Is Lamotrigine the New Valproate? The Role of Lamotrigine in the Management of Generalized Epilepsy
abstracts & commentary
Sources: Eriksson AS, et al. The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: A randomized, double-blind, crossover study. Epilepsia 1998;39(5):495-501; Beran RG, et al. Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy. Epilepsia 1998;39(12):1329-1333; Guerrini R, et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 1998;39(5):508-512.
Clinical experience with lamotrigine increasingly supports its use in primary generalized epilepsies. Retrospective and open label studies in children with generalized epilepsies provided the first data that lamotrigine could be effective as add-on therapy for generalized epilepsies.1 The results of double-blind, placebo-controlled trials of lamotrigine as an add-on treatment for generalized epilepsy are now becoming available. The first of these trials was a double-blind, placebo-controlled study of add-on lamotrigine in the treatment of patients with Lennox-Gastaut syndrome (LGS).2 LGS, a severe childhood generalized epilepsy characterized by multiple seizure types, including atypical absence, tonic and atonic seizures, diffuse slow-spike and wave on EEG, and permanent cognitive and psychomotor disturbances is often refractory to pharmacotherapy. In the study by Motte and colleagues, 33% of patients in the lamotrigine treatment group had a more than 50% reduction in seizure frequency. Underscoring the importance of using a placebo-control group, 16% of the patients receiving placebo in this study experienced a more than 50% reduction in seizure frequency. The treatment group showed a 32% reduction in mean seizure frequency, compared to a 9% reduction in the placebo-treated group.
Eriksson and colleagues have examined the efficacy of lamotrigine as add-on therapy in generalized epilepsy in a population of 30 children and adolescents. Twenty of the patients were diagnosed with LGS; the remaining 10 patients had a mix of generalized seizure types including tonic-clonic, tonic-atonic, myoclonic seizures, and atypical absence seizures. Eriksson et al designed the study to include an open-label segment to determine a response to lamotrigine and to titrate dose. The open-label phase lasted an average of five months, with a range of 2-12 months. A reduction in seizure frequency of more than 50% or an improvement in behavior or motor skills, or both, was taken as evidence of treatment response. Overall, approximately two-thirds of patients showed a response to lamotrigine. Lamotrigine responders were then randomized to a treatment period when they would receive lamotrigine or placebo. Following a washout period, the same population of responders then received the alternate treatment for an equal period of time. Thus, each individual served as his or her own control. Half of the responders—that is one-third of the initial cohort—experienced a more than 50% reduction in seizure frequency and showed improvement in behavior or motor skills, or both. The other half of the responders had a smaller improvement in seizure frequency but, nevertheless, showed improved behavior and/or motor skills. Responders had half as many seizures on lamotrigine as they did on placebo.
Most recently, Beran and colleagues provide evidence that lamotrigine is also effective in an adult population of 26 patients with generalized epilepsy. These patients ranged in age from 15-50 years, with a mean age of 29 years, and suffered from a range of seizure types including absence, tonic-clonic, and myoclonic, as well as combinations of these types. The study used a crossover design in which there were two treatment periods (lamotrigine or placebo) of eight weeks separated by a four-week washout period. During the lamotrigine treatment phase, doses were increased to a therapeutic range over three weeks. Beran et al found that lamotrigine treatment resulted in a more than 50% reduction of seizures in one-third of patients with absence seizures and in one-half of patients with tonic-clonic seizures. The study population included two individuals with myoclonic seizures in addition to other seizure types. Although one must be cautious interpreting results from two patients, it is interesting to note that neither patient with myoclonic seizures improved on treatment, and one experienced more frequent seizures. The evidence that lamotrigine aggravates myoclonic seizures is stronger in a study by Guerrini and colleagues. Guerrini et al found that lamotrigine worsened seizure frequency in 80% of patients—ranging in age from 2-18 years—with severe myoclonic epilepsy of infancy. Forty percent of the patients experienced a more than 50% increase in tonic-clonic seizures and 33% suffered a more than 50% worsening of myoclonic seizures.
Serious adverse effects attributable to lamotrigine were only seen in the study by Beran et al, who reported rash as a frequent side effect and as a reason for discontinuing treatment. In this study, five of 26 patients developed a mild rash that resolved without discontinuation of lamotrigine treatment. Two patients developed a more serious rash that required discontinuation of lamotrigine. All patients who developed rash were also taking valproate.
Commentary
Considerable clinical evidence has accumulated supporting the use of lamotrigine as an add-on treatment for generalized epilepsy. The availability of results from double-blinded, placebo-controlled trials adds weight to the conclusion that lamotrigine appears effective. A notable exception to this, however, is the result that lamotrigine may increase seizure frequency of some patients with myoclonic epilepsy.
The mechanism of action of lamotrigine in generalized epilepsy remains unresolved. Lamotrigine has been observed to improve behavior and mood in patients and can improve memory in the normal population.3 The mechanism for these effects is also unknown. The early data on lamotrigine identified the use-dependent blockade of voltage-dependent sodium channels as a mechanism of antiepileptic action. This mechanism is often associated with efficacy in the treatment of partial epilepsy. There is also increasing evidence that lamotrigine inhibits the voltage-gated calcium channels and limits the entry of calcium into neurons.4 More work is necessary to determine which mechanisms confer the antiepileptic and behavioral effects of lamotrigine.
The incidence of rash varied considerably in the cited studies and bears further examination. The risk of rash that may progress to Stevens-Johnson syndrome is a considerable concern of clinicians and is greatest with concomitant use of valproate. In the study by Eriksson et al, the open-label phase of dose escalation lasted several months, and none of the 30 patients in the trial developed a rash. In contrast, the study by Beran et al achieved a therapeutic dose of lamotrigine in three weeks, and 26% of the study group, seven of 26 patients, developed a rash. These results emphasize the importance of increasing the dose of lamotrigine gradually, especially when given with valproate, which inhibits the metabolism of lamotrigine and may result in a greater blood level. In conclusion, when introduced gradually into a patient’s regimen, lamotrigine is an effective add-on drug against generalized epilepsy and may also produce beneficial effects in behavior and mood. —fred a. lado & solomon l. moshé (Dr. Lado is EEG Fellow, Department of Neurology, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, NY. Dr. Moshé is Professor and Director, Pediatric Neurology and Clinical Neurophysiology, Department of Neurology, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, NY.)
References
1. Mikati MA, Holmes GL. Lamotrigine in absence and primary generalized epilepsies. J Child Neurol 1997; 12 Suppl 1:S29-37.
2. Motte J, et al. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N Engl J Med 1997;337(25):1807-1812.
3. Binnie C. Lamotrigine. In Epilepsy: A Comprehensive Textbook. Lippincott-Raven Press; 1997.
4. Wang SJ, et al. Lamotrigine inhibits depolarization-evoked Ca++ influx in dissociated amygdala neurons. Synapse 1998;29:355-362.
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