishing primary from secondarily generalized seizures, which is crucial as they are pathophysiologically distinct. These authors performed thorough evaluations to eliminate secondarily generalized seizures. This is especially important as they did not classify patients by epilepsy syndrome, but by seizure type. This selection process was likely chosen because only about 70% of patients with PGTC seizures have other generalized seizure types or family histories to suggest a distinct generalized epilepsy syndrome.

The latest AAN guidelines state that only topiramate has sufficient evidence to warrant its use as adjunctive therapy for refractory primary generalized epilepsy in adults (Neurology 2004; 62:1261; see Journal Watch Neurology Aug 6 2004). However, other modern broad-spectrum AEDs often are used in this setting, particularly zonisamide, levetiracetam, and lamotrigine. This study establishes that lamotrigine is an effective add-on treatment for refractory PGTC seizures. Results might have been even stronger if higher doses of lamotrigine had been used; serum concentrations of the drug, though variable, were low except in patients on valproate.

— Jong Woo Lee, MD

Dr. Lee is a Fellow in Epilepsy, Department of Neurology, Brigham and Women’s Hospital, Boston.

Published in Journal Watch Neurology February 23, 2006

Citation(s):

Biton V et al. Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures. Neurology 2005 Dec 13; 65:1737-43.

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