The relationship between treatment with valproate, lamotrigine and topiramate and the prognosis of the idiopathic generalized epilepsies
Nicolson A, Appleton RE, Chadwick DW and Smith DF;
Commented by , 24 Mar 2004
Background
Valproate is generally regarded as the gold standard for treating idiopathic generalised epilepsies (IGEs) (ref. 1). There are, however, increasing safety concerns about its use, particularly in women of childbearing potential (ref. 2,3,4,5,6).
Although newer generation drugs, particularly lamotrigine, are increasingly prescribed in IGEs (ref. 7), their efficacy profile in comparison with valproate has not been established. A recent small retrospective cohort study suggested that lamotrigine may have comparable efficacy to valproate (ref. 8).
Aim
To estimate clinical variables, including drug treatment, affecting remission rates in IGEs.
Methods
Retrospective survey of medical records of 962 IGE patients at large adult and pediatric epilepsy clinics in the U.K.
Results
Fifty-four percent of patients achieved one-year remission. Outcome was more favorable in generalized tonic-clonic seizures on awakening than in other syndromes.
One-year remission was observed in 51% of patients on valproate monotherapy (n=549), compared with 17% of those on lamotrigine monotherapy (n=156) and 35% of those on topiramate monotherapy (n=26).
The most important factor affecting outcome was the rank order in which a drug was given. For valproate, remission rates were about 50% when it was used as the first drug compared with 10% when 5 other AEDs had already failed.
Among patients on initial monotherapy, valproate was still associated with higher remission rates than lamotrigine (50% vs 28%).
Relapse rates after AED discontinuation were high (79%), particularly in patients with juvenile myoclonic epilepsy (94%).
Comment
This is the largest outcome study ever performed in IGEs. Nevertheless, several major limitations should be kept in mind:
· Assessment was retrospective, resulting in possible ascertainment bias (such as selective loss of seizure-free patients) and inaccuracies in quality of data, including diagnostic categories;
· A study conducted in specialized centres, including adult clinics, may have resulted in over-representation of severe epilepsies and epilepsies less likely to remit;
· Treatment was not randomized, and drug-associated differences in outcome could be affected by differences in confounders such as syndromic types and sequence in which AEDs were used.
The most important emerging message is a signal (not the demonstration!) that, contrary to what is believed by many physicians, lamotrigine may be considerably less efficacious than valproate, at least in some IGEs. The comparative efficacy of topiramate could not be meaningfully assessed due to small sample size.
At least to some extent, the higher remission rates on valproate compared with lamotrigine may be due to the fact that the latter was used more often in patients who had failed on valproate. Nevertheless, additional findings (including sub-analysis of patients switched from valproate to lamotrigine and viceversa) suggested that lamotrigine had indeed inferior efficacy. Unfortunately, the survey did not assess how these drugs compared in individual syndromes.
The authors suggest that patients failing on valproate should be given lamotrigine adjunctively rather than being switched from valproate to lamotrigine. Certainly, some findings in this survey support already available evidence that the combination of these drugs may be highly effective in patients refractory to either agent alone (ref. 9,10). Randomized trials comparing valproate and newer AEDs in specific IGE syndromes are urgently needed.
References
Ref. 1. Perucca E. Pharmacological and therapeutic properties of valproate: A summary after 35 years of clinical experience. CNS Drugs 2002;16:695-714
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Ref. 2. Adab N, Jacoby A, Smith DF et al. Additional educational needs in children born to mothers with epilepsy. J. Neurol.Neurosurg. Psychiatry 2001;70:15-21
Ref. 3. Craig J, Russell A, Parsons L, et al. The UK Epilepsy and Pregnancy Register: update of results 1996-2002. Epilepsia 2002; 43 (suppl 8):56
Ref. 4. Duncan S. Policystic ovarian syndrome in women with epilepsy: A review. Epilepsia 2001; 42 (suppl 3):60-65
Ref. 5. Moore SJ, Turnberry PD, Quinn A et al. A clinical study of 57 children with fetal anticonvulsant syndrome. J Med Genet 2000;37:489-49
Ref. 6. Tennis P, Eldridge RR and the International Lamotrigine Pregnancy Registry Scientific Advisory Committtee. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia 2002; 43:1161-1167
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Ref. 7. Perucca E. The management of refractory idiopathic epilepsies. Epilepsia 2001;42 (suppl 3), 31-35
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Ref. 8. Prasad A, Kuzniecky RI, Knowlton RC, Welty TE, Martin RC, Mendez M, Faught RE. Evolving antiepileptic drug treatment in juvenile myoclonic epilepsy. Arch Neurol. 2003;60(8):1100-5
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Ref. 9. Brodie MJ, Yuen AWC. Lamotrigine substitution study: evidence for synergism with sodium valproate. 105 Study Group. Epilepsy Res 1997;26:423–432.
Ref. 10. Pisani F, Oteri G, Russo MF, et al. The efficacy of valproate-lamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia 1999;40:1141–1146
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