Download The pharmacologic treatment of Dravet syndrome

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
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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.
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