Evaluation of health-care utilization in patients with Dravet syndrome and on adjunctive treatment with stiripentol and clobazam

Highlights

• Dravet syndrome imposes a substantial economic burden on patients, caregivers and society.

• Adjunctive stiripentol and clobazam resulted in seizure reduction in two-thirds of patients.

• Increased AED costs were leveled out by decreased inpatient costs and admissions.

• Electronic diaries are useful for long-term evaluation of seizure and economic outcome.

Abstract

Dravet syndrome (DS) is a rare, severe childhood epilepsy syndrome that imposes a substantial burden on patients and their caregivers. This study evaluated health-care utilization over a 2-year period in patients with DS at an outpatient clinic of a German epilepsy center. Data on the course of epilepsy, anticonvulsant treatment, and direct costs were recorded using the electronic seizure diary Epivista® and patients' files.

We enrolled 13 patients with DS (6 females, mean age: 12.3 ± 7.5 years) between 2007 and 2010 and evaluated them during a 1-year baseline. All patients had drug-resistant epilepsy and their seizures failed to improve with a mean number of 6.7 ± 3.4 anticonvulsants. They had an overall mean seizure frequency of 102.1 seizures per year (median: 31, range: 3–538) with 43.2 GTCSs per year (median: 14, range: 0–228). We estimated the annual total direct costs at €6506 ± 3974 (range: €1174–11,783) per patient with hospitalization (68.9% of total direct costs) as the major cost factor ahead of costs for anticonvulsants (24.0%). For the 1-year follow-up period, less severely affected patients were continued on conventional anticonvulsants (n = 4) or switched to adjunctive treatment with stiripentol and clobazam (n = 9). In the latter group, six patients (67%) were long-term responders, with between 25% and 100% seizure reduction with respect to either GTCSs or the overall seizure frequency. This reduction in seizure frequency was associated with a shift in the distribution of cost components towards higher medication costs and decreased hospitalization costs. The total direct costs increased by 42.7%, mainly due to the newly introduced stiripentol, with an annual cost of €6610.

This study showed that direct costs of patients with DS were above the average European costs of drug-resistant epilepsy in children. Treatment with new anticonvulsants resulted in reduction of seizures and inpatient admissions.

Introduction

Dravet syndrome (DS) or severe myoclonic epilepsy in infancy (SMEI) is a rare, genetic, severe childhood epilepsy syndrome that imposes a substantial burden on patients and their caregivers.

Disease onset is in the first year of life, with a first peak of symptoms at about 6 months of age, with long-lasting febrile and afebrile hemiclonic or generalized tonic–clonic seizures (GTCSs) and status epilepticus in previously normal children without developmental delay. Between the age of 1 and 4 years, further seizure types including myoclonic, focal, and atypical absence seizures appear. Seizures are usually refractory to conventional anticonvulsants and from the second year of life, affected children develop cognitive, behavior, and motor impairment [1], [2], [3], [4]. The incidence is between 1 in 20,000 and 1 in 40,000 children, and boys are more often affected than girls [2], [4], [5]. The majority of patients have a mutation in the voltage-gated sodium channel type I alpha subunit gene, SCN1A [4], [6].

Anticonvulsant treatment proves to be very difficult, and the children suffer from intractable myoclonus and seizures. There are no specific guidelines for the treatment of DS; so far, valproate, topiramate, bromide, and clobazam have been the most useful drugs [7], [8], [9]. A nonblinded, randomized treatment study comparing bromide, valproate, and phenobarbital was inconclusive due to small patient numbers [10].

A new treatment option for DS is stiripentol, and its efficacy was shown in two small, randomized, placebo-controlled trials in France and Italy [2], [11]. A decrease in seizures of at least 50% was observed in 66.7–71.4% of patients treated with stiripentol as add-on therapy to clobazam and valproate [2], [11]. Stiripentol is authorized in the European Union for use in conjunction with clobazam and valproate as adjunctive therapy of refractory GTCSs in patients with DS whose seizures are not adequately controlled with clobazam and valproate (orphan designation number: EU/3/01/071, European Medicines Agency, www.ema.europa.eu).

Economic evaluations are particularly important in patients with intractable epilepsies as these are associated with high costs [12], [13], [14]. Given the growing resource utilization and limited healthcare resources, it has become essential to gather reliable cost estimates as a scientific basis for resource allocation and health policy decision-making and to monitor the economic consequences of the introduction of new drugs into the market [15], [16].

To date, only few studies have evaluated health-care resource utilization in children and none in defined epileptic syndromes such as DS [14], [15], [16], [17]. Thus, the objectives of this retrospective study were the following: 1.) to determine the utilization of health-care resources in DS over a 1-year baseline period and 2.) to provide direct cost data for a follow-up of 1 year in patients who switched to stiripentol treatment as their seizures were not adequately controlled with clobazam and valproate.