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 Svres, 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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ropsychological findings. Epilepsia 2006; 47:(Suppl. 2) 45–8.
3. Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A,
lepsie myoclonique se´ve`re du nourrisson (syndrome de
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Dulac O. Lamotrigine and seizure aggravation in severe
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5. Chipaux M, Villeneuve N, Sabouraud P, et al. Unusual con-
controlled syndrome-dedicated trial. STICLO study group.
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7. Fisher JL. The anti-convulsant stiripentol acts directly on
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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:
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20. Oakley JC, Kalume F, Yu FH, Scheuer T, Catterall WA.
15. Kroll-Seger J, Portilla P, Dulac O, Chiron C. Topiramate in
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Developmental Medicine & Child Neurology 2011, 53 (Suppl. 2): 16–18
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