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N Engl J Med. 2010 Mar 4;362(9):790-9. doi: 10.1056/NEJMoa0902014.

Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy.

Collaborators (157)

Glauser TA, Cnaan A, Adamson PC, Hirtz DG, Shinnar S, Clancy RR, Capparelli EV, Grabowski G, Blumer J, Pellock JM, Grabowski G, Keddache M, Tangren G, Srodulski S, Capparelli EV, Blumer J, Adamson PC, Reed MD, Vinks AA, Shinnar S, Moshé SL, Mizrahi EM, Conry JA, Berg A, Dlugos D, Sogawa Y, Le Pichon JB, Overby P, Von Allmen G, Shinnar S, Masur D, O'Dell C, Levisohn PM, Masur J, Cnaan A, Weiler C, Dorsey E, Scott C, Thevathasan N, Nissen V, Nandwani G, Gleave M, Schneider J, Vasconcelos M, Evans S, Bintliff-Janisak B, Daniels K, Shabbout M, Shera D, Luan X, Lawrence L, Guo R, DiStefano-Pappas J, Grubb M, Taylor M, Bernhard G, Nevy J, Drummond N, Donaghue M, Davis M, Peccina N, Alvarado-Taylor T, Gilbert PR, Alldredge BK, Bourgeois B, Buchhalter JR, Hamberger MJ, Roecker EB, Rodman JH, Hoffman M, Montefiore K, LaGory D, Hirtz DG, Jacobs M, Janis S, Gilbert PR, Philbrook B, Schwam D, Kankirawatana P, Hoyle K, Weinstock A, Elgie M, Kelley KR, Tekateka M, Glauser TA, Clark PO, Scher MS, Morus D, Paolicchi J, Zamel K, Borror S, Elterman R, McEwen K, Levisohn PM, Brantz S, Chugani HT, Czachor J, Hernandez A, Kidd J, Wilfong AA, Schultz R, McVey SJ, Turk WR, Abram H, Oken S, Williams T, Shbarou R, Griebel ML, Howard L, Riggs A, Sankar R, Dewar S, Perez A, Wheless J, Ellis M, Duchowny M, Halac A, Barrera J, Zupanc M, Werner R, Novotny E Jr, Cardoza C, Ballaban-Gil K, O'Dell C, Miles DK, Miceli M, Frank LM, Conklin T, Clancy RR, Collins Y, Khurana D, Francis A, Chapman K, Rho JM, Reese-Porter A, Crumrine PK, Williams S, Eaton T, Roberts C, Borzy C, Dean S, Van Orman CB, Taylor S, Narus J, Trauner DA, Nespeca M, Romine K, Saneto RP, Sotero de Menezes M, Guidry L, Trevathan E, Bertrand M, Albers E, Grayson L, Conry JA, Shah S, Lowery D.



Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with ethosuximide, valproic acid, or lamotrigine. The most efficacious and tolerable initial empirical treatment has not been defined.


In a double-blind, randomized, controlled clinical trial, we compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy. Drug doses were incrementally increased until the child was free of seizures, the maximal allowable or highest tolerable dose was reached, or a criterion indicating treatment failure was met. The primary outcome was freedom from treatment failure after 16 weeks of therapy; the secondary outcome was attentional dysfunction. Differential drug effects were determined by means of pairwise comparisons.


The 453 children who were randomly assigned to treatment with ethosuximide (156), lamotrigine (149), or valproic acid (148) were similar with respect to their demographic characteristics. After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar (53% and 58%, respectively; odds ratio with valproic acid vs. ethosuximide, 1.26; 95% confidence interval [CI], 0.80 to 1.98; P=0.35) and were higher than the rate for lamotrigine (29%; odds ratio with ethosuximide vs. lamotrigine, 2.66; 95% CI, 1.65 to 4.28; odds ratio with valproic acid vs. lamotrigine, 3.34; 95% CI, 2.06 to 5.42; P<0.001 for both comparisons). There were no significant differences among the three drugs with regard to discontinuation because of adverse events. Attentional dysfunction was more common with valproic acid than with ethosuximide (in 49% of the children vs. 33%; odds ratio, 1.95; 95% CI, 1.12 to 3.41; P=0.03).


Ethosuximide and valproic acid are more effective than lamotrigine in the treatment of childhood absence epilepsy. Ethosuximide is associated with fewer adverse attentional effects. ( number, NCT00088452.)

2010 Massachusetts Medical Society

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