Lamotrigine versus valproic acid as first-line monotherapy in newly diagnosed typical absence seizures: An open-label, randomized, parallel-group study
Coppola G, Auricchio G, Federico R, Carotenuto M and Pascotto A;
Commented by , 22 Oct 2004
Background
Although valproic acid (VPA) is usually regarded as the drug of choice for typical absence seizures (ref. 1), there is evidence that lamotrigine (LTG) may also be effective (refs. 2-8). There has never been, however, a head-to-head comparison of these two drugs.
Aim
To compare the efficacy of VPA and LTG in children and adolescents with typical absence seizures.
Prospective randomized open-label parallel-group flexible-dose comparison, up to 12-month follow-up.
LTG was started at 0.5 mg/kg/day and increased in 1 mg/kg increments every 5 days up to a maximum of 12 mg/kg/day. For VPA, starting dose was 10 mg/kg/day, with 5 mg/kg increments every 3 days up to a maximum of 30 mg/kg/day.
Efficacy defined as seizure freedom based on clinical observation plus a 24-h ambulatory EEG testing plus one video-EEG session including hyperventilation.
Results
After 1 month, 10 of 19 (53%) children given VPA and 1 of 19 (5%) given LTG were seizure-free (p=0.004).
At 3 months, 12 (63%) children taking VPA and 7 (37%) taking LTG were controlled (p=0.19).
At 12 months, 13 children on VPA and 10 on LTG were controlled (p=0.51).
Mostly mild adverse effects were recorded in 11% of children given VPA or 32% taking LTG.
Professor Perucca's comment
The two primary agents to treat typical absence seizures are VPA and ethosuximide (ETS), but VPA is usually preferred because, unlike ETS, it protects against tonic-clonic seizures, which often co-exist in these patients (ref. 9).
VPA shows excellent efficacy but it has undesirable side effects. In particular, the risks for the unborn baby are a concern whenever VPA treatment is anticipated to continue into childbearing age (refs. 10-12).
LTG partly resembles VPA in having broad spectrum activity ageist many seizure types (ref. 13). LTG has been found to be superior to placebo in controlling absence seizures in an enriched trial (ref. 14), but its efficacy in comparison VPA has not been established.
The most valuable finding of this study is that, because of its slower titration requirements (and despite the use, in this study, of higher than recommended starting dosages), LTG onset of action is much slower than that of VPA, exposing children to uncontrolled seizures for many more weeks.
Unfortunately, however, the study was grossly underpowered to detect possible efficacy differences during the maintenance phase. This, although there was a clear trend for LTG to remain less efficacious at 3 and at 12 months, sample size was insufficient to determine whether this difference is real.
For practical purposes, a several weeks delay in controlling a benign condition such as childhood absence epilepsy has only limited importance. However, because treatment in these children is rarely continued into childbearing age, there seem to be no clear advantages in preferring LTG over VPA. While VPA may cause weight gain and, rarely, liver toxicity, LTG carries a higher risk of hypersensitivity reactions, and the risk of LTG-induced serious skin rashes is higher in children than in adults (ref. 15).
References
1. Perucca E. The management of refractory idiopathic epilepsies. Epilepsia 2001; 42 (suppl. 3): 31-5
2. Schlumberger E, Chavez F, Palacios L, et al. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia 1994; 35: 359-67
3. Ferrie CDE, Robinson RO, Knott C, et al. Lamotrigine as an add-on drug in typical absence seizures. Acta Neurol Scand 1995; 91: 200-2
4. Mikati MA, Holmes GL. Lamotrigine in absence and primary generalized epilepsies. J Child Neurol 1997; 12 (suppl 1): S29-37
5. Frank LM, Enlow T, Holmes GL, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 1999; 40: 973-9
6. Gericke CA, Picard F, de Saint-Martin A, et al. Efficacy of lamotrigine in idiopathic generalized epilepsy syndromes: A video-EEG-controlled, open study. Epileptic Disord 1999; 1: 159-65
7. Buoni S, Grosso S, Fois A. Lamotrigine in typical absence epilepsy. Brain Dev 1999; 21: 303-6
8. Barron TF, Hunt SL, Hoban TF, et al. Lamotrigine monotherapy in children. Pediat Neurol 2000; 23: 160-3
9. Perucca E. Pharmacological and therapeutic properties of valproate: A summary after 35 years of clinical experience. CNS Drugs 2002; 16: 695-714
10. National Institute of Clinical Excellence, Newer drugs for epilepsy. Technology Appraisal 76, London, 2004 (www.nice.org.uk/TA076guidance)
11. Perucca E. NICE guidance on newer drugs for epilepsy in adults. Brit Med J 2004; 328: 1273-4 (Note: Free full text article available)
12. Tomson T, Perucca E, Battino D. Navigating through signals towards foetal and maternal health: The challenge of treating epilepsy in pregnancy. Epilepsia 2004, in press
13. Perucca E. The clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fundam Clin Pharmacol 2001; 15: 405-17
14. Frank LM, Enlow T, Holmes GL, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 1999; 40: 973-9
15. Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated rash: Risk/benefit considerations in adults and children. Epilepsia 1999; 40: 985-91