Current therapeutic procedures in dravet syndrome

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY Current therapeutic procedures in Dravet syndrome 1 Inserm, U663, Paris, UniversitØ Paris Descartes, Paris, France. 2 AP-HP, Service de Neurologie et MØtabolisme, Hôpital Necker, Paris, France.
Correspondence to Dr Catherine Chiron at U663 – Service de Neurologie et MØtabolisme, Hôpital Necker, 149, rue de S›vres, 75015 Paris, France. E-mail: [email protected] Dravet syndrome is a highly pharmaco-resistant form of epilepsy. Valproate and benzodiazepines Accepted for publication 7 March 2011.
are the first-line treatment but are usually insufficient therapeutic options. Lamotrigine, carbamaz-epine and high doses of intravenous phenobarbital can aggravate seizures and should be avoided.
Topiramate, levetiracetam, bromide and ketogenic diet also provide substantial efficacy as adjunc-tive therapy and procedures. Stiripentol is the only new drug to demonstrate efficacy when com-bined with valproate and clobazam, as shown in two independent double-blind controlled trialsdedicated to Dravet children. In order to avoid side effects (mainly loss of appetite and loss ofweight) resulting from the inhibition of cytochromes P450 by stiripentol, the prescribed doses ofvalproate and clobazam should be reduced. Stiripentol has a proper antiepileptic effect andenhances GABAergic neurotransmission by acting on the alpha-3 subunit of GABAA receptors.
Stiripentol was approved as an orphan drug in Europe in 2007 for adjunctive therapy in Dravetsyndrome. More than 500 Dravet patients have currently been satisfactorily treated and recentexperiments in Japan have confirmed stiripentol’s benefit. In practice, valproate should beinitiated at the first onset of complicated febrile seizure in Dravet patients. Relapses justify theaddition of clobazam and stiripentol when available. Topiramate and a ketogenic diet are alterna-tives in pharmaco-resistant cases.
Dravet syndrome is one of the most pharmaco-resistant form 95% of cases. Seizure worsening is also described with carba- of epilepsy. The mental prognosis of these patients is poor, mazepine and vigabatrin; 61% and 64%, respectively, out of 46 with a cognitive decline from normal to severe retardation as patients worsened in a personal series.4 Recently, a global and soon as the second year of life. Although it has not been defi- definitive cerebral atrophy with dramatic neurological worsen- nitely proven, there is some evidence that the magnitude of ing was reported in three infants with Dravet syndrome who mental deterioration seems to be related to the frequency of had received high-dose intravenous phenobarbital and ⁄ or pen- seizures.1 Therefore, antiepileptic drugs (AED) that could tothal for convulsive status epilepticus.5 These four therapeu- have a positive impact on seizure activity would also be tic modalities must therefore be avoided in Dravet patients.
expected to favourably affect cognitive prognosis.
In contrast, two new drugs are useful for treating Most authors agree that the response to conventional AEDs these patients, stiripentol (STP) and topiramate. STP is generally disappointing. Valproate and benzodiazepines may (DIACOMITÒ, BIOCODEX) is structurally unrelated to any decrease the frequency and duration of convulsive seizures, other marketed AED. A GABAergic effect of STP has been but their effect is modest. Some investigators associate pheno- demonstrated in vitro on immature rats.6 STP acts as a direct barbital, phenytoin and ethosuximide with poor outcome. Jap- allosteric modulator of the GABAA receptor mainly through anese authors recently reported bromide as the best compound the development-related alpha-3 subunit.7 In humans, STP for preventing status epilepticus in their practice in a retro- also inhibits the cytochrome P450 (CYP) system in the liver, spective review of 99 children with Dravet syndrome.2 resulting in an increased plasma concentration of the con- Some AEDs can paradoxically worsen seizures in Dravet syn- comitant AEDs metabolized by CYP. In Dravet patients, such drome. This effect was observec with Lamotrigine in 80% of a pharmacokinetic interaction particularly applies to clobazam, 20 patients recruited in three epilepsy centers.3 A>50% increase in generalized tonic-clonic seizures (GTCS) was STP efficacy in children with Dravet syndrome was first observed in 40% of 20 patients, and an increase in myoclonic suggested in one open exploratory trial and then confirmed in seizures in 33% of 18 patients. Clear-cut worsening appeared two randomized placebo-controlled trials, which were inde- within 3 months in most patients but was insidious, resulting pendently conducted in France and Italy.9,10 STP was used as in the discontinuation of lamotrigine after a mean duration of adjunctive therapy with valproate (VPA) and clobazam (CLB) 14 months treatment. Improvement followed withdrawal in as comedications. Despite a relatively small sample size in both ª The Author. Developmental Medicine & Child Neurology ª 2011 Mac Keith Press trials, 41 patients in France and 23 in Italy, 71% and 67%, patients, respectively. These were generally mild and transient, respectively, of patients were responders in the STP group and related to rapid dosage titration. Adverse effects usually versus 5% and 9%, respectively, in the placebo arm (p<0.002).
attributed to valproate, such as apathy and elevated blood A meta-analysis of these two trials showed that the odds ratio ammonia levels, were recently reported in patients receiving a of responding to STP relative to placebo was 32 (CI: 6.2, 161) combination of topiramate and valproate, possibly due to an and that STP reduced the overall seizure rate by 70% (93%; interaction between these drugs. In a retrospective study of 36 Dravet patients that were retrospectively considered to have STP safety profile is good. Most adverse events are related poor control on stiripentol, 78% showed a more than 50% to a significant increase in the plasma concentration of VPA, reduction in the frequency of generalized tonic-clonic seizures CLB and Nor-CLB after the addition of STP; these effects and status epilepticus after the introduction of topiramate, and disappear when the dose of comedication is decreased.9,10 17% remained seizure-free for at least 4 months.15 The com- They include drowsiness, ataxia, nausea, abdominal pain, and bination of stiripentol and topiramate did not induce addi- loss of appetite resulting in weight loss. Asymptomatic neutro- tional side effects and did not require any particular dosage penia is also occasionally observed. An ongoing post-market- ing survey in Europe confirms the good long-term safety of A preliminary open report also emerged using levetiracetam STP within a 32 month period in 97 Dravet patients newly as adjunctive therapy on 28 Dravet children, with 64% of responders at a mean 16 month follow-up.16 We did not con- In the long term, the frequency and the duration of seizures firm such results in a personal series of nine patients, but all of remain significantly reduced with the STP-VPA-CLB combi- them were poorly controlled by STP, whereas only 9% of nation, as does the number of episodes of convulsive status ep- Striano’s patients had previously received STP.
ilepticus.4 Efficacy seems to be better in the youngest patients, The efficacy of the ketogenic diet was also reported in two especially under the age of 2 years, with a strong benefit of retrospective Dravet series, with 13 out of 20 and 10 out of six STP in shortening the prolonged convulsions. Given the pre- experiencing a significant reduction of seizures, although none sumed negative impact of early status epilepticus on cognitive of them had previously received STP or topiramate.17,18 In a outcome, STP may therefore be beneficial as soon as the diag- personal series of 12 Dravet children that were poorly con- nosis of Dravet syndrome is confirmed.
trolled with the triple therapy (CLB+VPA+STP) and prospec- STP was the first antiepileptic drug that obtained an orphan tively put on a ketogenic diet, all of them experienced designation at the European Medical Agency (EMA) in 2001.
behavioural improvement, and seizure frequency was reduced STP was registered in Europe as an orphan drug in January by half at 3 months and by one-third at 6 months.
2007 for the GTCS of Dravet patients as adjunctive therapy Although many therapeutic procedures have been cur- with VPA and CLB, based on the two confirmatory placebo- rently developed in Dravet syndrome, controlled trials are controlled trials. For the first time outside Europe, open data very scarce and are difficult to perform in such rare and have been recently reported from Japan that confirm a respon- devastating epileptic encephalopathy of early infancy. Never- der rate of 61% and 48%, respectively, for convulsive Dravet theless, animal models of Dravet syndrome are now avail- seizures in the short and long terms,12 despite the fact that able19,20 that should avoid exposing human patients to about half these patients did not receive valproate and cloba- unnecessary trials. As epileptic seizures and especially status zam as comedications. Therefore, not only Caucasian patients, epilepticus in the first years of life are likely to play a role in but also Japanese patients can benefit from STP despite their the mental retardation, any drug that might decrease their pharmacogenetic differences for CYP polymorphisms that frequency may be beneficial as soon as the diagnosis is con- may modify pharmacokinetic drug-drug interactions.
firmed. Another key point is to avoid drugs that cause poten- Topiramate has not been as extensively studied as stiripen- tol in Dravet syndrome. In two open studies conducted in 18patients each, add-on topiramate was given at maximum dos- ages of 6 to 8 and 12mg ⁄ kg ⁄ day, respectively.13,14 After a Dr Catherine Chiron received appointments from BIOCODEX mean 1-year follow-up, 55% of the patients from both studies as Principal Investigator of therapeutic trials in Dravet syn- experienced a more than 50% seizure decrease and three were drome. Clinical trials: as main (head) clinical or laboratory seizure free. It should be noted that none of these patients had investigator, or study coordinator (Pfizer, UCB, BIOCODEX); previously received STP. There was no worsening of patients’ Occasional involvements: expert reports (Pfizer, BIOCODEX); conditions, and side-effects were observed in nine and four Conferences: attendance as audience member (UCB, Janssen).
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3. Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, lepsie myoclonique se´ve`re du nourrisson (syndrome de 2. Tanabe T, Awaya Y, Matsuishi T, et al. Management of and Dulac O. Lamotrigine and seizure aggravation in severe Dravet). Arch Pediatr 2002; 9: 1120–7.
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myoclonic epilepsy in infancy (SMEI; Dravet syndrome) – A 5. Chipaux M, Villeneuve N, Sabouraud P, et al. Unusual con- controlled syndrome-dedicated trial. STICLO study group.
16. Striano P, Coppola G, Pezella M, et al. An open-label trial of sequences of status epilepticus in Dravet syndrome. Seizure levetiracetam in severe myoclonic epilepsy of infancy. Neurol- 11. Kassai B, Chiron C, Augier S, et al. Severe myoclonic epi- 6. Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H. Stiripentol, lepsy in infancy: a systematic review and a meta-analysis of 17. Caraballo RH, Cersosimo RO, Sakr D, Cresta A, Escobal N, a putative antiepileptic drug, enhances the duration of open- individual patient data. Epilepsia 2008; 49: 343–8.
Fejerman N. Ketogenic diet in patients with Dravet syn- ing of GABA-receptor channels. Epilepsia 2006; 47: 704–16.
12. Inoue Y, Ohtsuka Y, Oguni H, et al. Stiripentol open study drome. Epilepsia 2005; 46: 1539–44.
7. Fisher JL. The anti-convulsant stiripentol acts directly on in Japanese patients with Dravet syndrome. Epilepsia 2009; 18. Kang HC, Kim YJ, Kim DW, Kim HD. Efficacy and safety the GABA(A) receptor as a positive allosteric modulator.
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13. Coppola G, Capovilla G, Montagnini A, et al. Topiramate as ean multicentric experience. Epilepsia 2005; 46: 272–9.
8. Giraud C, Treluyer JM, Rey E, et al. In vitro and in vivo add-on drug in severe myoclonic epilepsy in infancy: an Ital- 19. Yu FH, Mantegazza M, Westenbroek RE, et al. Reduced inhibitory effect of stiripentol on clobazam metabolism.
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14. Nieto-Barrera M, Candau R, Nieto-Jimenez M, Correa A, model of severe myoclonic epilepsy in infancy. Nat Neurosci 9. Perez J, Chiron C, Musial C, et al. Stiripentol: efficacy and del Portal LR. Topiramate in the treatment of severe myo- tolerability in children with epilepsy. Epilepsia 1999; 40: clonic epilepsy in infancy. Seizure 2000; 9: 590–4.
20. Oakley JC, Kalume F, Yu FH, Scheuer T, Catterall WA.
15. Kroll-Seger J, Portilla P, Dulac O, Chiron C. Topiramate in Temperature- and age-dependent seizures in a mouse model 10. Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe the treatment of highly refractory patients with dravet syn- of severe myoclonic epilepsy in infancy. Proc Natl Acad Sci U myoclonic epilepsy in infancy: a randomised placebo- drome. Neuropediatrics 2006; 37: 325–9.
Developmental Medicine & Child Neurology 2011, 53 (Suppl. 2): 16–18


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