Elsevier

Epilepsy Research

Volume 109, January 2015, Pages 81-89
Epilepsy Research

Efficacy and tolerability of the ketogenic diet in Dravet syndrome – Comparison with various standard antiepileptic drug regimen

https://doi.org/10.1016/j.eplepsyres.2014.10.014Get rights and content

Highlights

Summary

There is strong evidence for the use of the ketogenic diet (KD) in Dravet syndrome (DS). The purpose of this study was to evaluate both effectiveness and tolerability in comparison with various antiepileptic drugs (AEDs).

Methods

32 children (19 males) with genetically confirmed DS treated at our center since 1999 were analyzed retrospectively. Data collected from patients’ files included type of mutation, age at treatment initiation and treatment lag, overall seizure frequency and frequency of different seizure types, especially prolonged seizures and status epilepticus (SE). Efficacy and safety of the KD were evaluated. In addition, the effect on seizure count was compared with that of various AED regimen and the vagus nerve stimulation (VNS).

Results

Overall response to the KD was 70% at 3 months and 60% at 12 months. No SE occurred while patients were on the diet, and the frequencies of prolonged generalized and myoclonic seizures were reduced. No severe side effects requiring withdrawal of the KD were observed. Although the effect of the KD was independent of age at initiation, it had to be withdrawn due to noncompliance more frequently in solid fed older children compared with infants treated with the liquid ketogenic formula. The KD was not significantly inferior to the current gold standard AED triple combination of Stiripentol + Valproate + Clobazam (89%), Bromides (78%), Valproate alone (48%), Topiramate (35%) and VNS (37%) and significantly more effective than Levetiracetam (30%; p = 0.037, Pearson's Chi-square).

Significance

These data suggest that the KD ranks among currently used AEDs as an effective treatment for seizures in DS. According to our results (good effect on SE and prolonged seizures, good tolerability, less compliance problems due to formula treatment) the KD should be considered as an early treatment option in infants with DS.

Introduction

Dravet syndrome (DS) is a rare genetic infantile onset epileptic encephalopathy with multiple seizure types, recurrent status epilepticus (SE), developmental slowing and cognitive impairment (Scheffer, 2011, Ragona et al., 2011).

DS is almost invariably refractory to most conventional antiepileptic drugs (AEDs). Sodium channel-blockers – i.e. carbamazepine (CBZ), oxcarbazepine (OXC), and lamotrigine (LTG) – aggravate both seizures and interictal EEG (Genton, 2000), and may also provoke status epilepticus (SE). Stiripentol (STP) was licensed under the European orphan drug scheme in 2001 and – in combination with Valproate (VPA) and Clobazame (CLB) – is currently regarded as the “gold standard treatment” (Chiron et al., 2000, Wirrell et al., 2013). Other AEDs such as Bromides (Lotte et al., 2012, Oguni et al., 1994), Levetiracetam (LEV) and Topiramate (TPM) are reported to be effective but to a lower degree than the “triple combination” STP + VPA + CLB (Chiron, 2011, Korff et al., 2007, Kroll-Seger et al., 2006). There are only limited data on Vagus-Nerve-Stimulation (VNS) in DS. However, good efficacy and only mild short and long term side effects were reported from small case series (Cersosimo et al., 2011, Spatola et al., 2013, Zamponi et al., 2011).

The KD has been well established as a treatment option for childhood epilepsies since the 1920s, and efficacy was also documented in a recently published randomized trial (Neal et al., 2008). There is strong evidence that the KD effectively controls seizures in patients with DS (Caraballo, 2011, Caraballo et al., 2005, Kang et al., 2005, Korff et al., 2007, Laux and Blackford, 2013), especially when added to the gold standard triple combination (Nabbout et al., 2011). Further, the diet has been reported to exhibit neuroprotective effects (Dutton et al., 2011, Luan et al., 2012) and to control long lasting SE refractory to conventional AED treatment (Nabbout et al., 2010).

Despite this long-standing clinical efficacy of the KD in DS, the diet has not yet been evaluated in comparison with or in combination with other treatment regimen currently recommended for DS. This study was therefore performed to determine the place of the KD among other treatment options currently available.

Section snippets

Methods

Clinical records of all children with a genetically confirmed diagnosis of DS treated at our center since 1999 were examined retrospectively. Demographic as well as genetic data were used. Detailed seizure diaries had to be available.

Evaluation of treatment outcome: Seizure frequency three months before initiation of any new treatment was defined as “baseline”. The duration of any new treatment after initiation had to be at least three months. In order to prevent bias, treatment periods with

Patients’ characteristics

32 children (19 male) with DS were treated at our center since 1999. Genetic testing exhibited 31 SCN1A mutations (16 missense mutations, six truncating mutations, two deletions, four splicing mutations, and three frame-shift mutations) and one GABRG2 mutation (missense mutation) (Table 1). Follow-up was mean 6.89 years ± 5.93 (min. 0.15–max. 17.80) and age at last follow-up was mean 10.60 ± 6.28 years (min. 0.96–max. 21.04). AEDs used are displayed in Table 2.

Treatment with the KD

From March 1999 to April 2014 127

Discussion

This study investigated the treatment outcomes of various treatment regimens with special emphasis on the KD in a cohort of 32 patients with genetically ascertained DS.

The overall long-term responder rate for the KD at our center was 60%. Other centers observed higher responder rates from 63% to 66.5% (Caraballo, 2011, Caraballo et al., 2005, Kang et al., 2005, Korff et al., 2007, Laux and Blackford, 2013), but the children reported in these publications were younger than our cohort. Children

Conclusion

Despite all the above mentioned limitations, our data showed equal efficacy of the KD compared with various AEDs currently available for the treatment of DS and compared with VNS. Further, only few and mild side effects and no neurotoxic effects were observed. There was an excellent effect of the KD on SE and prolonged GTCS. This result may perhaps provide a rational basis for considering the KD during infancy with the aim to reduce mortality and morbidity and to ameliorate cognitive outcome.

Conflicts of Interest

None of the authors has any conflict of interest to disclose.

Acknowledgements

We are grateful to the participants and their families to have supported our research.

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