Efficacité et tolérance à long terme du stiripentol dans le traitement de l’épilepsie myoclonique sévère du nourrisson (syndrome de Dravet)

doi:10.1016/S0929-693X(02)00090-8

Archives de Pédiatrie

Volume 9, Issue 11, November 2002, Pages 1120-1127

https://doi.org/10.1016/S0929-693X(02)00090-8 Get rights and content

Résumé

Objectif. – Décrire l’efficacité et la tolérance à long terme du stiripentol en adjonction au valproate et au clobazam dans une série exhaustive de patients présentant une épilepsie myoclonique sévère du nourrisson (syndrome de Dravet), épilepsie dans laquelle un essai randomisé contre placebo a récemment permis de démontrer l’efficacité à court terme de ce traitement.

Résultats. – Les 46 patients inclus ont présenté une diminution significative de fréquence et de durée des crises (p < 0,001) et une réduction de 54 % du nombre des états de mal convulsifs après une médiane de trois ans de traitement. L’efficacité du traitement était nette (crises moins fréquentes 〚p = 0,002〛, moins longues 〚p = 0,002〛 et disparition des états de mal) chez dix patients, modérée (crises moins longues 〚p = 0,001〛 mais aussi fréquentes avec encore quelques états de mal) chez 20 enfants, inexistante chez quatre et inévaluable chez les 12 autres surtout en raison d’une intolérance. L’efficacité était meilleure chez les enfants les plus jeunes. Les effets indésirables les plus fréquemment observés étaient digestifs (perte d’appétit, perte de poids) et plus marqués chez les enfants âgés de plus de 12 ans, rendant impossible l’obtention d’une dose optimale de 50 mg kg^–1 j^–1 de stiripentol.

Conclusion. – Cette étude rétrospective du suivi d’une large population de patients avec épilepsie myoclonique sévère du nourrisson traités par stiripentol, valproate et clobazam, montre que l’efficacité de cette polythérapie est maintenue à long terme et suggère qu’elle doit être instaurée le plus tôt possible pour supprimer les états de mal convulsifs.

Abstract

Objective. – To describe the long term efficacy and tolerance of stiripentol associated with valproate and clobazam in an exhaustive cohort of patients with severe myoclonic epilepsy of infancy (Dravet’s syndrome), in which short term efficacy of such a treatment has recently been demonstrated in a placebo-controlled trial.

Results. – In 46 patients the frequency and the duration of seizures was significantly reduced (p < 0.001) as well as the number of convulsive status at a median of three-year follow-up. Ten patients were dramatically improved (seizures significantly decreased in number 〚p = 0.002〛 and duration 〚p = 0.002〛 and status epilepticus disappeared), 20 were moderately improved (seizures significantly decreased in duration 〚p = 0.001〛 and status were less numerous), four had no response and efficacy was non evaluable in 12 mainly because of adverse events. Efficacy was better in the youngest patients. The most frequent adverse events were loss of appetite and loss of weight. They could be so severe in patients over 12 years of age that the stiripentol dosage could not be increased to 50 mg kg^–1 j^–1.

Conclusion. – This follow-up study shows that stiripentol added to valproate and clobazam maintains its efficacy at long term in children with severe myoclonic epilepsy of infancy and suggests that the tritherapy should be introduced as early as possible in these patients in order to suppress the convulsive status epilepticus.

Section snippets

Patients et méthodes

De mai 1996 à mars 2000, tous les enfants souffrant d’une EMSN, suivis dans le service de neuropédiatrie à l’hôpital Saint-Vincent-de-Paul (Paris) et traités par la trithérapie STP, VPA et CLB, ont été inclus dans l’étude. Dans tous les cas, le STP avait été ajouté à l’association VPA + CLB qui s’était avérée inefficace. Le diagnostic d'EMSN était fondé sur l'association des critères suivants : convulsions le plus souvent prolongées plus de 15 minutes, ayant débuté dans la première année,

Population globale (Tableau 1)

Quarante-six patients (25 garçons et 21 filles) recevant la triple association thérapeutique ont été suivis pendant une durée médiane de 2,9 ans (2 mois à 5 ans et demi). En fin de suivi, le nombre de crises, la durée des crises et la fréquence des EMC étaient significativement réduites (p < 0,001). Toutefois, aucun patient n’avait complètement cessé de faire des crises et globalement, la réponse au traitement était caractérisée par une réduction de la durée des crises, la nette réduction du

Discussion

Le syndrome de Dravet jusque-là sans traitement efficace doit sa gravité au retard mental et à la détérioration motrice qui apparaissent dans tous les cas au bout de quelques mois d’évolution de l’épilepsie. Il en résulte une véritable encéphalopathie épileptogène altérant les fonctions cérébrales d’enfants antérieurement normaux. C’est dire à quel point une amélioration des possibilités thérapeutiques y est nécessaire. Dans cette indication, l’efficacité du STP à court terme a récemment été

Conclusion

La place du STP dans le traitement de l’EMSN semble maintenant mieux se dessiner. Le STP mérite d’être débuté dès la première année de la vie, quand le diagnostic est suspecté sur la survenue de crises convulsives fébriles et non fébriles, dès la constatation des échecs successifs du VPA puis de son association au CLB. Le STP est prescrit en association avec ces deux médicaments à une posologie égale ou supérieure à 50 mg kg^–1 j^–1. Il est important de fournir aux parents des informations orales

Remerciements

Les auteurs remercient le Dr. Leguern (Laboratoires Biocodex) pour sa relecture du manuscrit.

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Cited by (78)

Long-term safety and effectiveness of stiripentol in patients with Dravet syndrome: Interim report of a post-marketing surveillance study in Japan
2021, Epilepsy Research
Citation Excerpt :
The older the patient was when they started STP treatment, the higher the incidence of ADRs. A previous study has also reported that ADRs (especially gastrointestinal symptoms, such as loss of appetite and weight reduction) with STP were more common in children with DS who were ≥12 years of age than in younger children (Thanh et al., 2002). However, the reason for this finding in the earlier study and in our surveillance study is unclear.
A post-marketing surveillance study is investigating the safety and effectiveness of stiripentol during real-world clinical use in Japanese patients with Dravet syndrome (DS).
The safety and effectiveness of stiripentol were prospectively investigated over 104 weeks in all patients with DS who were administered the drug from November 2012 through July 2019 in Japan. Patients administered stiripentol for the first time after its approval were defined as “new patients,” and those who continued to take the drug after participating in domestic clinical studies were defined as “continuous-use patients.” The responder rate was defined as the proportion of patients with a ≥50 % decrease in seizure episodes at the time of assessment of stiripentol effectiveness compared with the 4 weeks before starting stiripentol. Overall improvement was evaluated by the physician in charge based on the comprehensive assessment of the patient’s condition after stiripentol treatment.
Of 411 patients whose information was collected, 410 patients (376 new and 34 continuous-use) were included in the safety analysis set, and 409 (376 new and 33 continuous-use) were included in the effectiveness analysis set. The median age of new patients was 7 years (range: 0.5–50 years) at the time of stiripentol initiation; 99 % of patients were taking concomitant sodium valproate and 93 % clobazam. Adverse drug reactions occurred in 70 % of new patients; the most common were somnolence (39 %) and loss of appetite (25 %). No new safety concerns due to stiripentol were observed. The responder rate in new patients was 43 % (110/257 patients) for convulsive seizures (tonic-clonic and/or clonic convulsions), 55 % (58/105 patients) for focal impaired awareness seizures, and 62 % (56/90 patients) for generalized myoclonic seizures and/or generalized atypical absence seizures. Overall improvement (after 104 weeks or at the time of drug discontinuation) was rated as marked or moderate in 160/353 of new patients (45 %).
Stiripentol is safe and effective during long-term use in patients with DS in routine clinical practice.
Potential induction of epileptic spasms by nonselective voltage-gated sodium channel blockade: Interaction with etiology
2021, Epilepsy and Behavior
Epileptic spasms are often preceded by focal (or multifocal) seizures. Based on a series of case reports suggesting that carbamazepine and oxcarbazepine may induce epileptic spasms, we set out to rigorously evaluate the potential association between exposure to voltage-gated sodium channel blockade and latency to epileptic spasms.
We identified 50 cases (children with focal seizures and evolution to epileptic spasms) and 50 controls (children with focal seizures without evolution to epileptic spasms). For each patient, we reviewed all sequential neurology encounters between onset of epilepsy and emergence of epileptic spasms. For each encounter we recorded seizure-frequency and all anti-seizure therapy exposures. Using multivariable Cox proportional hazards regression, we evaluated the association between voltage-gated sodium channel exposure (carbamazepine, oxcarbazepine, lacosamide, or phenytoin) and latency to epileptic spasms onset, with adjustment for etiology and seizure-frequency.
Latency to epileptic spasms onset was independently associated with exposure to sodium channel blockade (hazard ratio = 2.4; 95% CI 1.1–5.2; P = 0.03) and high-risk etiology (hazard ratio = 2.8; 95% CI 1.5–5.1; P = 0.001). With assessment for interaction between sodium channel blockade and etiology, we identified an estimated 7-fold increased risk of epileptic spasms with the combination of sodium channel blockade and high-risk etiology (hazard ratio = 7.0, 95% CI 2.5–19.8; P < 0.001).
This study suggests that voltage-gated sodium channel blockade may induce epileptic spasms among children at risk on the basis of etiology. Further study is warranted to replicate these findings, ascertain possible drug- and dose-specific risks, and identify potential mechanisms of harm.
Dravet Syndrome: A Review of Current Management
2020, Pediatric Neurology
Dravet syndrome is a debilitating epileptic encephalopathy of childhood with few treatment options available in the United States before 2018. In the modern era, new genetic testing options will allow diagnosis closer to disease onset. Three new medicines—stiripentol, cannabidiol, and fenfluramine—have documented efficacy and safety as adjunctive therapies for treating pharmacoresistant Dravet syndrome. Early diagnosis resulting in earlier treatment with these and other medications may improve prognosis of long-term outcomes, including less severity of cognitive, motor, and behavioral impairments. New rescue medication formulations can now manage acute seizures and help prevent status epilepticus via intranasal, buccal, and intramuscular routes as opposed to rectal administration. Preventing status epilepticus and generalized tonic-clonic seizures could potentially lower the risk of sudden unexpected death in epilepsy. With this changing landscape in diagnostic and treatment options comes questions and controversies for the practicing clinician, especially as diagnostic techniques outpace clinical treatment strategies. Critical decision points include when to start treatment, what pharmacotherapy combinations to try first, which rescue medication to recommend, and how to advise parents on controversial topics (e.g., immunizations). Given that most patients require polypharmacy, clinicians must be cognizant of drug-drug interactions between new medicines, existing anti-epileptic drugs, and other medications to manage comorbidities and must have an understanding of available therapeutic drug monitoring strategies and pharmacokinetic parameters. This review places new diagnostic, treatment and acute care options into the modern era and provides an overview of the challenges and opportunities facing the pediatric epileptologist in this rapidly changing landscape.
Recent advances in treatment of epilepsy-related sodium channelopathies
2020, European Journal of Paediatric Neurology
Voltage-gated sodium channels (VGSCs) play a crucial role in generation of action potentials. Pathogenic variants in the five human brain expressed VGSC genes, SCN1A, SCN2A, SCN3A, SCN8A and SCN1B have been associated with a spectrum of epilepsy phenotypes and neurodevelopmental disorders. In the last decade, next generation sequencing techniques have revolutionized the way we diagnose these channelopathies, which is paving the way towards precision medicine. Knowing the functional effect (Loss-of-function versus Gain-of-function) of a variant is not only important for understanding the underlying pathophysiology, but it is particularly crucial to orient therapeutic decisions. Here we provide a review of the literature dealing with treatment options in epilepsy-related sodium channelopathies, including the current and emerging medications.
Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel
2017, Pediatric Neurology
To establish standards for early, cost-effective, and accurate diagnosis; optimal therapies for seizures; and recommendations for evaluation and management of comorbidities for children and adults with Dravet syndrome, using a modified Delphi process.
An expert panel was convened comprising epileptologists with nationally recognized expertise in Dravet syndrome and parents of children with Dravet syndrome, whose experience and understanding was enhanced by their active roles in Dravet syndrome associations. Panelists were asked to base their responses to questions both on their clinical expertise and results of a literature review that was forwarded to each panelist. Three rounds of online questionnaires were conducted to identify areas of consensus and strength of that consensus, as well as areas of contention.
The panel consisted of 13 physicians and five family members. Strong consensus was reached regarding typical clinical presentation of Dravet syndrome, range of electroencephalography and magnetic resonance imaging findings, need for genetic testing, critical information that should be conveyed to families at diagnosis, priorities for seizure control and typical degree of control, seizure triggers and recommendations for avoidance, first- and second-line therapies for seizures, requirement and indications for rescue therapy, specific recommendations for comorbidity screening, and need for family support. Consensus was not as strong regarding later therapies, including vagus nerve stimulation and callosotomy, and for specific therapies of associated comorbidities. Beyond the initial treatment with benzodiazepines and use of valproate, there was no consensus on the optimal in-hospital management of convulsive status epilepticus.
We were able to identify areas where there was strong consensus that we hope will (1) inform health care providers on optimal diagnosis and management of patients with Dravet syndrome, (2) support reimbursement from insurance companies for genetic testing and Dravet syndrome–specific therapies, and (3) improve quality of life for patients with Dravet syndrome and their families by avoidance of unnecessary testing and provision of an early accurate diagnosis allowing optimal selection of therapeutic strategies.
Treatment of Dravet Syndrome
2016, Canadian Journal of Neurological Sciences

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Mémoire originalEfficacité et tolérance à long terme du stiripentol dans le traitement de l’épilepsie myoclonique sévère du nourrisson (syndrome de Dravet)Long term efficacy and tolerance of stiripentol in severe myoclonic epilepsy of infancy (Dravet’s syndrome)

Résumé

Abstract

Section snippets

Patients et méthodes

Population globale (Tableau 1)

Discussion

Conclusion

Remerciements

Am J Hum Genet

Lancet

Epilepsy Res

Eur J Pharmacol

Brain Res

Proposal for revised classification of epilepsies and epileptic syndromes

Epilepsia

Epidemiology of severe myoclonic epilepsy of infancy

Epilepsia

Severe myoclonic epilepsy in infants

Epilepsie myoclonique sévère de l'enfant

Diagnosing idiopathic/symptomatic epilepsy syndromes in infancy

Arch Dis Child

Clinical and neuropathological findings in a case of severe myoclonic epilepsy of infancy

Epilepsia

Genetic predisposition to severe myoclonic epilepsy in infancy

Epilepsia

Severe myoclonic epilepsy of infancy: extended spectrum of GEFS+?

Epilepsia

Mémoire original
Efficacité et tolérance à long terme du stiripentol dans le traitement de l’épilepsie myoclonique sévère du nourrisson (syndrome de Dravet)Long term efficacy and tolerance of stiripentol in severe myoclonic epilepsy of infancy (Dravet’s syndrome)