Epilepsy & Behavior 34 (2014) 86–91
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Evaluation of health-care utilization in patients with Dravet syndrome and on adjunctive treatment with stiripentol and clobazam Adam Strzelczyk a,⁎, Susanne Schubert-Bast b, Jens P. Reese a,c, Felix Rosenow a, Ulrich Stephani d,e, Rainer Boor d,e a
Department of Neurology, Epilepsy Center Hessen, Philipps-University, Marburg, Germany Center for Child and Adolescent Medicine, Section Neuropediatrics, Ruprecht-Karls University, Heidelberg, Germany Institute of Medical Sociology and Social Medicine, Philipps-University, Marburg, Germany d Department of Pediatric Neurology, Kiel University, Germany e Northern German Epilepsy Centre for Children and Adolescents, Raisdorf, Germany b c
a r t i c l e
i n f o
Article history: Received 28 February 2014 Revised 16 March 2014 Accepted 17 March 2014 Available online 13 April 2014 Keywords: Cost Epilepsy Economic burden Dravet syndrome Stiripentol Pharmacoeconomic study
a b s t r a c t 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. © 2014 Elsevier Inc. All rights reserved.
1. 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
⁎ Corresponding author at: Department of Neurology and Epilepsy Center Hessen, Philipps-University Marburg, Baldingerstrasse, 35043 Marburg, Germany. Tel.:+49 6421 5862990; fax: +49 6421 5865444. E-mail address: [email protected]
http://dx.doi.org/10.1016/j.yebeh.2014.03.014 1525-5050/© 2014 Elsevier Inc. All rights reserved.
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 [1–4]. 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 [7–9]. A nonblinded, randomized treatment study comparing bromide,
A. Strzelczyk et al. / Epilepsy & Behavior 34 (2014) 86–91
valproate, and phenobarbital was inconclusive due to small patient numbers . 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 [12–14]. 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 [14–17]. 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.
2.2. Cost assessment Costs of hospitalization, medication, outpatient treatment, diagnostics, and emergency transport were assessed based on data provided by the patients' parents. A 1-year baseline period and 1-year followup period were analyzed. Direct costs were evaluated according to German recommendations for performing health economic evaluations [25–27]. The aim of this study was to calculate the genuine costs due to epilepsy and not the costs that might have been due to other diseases not related to epilepsy. Therefore, the patients and physicians were asked in detail whether or not the medication, service, or resource was used speciﬁcally for epilepsy. The evaluation of costs was performed by means of a bottom-up approach from the perspective of the statutory health insurance (Gesetzliche Krankenversicherung, GKV). Drug costs were obtained from the ofﬁcial German price list of drugs “Rote Liste” . Costs for inpatient care were calculated based on the German Diagnosis Related Groups (G-DRG; www.g-drg.de). The charges for outpatient care including specialist consultations and ambulatory diagnostics were obtained from the ofﬁcial German doctor's fee scale (Einheitlicher Bewertungsmaßstab, EBM) . All costs were calculated for the 1-year evaluation periods and are provided in 2011 Euro (€). To allow a comparison between different patients and evaluation periods, all cost data were adjusted for inﬂation to 2011. Calculations were performed according to previously described methods . Because of the retrospective design of the study, indirect costs such as parents' days off due to their children's seizures, cognitive outcome, and quality-of-life measurements could not be evaluated. For further details of the cost calculations, see previous studies .
2. Patients and methods 2.3. Data entry and statistical analysis 2.1. Study setting and design The study was performed at the Northern German Epilepsy Centre for Children and Adolescents in Raisdorf, Germany. We retrospectively evaluated all patients with DS treated between 2007 and 2010. The clinical diagnosis of DS  and classiﬁcation of seizure types were performed in accordance with the criteria of the International League Against Epilepsy [19,20]. Inclusion criteria were the following: (1) treatment after the time of implementation of the electronic seizure diary Epivista® at the epilepsy center for children and adolescents (July 2007), (2) active epilepsy with at least one seizure during the 12-month baseline, and (3) seamless electronic documentation of all relevant clinical data. Informed parental consent was obtained to use the clinical data for study purposes. The baseline period comprised 1 year (365 days) and was followed by 1 year of follow-up. To evaluate the clinical efﬁcacy of adjuvant stiripentol, long-term responders were deﬁned as those with a more than 25% reduction in seizure frequency between baseline and followup phases of 1 year each. We therefore predeﬁned two groups for analysis: 1.) the seizure remission group on conventional anticonvulsants such as valproate, topiramate, or bromide; and 2.) the group with refractory seizures, treated with stiripentol and clobazam. Because of the retrospective analysis, changes in comedication occurred during the baseline and follow-up periods. Seizures were assessed using the electronic seizure diary Epivista®. Epivista® is a freely available, internet-based program and allows seamless electronic documentation on a daily basis and export of data for further statistical analysis [21,22]. Epivista® was evaluated in two studies on treatment with lamotrigine in myoclonic astatic epilepsy  and everolimus in patients with tuberous sclerosis with intractable epilepsy . All seizure types, medications, dosages, and other disease aspects as well as open comments can be entered in an easy manner. Additionally, the system possesses an email function. Thus, continuous follow-up is possible for inpatient and outpatient care. Epivista® was used by the patients' parents after standardized training. Extracted data were additionally compared with patient charts [23,24].
Statistical analyses were performed using IBM SPSS Statistics 21 (SPSS Inc., Chicago, IL, USA). Cost data are presented as mean ± standard deviation (SD), minimum, maximum, and median or percentages where appropriate. In addition, 95% conﬁdence intervals (CIs) are provided using the bootstrap method according to the bias-corrected accelerated (bca) approach, considering the fact that most cost variables are right-skewed . 3. Results 3.1. Patient group We enrolled 13 patients (6 females) with DS in this evaluation, and their mean age was 12.3 ± 7.5 years (median: 11, range: 3–28). In 11 out of 13 patients (84.6%), a mutation in the SCN1A gene could be conﬁrmed. All patients had drug-resistant epilepsy as they had not achieved sustained seizure freedom on adequate trials of two tolerated and appropriately chosen and used antiepileptic drug schedules . They had failed a mean number of 6.7 ± 3.4 AEDs (median: 6, range: 3–14 failed AEDs). The patients were taking a mean number of 2.4 AEDs (SD: 0.7, range: 1–3 AEDs). Valproate (n = 11, 84.6%), topiramate (n = 10, 76.9%), and bromide (n = 5, 38.5%) were the most frequently prescribed drugs. The patients 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) during the 1year baseline phase. Single myoclonic jerks were not taken into account for the seizure count. The mean baseline duration was 365 days, and the follow-up duration was 361 ± 15 days (range: 310–365) as one patient was lost to follow-up on day 310. The cost data of this patient were adjusted for 365 days. 3.2. Direct costs in Dravet syndrome — baseline evaluation Table 1 shows the epilepsy-speciﬁc direct costs of the patients with DS during the 1-year baseline evaluation period. We estimated the
A. Strzelczyk et al. / Epilepsy & Behavior 34 (2014) 86–91
Table 1 Annual direct costs of patients with Dravet syndrome from the societal perspective (n = 13, in €, year 2011 values). Direct cost components
Total direct costs Medication (AEDs) Valproate (n = 11, 750 mg ± 97 mg)a Topiramate (n = 10, 92.5 mg ± 40 mg)a Clobazam (n = 2, 7.5 mg ± 3.5 mg)a Other AEDs Other non-AED costs Hospitalization Emergency transport service Outpatient care Diagnostic tests
6506 1559 140 813 10 597 4946 4483 391 46 26
±3974 ±1356 ±101 ±681 ±31 ±925 ±4136 ±3684 ±903 ±56 ±42
% of total direct costs 24.0%
76.0% 68.9% 6.0% 0.7% 0.4%
1174 47 0 0 0 0 136 0 0 0 0
5088 1332 147 922 0 305 3701 3647 0 24 11
12,980 4623 337 1735 111 3031 12,437 11,254 3146 214 128
4598 885 92 467 1 216 3101 2866 75 24 7
8692 2372 186 1183 18 1065 7037 6315 875 79 48
95% CI = 95% conﬁdence interval using the bootstrap bias corrected and accelerated method; total direct costs = sum of costs for medication (AEDs), and other non-AED costs; other non-AED costs = sum of costs for hospitalization, emergency transport service, outpatient care, and diagnostic tests. a Mean daily dose ± SD; SD = standard deviation.
annual total direct costs at €6506 ± 3974 (range: €1174–11,783) per patient. Hospitalization (68.9% of total direct costs) was the major cost factor, ahead of costs for anticonvulsants (24.0%). Overall, 11 patients (84.6%) were admitted for 2 to 25 days (mean hospital stay: 11.5 ± 7.6 days) during the baseline period. Annual costs for different anticonvulsants were €140 ± 101 for valproate (n = 11, mean dose per body weight: 13.3 ± 7.3 mg/kg, range: 3–25 mg/kg), €813 ± 681 for topiramate (n = 10, mean dose per body weight: 2.0 ± 0.9 mg/kg, range: 0.3–3.0 mg/kg), and €597 ± 927 for other AEDs (bromide: n = 5, levetiracetam: n = 3, ruﬁnamide: n = 3, oxcarbazepine: n = 2, sultiame: n = 2, and zonisamide: n = 1). 3.3. Direct costs of the patients in seizure remission on conventional anticonvulsants Four patients had few seizures, with a mean annual seizure frequency of 7.8 seizures (median: 7, range: 3 to 14) with 4.4 GTCSs per year (median: 4.5, range: 0–8). In these patients, treatment with conventional anticonvulsants such as valproate, topiramate, and bromide
was continued. A long-term complete seizure remission of 1 year could be achieved in these patients. Table 2 shows the direct costs of these patients (mean age: 16.8 ± 9.4 years, range: 5–28) during the 1-year baseline and 1-year follow-up periods. The total direct costs decreased slightly by 26.7%, mainly due to fewer hospitalizations as only one patient was admitted to the hospital for 3 days. Spending on anticonvulsants as well as outpatient treatment and diagnostic procedures remained stable.
3.4. Direct costs of the patients with Dravet syndrome with treatment-refractory seizures on adjunctive treatment with stiripentol and clobazam In nine patients, seizures were refractory to conventional anticonvulsants, and they were started on stiripentol and clobazam. The mean age was 10.3 ± 6.2 years (range: 3–23), and these patients suffered from 144 seizures per year (median: 89, range: 4–538) with 60.6 GTCSs per year (median: 45, range: 4–228) during the 1-year baseline phase.
Table 2 Annual direct costs in patients with Dravet syndrome in seizure remission on conventional anticonvulsants and on adjunctive therapy with stiripentol and clobazam (in €, year 2011 values, societal perspective). Direct cost components
Baseline period Mean + SD
Patients on conventional anticonvulsants (n = 4) Total direct costs 2378 ± 1214 Medication (AEDs) 1156 ± 597 Valproate 171 ± 81 Topiramate 869 ± 614 Clobazam 0 Other AEDs 116 ± 184 Other non-AED costs 1222 ± 1656 Hospitalization 1129 ± 1709 Emergency transport service 0 Outpatient care 30 ± 30 Diagnostic tests 64 ± 65
Follow-up period Minimum
Mean + SD
1744 ± 734 1351 ± 395 159 ± 96 1096 ± 614 0 97 ± 194 392 ± 645 338 ± 677 0 39 ± 34 15 ± 11
1052 1001 62 553
2648 1916 281 1635
1182–2336 1100–1602 93–226 822–1369
0 50 0
387 1360 1354
0–97 53–734 0–677
11,901 ± 5472 1276 ± 852 115 ± 79 643 ± 601 91 ± 31 429 ± 786 6610 ± 3553 4014 ± 5694 3423 ± 5117 490 ± 899 64 ± 38 38 ± 48
3820 230 0 0 40 0 2408 59 0 0 0 5
20,890 2790 227 1621 134 2066 12,874 16,801 14,345 2183 120 155
1174 412 67 188
4063 1841 246 1595
1607–3558 799–1513 112–221 517–1231
0 136 0
387 3651 3611
0–290 168–2788 451–1805
Patients on adjunctive therapy with stiripentol and clobazam (n = 9) Total direct costs 8340 ± 3291 4653 12,980 Medication (AEDs) 1738 ± 1584 47 4623 Valproate 126 ± 110 0 337 Topiramate 788 ± 742 0 1735 Clobazam 14 ± 36 0 111 Other AEDs 810 ± 1050 0 3031 Stiripentol 0 Other non-AED costs 6601 ± 3823 2353 12,437 Hospitalization 5974 ± 3336 1805 11,254 Emergency transport service 565 ± 1054 0 3146 Outpatient care 53 ± 65 0 214 Diagnostic tests 9±6 0 16
Change to baseline
6558–10,131 927–2590 66–193 312–1281 0–37 224–1610 4563–8659 4037–7953 108–1023 24–93 6–12
95% CI −26.7% +16.9%
7678–16,390 783–1835 66–161 335–953 70–111 27–961 4590–8703 520–8781 200–7455 31–1133 37–90 14–76
SD = standard deviation; 95% CI = 95% conﬁdence interval using the bootstrap bias corrected and accelerated method; total direct costs = sum of costs for medication (AEDs), stiripentol and other non-AED costs; other non-AED costs = sum of costs for hospitalization, emergency transport service, outpatient care, and diagnostic tests.
NR = nonresponder; total direct costs = sum of costs for medication (AEDs), stiripentol and other non-AED costs; other non-AED costs = sum of costs for hospitalization, emergency transport service, outpatient care, and diagnostic tests.
14,345 7222 897 0 903 7441 0 0 0 16,802 7239 2938 122 956 7753 99 59 166 2408 5275 4398 7197 4688 12,874 8421 3268 10,964 19,439 13,560 8688 9111 8434 20,891 10,259 3821 12,914 3 years 3 years 7 years 9 years 10 years 11 years 12 years 15 years 23 years 1 2 3 4 5 6 7 8 9
Yes Yes Yes Yes Yes Yes Yes Yes No
6 79 21 68 4 14 80 45 228
538 89 31 191 4 20 130 53 240
12,765 9563 12,980 4653 6465 5088 8783 10,059 4703
328 261 1506 2300 3683 47 4623 1900 1002
12,437 9302 11,475 2353 2782 5041 4161 8160 3701
11,254 9248 8241 2289 1806 5036 4120 8125 3647
9 414 8 35 0 2 53 44 140
NR NR N50% N25% 100% N75% N25% NR N25%
403 425 16 42 0 4 106 45 142
N25% NR N25% N75% 100% N75% NR NR N25%
230 1046 1352 1792 2790 263 1739 494 1784
Other non-AED costs Stiripentol Medication (AEDs) Total direct costs Overall seizure reduction Overall seizure frequency GTCS reduction
GTCS frequency Hospitalization Other non-AED costs Medication (AEDs) Total direct costs Overall seizure frequency GTCS frequency
SCN1A mutation Age
Although DS is a severe type of childhood epilepsy, seizure reduction can be achieved with different therapeutic strategies, and this is reﬂected not only by an improvement in quality of life but also by a reduction of costs and prevention of inpatient treatment. This study is the ﬁrst health economic evaluation to address, speciﬁcally, patients with DS, a rare genetic epileptic syndrome, and the inﬂuence of adjunctive therapy with stiripentol and clobazam on costs in patients with Dravet syndrome with treatment-refractory seizures. We evaluated the patients with seizure remission on conventional AEDs and patients with refractory seizures before and on adjunctive treatment with stiripentol and clobazam and could demonstrate that costs of hospitalization decrease markedly if seizure reduction can be achieved. In contrast, costs for AEDs remain stable or increase if newer agents such as stiripentol are used. To facilitate comparison between the different groups, all cost values are provided in 2011 year prices and tariffs. Therefore, the difference in costs between the groups reﬂects changes in the utilization of health-care resources. The strength of this study is that it provides cost data on the patients with DS over a 2-year period in a baseline and follow-up cohort in seizure remission either on conventional AEDs or on adjunctive treatment with stiripentol and clobazam. Results from the baseline period of this study were similar to those of other cost-of-illness studies in children with drug-resistant epilepsy, which also pointed towards hospitalization as the major direct cost factor in 20% to 67% of total direct costs [12,15]. In our study, inpatient treatment caused 68.9% of the total direct costs, comparable to the results of previous studies [12,15], especially as the percentage would have decreased if we had evaluated further direct cost components such as ancillary treatment, transport, or rehabilitation costs. The mean seizure frequency in our cohort (12 seizures per month) was slightly lower than the 18 seizures per month in the French STICLO study  and lower than the 30 seizures per month in the Italian STICLO study . However, both STICLO studies required a minimal number of seizures per protocol for recruitment. Also, our patients were slightly older in comparison with patients included in the French
Table 3 Annual direct costs in patients with Dravet syndrome with treatment-refractory seizures during baseline and on adjunctive therapy with stiripentol and clobazam (in €, year 2011 values, societal perspective).
Upon adjunctive therapy with stiripentol and clobazam, six patients were long-term responders with respect to either GTCSs or the overall seizure frequency: for details on seizure frequency and responder status per patient, please refer to Table 3. In the GTCS responder group, the seizure frequency decreased to 39.7 GTCSs per year (median: 21.5, range: 0–140). The overall seizure frequency decreased to 101.1 seizures per year (median: 29, range: 0–403) among the responders. Among the nonresponders, GTCSs increased to 155.5 seizures per year (median: 44, range: 9–414), and overall seizure frequency to 192 seizures per year (median: 106, range: 45–425). Table 2 provides the direct costs of adjunctive treatment with stiripentol and clobazam of the patients with Dravet syndrome with treatment-refractory seizures during the 1-year baseline and 1-year follow-up periods. Overall, there was an increase of €3561 (+ 42.7%) in total direct costs. This was mainly due to the newly introduced stiripentol, with an annual cost of €6610. Stiripentol was administered at a mean dose per body weight of 20.8 ± 5.1 mg/kg (range: 12– 29 mg/kg) and clobazam at a mean dose per body weight of 0.12 ± 0.02 mg/kg (range: 0.1–0.16 mg/kg). The costs for other anticonvulsants decreased by €462 (−26.6%). On the other hand, non-AED direct costs decreased markedly by €2587 (− 39.2%). This was mainly due to fewer inpatient admissions. Only ﬁve patients (5/9, 55.6%) were admitted for 2 to 32 days (mean hospital stay: 13.7 ± 12.5 days) during the follow-up period, and four patients were not admitted at all. The direct costs for hospitalization, therefore, decreased by €2551 (− 42.7%). Spending for emergency transport service (−€75), outpatient treatment (+€11), and diagnostic procedures (+€29) remained stable. Cost data for each patient during baseline and follow-up are provided in detail in Table 3.
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A. Strzelczyk et al. / Epilepsy & Behavior 34 (2014) 86–91
STICLO trial (n = 21, mean age 9.4 years) or in a recently published retrospective US study (n = 82, mean age: 6.9 years) on adjunctive treatment with stiripentol [11,34]. In the latter study, 48 children received stiripentol with concurrent clobazam and valproate for a median duration of 20.7 months. They saw a similar responder rate to our study of two-thirds, with the overall seizure frequency reduced in 30 patients (63%; 17 marked and 13 mild), unchanged in 16 patients (33%), and increased in 2 patients . The demonstrated shift in direct cost components upon seizure reduction in our study suggests that higher costs for new efﬁcacious AEDs may be associated with a decrease in costs for hospitalization. We did not perform separate cost calculations for responders and nonresponders on adjunctive treatment with stiripentol and clobazam because of the small group numbers. Table 3 provides detailed seizure and cost data for each patient during the baseline and follow-up periods, showing that it is not only seizure remission that was associated with decreased costs. In patients #7 and #8, there were no hospital costs despite a poor response to adjunctive treatment, in contrast to patient #6 who was in need of frequent inpatient admissions despite a good seizure response to anticonvulsant treatment. Such ostensibly incomprehensible results are usually balanced out with larger group sizes, but they may also be explained by factors such as a difference in seizure severity or improved parental education. In line with our ﬁndings, Wirrell and colleagues  could demonstrate a reduction in the frequency of emergency room or hospital visits in patients on stiripentol with concurrent clobazam and valproate. Improvements in delivery of rescue medication and its wider utilization may add further potential to diminish hospital admission and emergency transport costs . We could conﬁrm from previous studies [23,24] that the seizure diary Epivista® allows an internet-based assessment of the clinical course in individual patients. These data are reliable and can be exported and successfully used for statistical analysis. Epivista® may be used to carry out prospective monocentric and multicentric clinical trials. 4.1. Limitations Because of the retrospective design, we did not evaluate indirect costs in terms of loss in the professional work of the parents due to the epileptic seizures. Therefore, we cannot prove that there is a decrease in indirect costs for the parents. This seems, however, quite likely as previous studies have shown a positive correlation between indirect costs and seizure remission or reduction in seizure frequency [16,36,37]. Also, further cost components such as the need for nursing or supervision, transport costs, ancillary treatments, and costs for protective devices were not included. We also cannot provide longitudinal quality-of-life and neuropsychological data on the patients evaluated in our study. The long-term course of patients with DS is usually associated with cognitive impairment, hyperactivity, and gait deterioration [38,39]. A study on coping with DS showed that parental experiences evolved from terrible anxiety about the diagnosis to extreme stress due to repeated seizures . Eventually, parents become resigned to a life with restricted social contact but ﬁnd more personal contentment. Both factors may negatively inﬂuence quality of life in patients as well as their caregivers and hinder the access to the labor market in the latter. Despite the careful study design, this cost-of-illness study suffers from certain limitations inherent to such investigations. As we asked the patients' parents to provide data regarding several direct cost components, the possibility of incomplete recall in some of the cost categories cannot be excluded and could have resulted in an underestimation of costs. Another limitation of the study is the relatively small group of 13 patients, which could have led to large variability in cost estimates. The slightly older age at recruitment compared with other studies might underestimate the costs as younger children suffer from more seizures and are more frequently hospitalized. Also, older children
might experience fewer seizures due to the course of disease, and this may overestimate costs at baseline [11,34]. All patients' parents kept seizure diaries with good compliance and high accuracy. 5. Conclusions Further studies are warranted to answer questions on the future development of direct cost components with a focus on hospitalization and anticonvulsants. From the societal perspective, major efforts should focus on the reduction of seizures for maintaining quality of care and reducing the need for hospitalization in patients with epilepsy, thus improving the life quality of patients and their caregivers. 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 may result in a reduction of seizures and inpatient admissions. Acknowledgments This study was supported by an unrestricted grant from Desitin Arzneimittel GmbH. The funding sources had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. Conﬂict of interest statement A. Strzelczyk has received support and honoraria from Bayer HealthCare, Boehringer Ingelheim, Desitin, Eisai, Pﬁzer, and UCB Pharma. S. Schubert-Bast has received travel support and honoraria from Desitin, Eisai, and UCB Pharma. F. Rosenow has received honoraria as scientiﬁc advisor from GlaxoSmithKline, Eisai, UCB Pharma, and Pﬁzer. He has received speaker honoraria from UCB Pharma, GlaxoSmithKline, Eisai, Desitin, and Medtronic and educational grants from Nihon-Kohden, UCB Pharma, Medtronic, Cyberonics, and Cerbomed. U. Stephani serves on advisory boards of the pharmaceutical companies Desitin, Eisai, and Viropharma and receives support from UCB Pharma, Deutsche Forschungsgemeinschaft (DFG; German Research society), and the German chapter of the ILAE. R. Boor has received honoraria as scientiﬁc advisor from Desitin, Novartis, Viropharma, and UCB Pharma. He has received speaker honoraria from Eisai and Desitin and travel support from Biocodex, Desitin, Eisai, and UCB Pharma. None of the other authors has any conﬂict of interest to disclose regarding the content of the article. We conﬁrm that we have read the Journal's position on ethics and procedures and conﬁrm that this report is consistent with these guidelines. References  Catarino CB, Liu JY, Liagkouras I, Gibbons VS, Labrum RW, Ellis R, et al. Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain 2011;134:2982–3010.  Kassai B, Chiron C, Augier S, Cucherat M, Rey E, Gueyfﬁer F, et al. Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data. Epilepsia 2008;49:343–8.  Wolff M, Casse-Perrot C, Dravet C. Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological ﬁndings. Epilepsia 2006;47(Suppl. 2):45–8.  Brunklaus A, Ellis R, Reavey E, Forbes GH, Zuberi SM. Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain 2012;135: 2329–36.  Hurst DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia 1990;31: 397–400.  Zuberi SM, Brunklaus A, Birch R, Reavey E, Duncan J, Forbes GH. Genotype–phenotype associations in SCN1A-related epilepsies. Neurology 2011;76:594–600.  Chiron C, Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia 2011;52(Suppl. 2):72–5.  Kroll-Seger J, Portilla P, Dulac O, Chiron C. Topiramate in the treatment of highly refractory patients with Dravet syndrome. Neuropediatrics 2006;37:325–9.
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