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Epilepsia, 52(Suppl. 2):72–75, 2011 doi: 10.1111/j.1528-1167.2011.03007.x DRAVET SYNDROME The pharmacologic treatment of Dravet syndrome *yzCatherine Chiron and *yzOlivier Dulac *Inserm, U663, Paris, France; yUniversity Paris Descartes, Faculty of Medicine, Paris, France; and zNeuropediatric Department, APHP, Necker Hospital, Paris, France from pharmacokinetic interactions of stiripentol powerfully inhibiting cytochromes P450. Stiripentol acts as a c-aminobutyric acid (GABA)ergic agent, mainly via the a3 subunit of GABAA receptors. Stiripentol (Diacomit) was approved as an orphan drug in 2007 in Europe for adjunctive therapy in DS. Up to now, >500 children have been safely treated, and recent experiment in Japan confirmed stiripentol benefit in DS children with comedications other than valproate and clobazam. Because early status epilepticus is likely to negatively impact cognitive outcome, we recommend the introduction of stiripentol as soon as the diagnosis of DS is clinically confirmed. Topiramate and the ketogenic diet are alternatives in pharmacoresistant cases. KEY WORDS: Dravet syndrome, Child, Epilepsy, Stiripentol, Topiramate. SUMMARY Dravet syndrome (DS) is one of the most pharmacoresistant epilepsy syndromes. Valproate is used as a first-line agent to prevent the recurrence of febrile seizures and oral/nasal/rectal benzodiazepine is used for any long-lasting seizures, but these agents are most often insufficient. Lamotrigine, carbamazepine, and high doses of intravenous phenobarbital should be avoided because they may worsen seizures. Topiramate, levetiracetam, bromide, and the ketogenic diet may provide substantial efficacy as adjunctive therapy/procedure. Stiripentol is the only compound that proved its efficacy in DS through two independent randomized placebo-controlled trials, when combined with valproate and clobazam. Their dose has to be decreased to minimize the side effects (mostly loss of appetite) resulting is well known to occur particularly in delayed infants, which is not the case here, and that any unexplained and repeated vomiting could express poor tolerability; this approach is much more reliable than systematic monitoring of transaminases (Camfield et al., 1986). To prevent further long-lasting seizures, the parents should be encouraged to administer oral/nasal/rectal benzodiazepine–diazepam or midazolam for any seizure lasting more than a few minutes. However, repetition of the seizures permits the diagnosis to be considered, and to no longer consider complicated febrile seizures but epilepsy most likely related to a mutation in SCN1A. Diagnosis usually becomes possible before the end of the first year of life, and raises the issue of the most appropriate treatment. According to Dravet and Bureau (2008), an impressive list of drugs has been administered: phenobarbital, valproate, phenytoin, and benzodiazepines—clonazepam or nitrazepam more than clobazam—for convulsive seizures; ethosuximide, piracetam and benzodiazepines—for myoclonus; and clorazepate, methsuximide, acetazolamide, allopurinol, sulthiame, and zonisamide for other As for many epilepsy syndromes, the syndromic diagnosis in Dravet syndrome (DS) builds up progressively in the course of the disease. Indeed, first seizures usually consist of complicated febrile seizures before the full blown pattern appears. The main challenges are to reduce as much as possible the seizure frequency, to prevent the occurrence of status epilepticus, and to optimize the development of cognitive functions. Before the diagnosis is established, complicated febrile seizures deserve daily treatment from the first episode, since they occur very early and the risk of recurrence is, therefore, high. Valproate is the most efficacious compound to prevent such a recurrence (Rantala et al., 1997). The risk of acute hepatic failure is taken into account, with an explanation to parents and caretakers that this condition Address correspondence to Catherine Chiron, U663, Service de Neurologie et Metabolisme, Hopital Necker, 149 rue de Sevres, 75015 Paris, France. E-mail: [email protected] Wiley Periodicals, Inc. ª 2011 International League Against Epilepsy 72 73 The Pharmacologic Treatment of Dravet Syndrome seizure types, vigabatrin being occasionally useful in adolescence. However, the benefit of all these compounds is mild, and there are no trials to validate the impression of any effect. Soon after the identification of the syndrome, compounds that worsened symptoms were identified, namely lamotrigine that involves up to 80% of the patients, although with the very progressive introduction of this compound several weeks may be required to disclose the effect (Guerrini et al., 1998); carbamazepine and vigabatrin worsening is in the order of 60% (Thanh et al., 2002). This effect could be reproduced in isolated hippocampi of newborn rats whose interconnections had been preserved and who were depleted of magnesium: not only is there worsening during the time of drug administration, but the negative effect persists after washout (Quilichini et al., 2003). In addition, infants with DS were recently reported who received intravenous high dosing phenobarbital and/ or Pentothal for convulsive status epilepticus and developed global and definitive cerebral atrophy with dramatic neurologic worsening (Chipaux et al., 2010). This Raises the Issue of Which Compounds can Benefit the Patient Bromide was introduced by Doose in 1990 for the treatment of convulsive epilepsies in infancy: at the dose of 60–80 mg/kg, 32% became free of tonic–clonic seizures and another 47% experienced >50% decrease in seizure frequency (Ernst et al., 1988). However, the compound had no effect on minor seizures that were even worsened, and there was no effect on focal and tonic seizures. Acne, loss of appetite and weight, and fatigue were the main adverse effects. Japanese authors reported the compound as the most efficient in their DS cohort (Tanabe et al., 2008). Topiramate was recognized as a possible indication by three studies: Nieto-Barrera et al. (2000) and Coppola et al. (2002), who indicated that 56% responders had a >50% decrease of seizure frequency and 16.7% became seizure-free, and Kroll-Seger et al. (2006) who had 78% responders and 17% seizure-free. In all three reports, half the patients had adverse effects: anorexia and behavior troubles. Levetiracetam gave in a single study the same results for convulsive seizures but in addition seemed useful for myoclonus (Striano et al., 2007). Stiripentol (STP) is the only compound for which a placebo-controlled double-blind trial has been performed. This agent, which is structurally unrelated to any currently marketed antiepileptic compound, proved to be GABAergic in vitro on immature rats (Quilichini et al., 2006) and to act as a direct allosteric modulator of the GABAA receptor mainly through the a3 subunit, which is expressed predominantly during development (Fisher, 2009). In humans, STP also inhibits the cytochrome P450 (CYP) system in the liver, resulting in an increased plasma concentration of concomitant AEDs, particularly clobazam, mainly through CYP 2C19 (Giraud et al., 2006). STP efficacy in children with DS was first suspected in one open exploratory trial (10 of 20 responders; Perez et al., 1999) and then confirmed in two randomized placebo-controlled trials, independently conducted in France and Italy (Chiron et al., 2000). In these studies STP was combined with clobazam (CLB) and valproate (VPA). Respectively, 71% and 67% of patients were responders on STP against 5% and 9% on placebo (p < 0.002). A meta-analysis of these two trials showed that STP significantly multiplies by 32 the odds of responders [confidence interval (CI) 6.2–161] and reduces the overall seizure rate by 70% (93%; 47%; Kassai et al., 2008). The limited number of patients (41 and 23) required to demonstrate a significant difference between STP and placebo is remarkable in these two studies focused on a nosologically and etiologically homogeneous syndrome, whereas for other compounds >100 patients were necessary for more heterogeneous groups such as partial onset seizures or Lennox-Gastaut syndrome (Motte et al., 1997; Glauser et al., 2006). Long-term efficacy assessed in a monocenter cohort of 46 DS patients treated with STP, VPA, and CLB for a median 3 years showed a significant reduction of both frequency and duration of seizures (Thanh et al., 2002). Efficacy was best in infants, with a strong benefit of STP to shorten prolonged convulsions. An open add-on study conducted in Japan on 25 DS patients reported a responder rate for generalised tonic– clonic seizures of 61% at short term (mean 6 weeks) and 48% at long term (mean 6 months; Inoue et al., 2009). Efficacy seemed to be higher than in the French study in the eight patients older than 13 years, and tolerability was not a concern. About half these patients received VPA and CLB comedication; the others received clonazepam, phenobarbital, zonisamide, or bromide. Therefore, not only Caucasian patients, but also Japanese patients can benefit from STP despite a higher rate of homozygous polymorphism of CYP 2C19 rendering inefficient the inhibitory effect of STP on CLB. Together with the variety of comedications, this provides an indirect argument for STP being anticonvulsant per se in these patients. Adverse events were reported in about half the patients and included drowsiness, slowing of mental function, ataxia, diplopia, loss of appetite with weight loss, nausea, and abdominal pain. Asymptomatic neutropenia is occasionally observed. Most adverse events are related to a significant increase in the plasma concentrations of VPA, CLB, and Nor-CLB after adding STP, and disappear when the comedication dose is decreased (Perez et al., 1999; Chiron et al., 2000). A European still ongoing Epilepsia, 52(Suppl. 2):72–75, 2011 doi: 10.1111/j.1528-1167.2011.03007.x 74 C. Chiron and O. Dulac postmarketing survey confirmed the good long-term safety of STP in the 97 DS patients newly treated within a 32-month period. Pharmacokinetic of STP was studied with a population approach in a prospective series of 35 children with DS who were receiving the STP–VPA–CLB combination (personal data). The final model was a one-compartment model with first-order absorption and elimination rate. Because elimination clearance and volume of distribution were found to be related to body weight, it was concluded that STP dose should be adjusted with respect to body weight in children. The recommended STP dose is 50 mg/ kg/day in two or three administrations. Due to pharmacokinetic drug–drug interactions, it is advised to prescribe VPA and CLB at the maximum doses of 20 and 0.5 mg/ kg/day, respectively. STP was the first AED granted orphan drug status at the European Medical Agency (EMEA) in 2000. STP was registered as an orphan drug in January 2007 in Europe for DS as adjunctive therapy with VPA and CLB, based on the two confirmatory placebo-controlled trials. However, this approval is conditional: EMA required an additional efficacy study in children with DS to determine whether the combination of STP + CLB is more efficient than CLB at maximum tolerated doses. A European trial is currently starting and this faces important difficulties in manufacturing the blind products and recruiting STP-naive children. It is noteworthy that the scientific background has dramatically changed since this trial was designed in 2007: STP proved to be antiepileptic per se in animal models; data confirming STP efficacy in DS were generated outside Europe (particularly in Japan, Canada, and United States), and safety data increased. Animal models of DS are now available (Yu et al., 2006; Oakley et al., 2009) that should prevent exposing human patients to unnecessary cognitive studies. Indeed, epileptic seizures, and especially the number of status epilepticus events in the first years of life are likely to contribute to the mental retardation so that any drug that could decrease their frequency, as STP does, may be beneficial as soon as the diagnosis is confirmed. Disclosures Catherine Chiron has received support from Biocodex, Johnson and Johnson, and Eisai. Olivier Dulac has received support from Biocodex. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References Camfield C, Camfield P, Smith E, Tibbles JA. (1986) Asymptomatic children with epilepsy: little benefit from screening for anticonvulsant-induced liver blood or renal damage. Neurology 36: 838–841. Epilepsia, 52(Suppl. 2):72–75, 2011 doi: 10.1111/j.1528-1167.2011.03007.x Chipaux M, Villeneuve N, Sabouraud P, Desguerre I, Boddaert N, Depienne C, Chiron C, Dulac O, Nabbout R. (2010) Unusual consequences of status epilepticus in Dravet syndrome. Seizure 19: 190–194. Chiron C, Marchand MC, Tran A, Rey E, d’Athis P, Vincent J, Dulac O, Pons G. (2000) Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial, STICLO study group. Lancet 356:1638–1642. Coppola G, Capovilla G, Montagnini A, Romeo A, Spano M, Tortorella G, Veggiotti P, Viri M, Pascotto A. (2002) Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial. Epilepsy Res 49:45–48. Dravet C, Bureau M. (2008) Severe Myoclonic Epilepsy in Infancy (Dravet syndrome). In Engel J, Pedley TA (Eds) Epilepsy, a comprehensive textbook. 2nd ed. Lippincott Williams Wilkins, Philadelphia, pp. 2337–2342. Ernst JP, Doose H, Baier WK. (1988) Bromides were effective in intractable epilepsy with generalized tonic-clonic seizures and onset in early childhood. Brain Dev 10:385–388. Fisher JL. (2009) The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator. Neuropharmacology 56:190–197. Giraud C, Treluyer JM, Rey E, Chiron C, Vincent J, Pons G, Tran A. (2006) In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism. Drug Metab Dispos 34:608–611. Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, Lu Z. (2006) Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 66:1654–1660. Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O. (1998) Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 39:508–512. Inoue Y, Ohtsuka Y, Oguni H, Tohyama J, Baba H, Fukushima K, Ohtani H, Takahashi Y, Ikeda S. (2009) Stiripentol open study in Japanese patients with Dravet syndrome. Epilepsia 50:2362–2368. Kassai B, Chiron C, Augier S, Cucherat M, Rey E, Guerrini R, Vincent J, Dulac O, Pons G. (2008) Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data. Epilepsia 49:343–348. Kroll-Seger J, Portilla P, Dulac O, Chiron C. (2006) Topiramate in the treatment of highly refractory patients with Dravet syndrome. Neuropediatrics 37:325–329. Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, Manasco P. (1997) Lamotrigine for generalized seizures associated with the Lennox–Gastaut syndrome, Lamictal Lennox–Gastaut Study Group. N Engl J Med 337:1807–1812. Nieto-Barrera M, Candau R, Nieto-Jimenez M, Correa A, del Portal LR. (2000) Topiramate in the treatment of severe myoclonic epilepsy in infancy. Seizure 9:590–594. Oakley JC, Kalume F, Yu FH, Scheuer T, Catterall WA. (2009) Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy. Proc Natl Acad Sci USA 106:3994– 3999. Perez J, Chiron C, Musial C, Rey E, Blehaut H, d’Athis P, Vincent J, Dulac O. (1999) Stiripentol: efficacy and tolerability in children with epilepsy. Epilepsia 40:1618–1626. Quilichini PP, Diabira D, Chiron C, Milh M, Ben Ari Y, Gozlan H. (2003) Effects of antiepileptic drugs on refractory seizures in the intact immature cortico-hippocampal formation in vitro. Epilepsia 44:1365–1374. Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H. (2006) Stiripentol a putative antiepileptic drug enhances the duration of opening of GABA-receptor channels. Epilepsia 47:704–716. Rantala H, Tarkka R, Uhari M. (1997) A meta-analytic review of the preventive treatment of recurrences of febrile seizures. J Pediatr 131:922–925. Striano P, Coppola G, Pezella M, Ciampa C, Specchio N, Ragona F, Mancardi MM, Gennaro E, Beccaria F, Capovilla G, Rasmini P, Besana D, Coppola G, Elia M, Granata T, Vecchi M, Vigevano F, Viri M, Gaggero R, Striano S, Zara F. (2007) An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy. Neurology 69:250–254. 75 The Pharmacologic Treatment of Dravet Syndrome Tanabe T, Awaya Y, Matsuishi T, Iyoda K, Nagai T, Kurihara M, Yamamoto K, Minagawa K, Maekawa K. (2008) Management of and prophylaxis against status epilepticus in children with severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome) – a nationwide questionnaire survey in Japan. Brain Dev 30:629–635. Thanh TN, Chiron C, Dellatolas G, Rey E, Pons G, Vincent J, Dulac O. (2002) Efficacy and tolerability of stiripentol in the treatment of severe myoclonic epilepsy in infancy (Dravet syndrome). Arch Pediatr 9:1120–1127. Yu FH, Mantegazza M, Westenbroek RE, Robbins CA, Kalume F, Burton KA, Spain WJ, McKnight GS, Scheuer T, Catterall WA. (2006) Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci 9:1142–1149. Epilepsia, 52(Suppl. 2):72–75, 2011 doi: 10.1111/j.1528-1167.2011.03007.x