Efficacy and tolerability of the ketogenic diet in Dravet syndrome – Comparison with various standard antiepileptic drug regimen
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.
References (35)
- et al.
Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group
Lancet
(2000) - et al.
Long-term outcome and tolerability of the ketogenic diet in drug-resistant childhood epilepsy – the Austrian experience
Seizure
(2010) When antiepileptic drugs aggravate epilepsy
Brain Dev.
(2000)- et al.
Dietary treatments for epilepsy: management guidelines for the general practitioner
Epilepsy Behav.
(2011) - et al.
Ketogenic diet reduces Smac/Diablo and cytochrome c release and attenuates neuronal death in a mouse model of limbic epilepsy
Brain Res. Bull.
(2012) - et al.
Efficacy of the ketogenic diet in focal versus generalized seizures
Pediatr. Neurol.
(2001) - et al.
The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial
Lancet Neurol.
(2008) - et al.
Severe myoclonic epilepsy in infants – a review based on the Tokyo Women's Medical University series of 84 cases
Brain Dev.
(2001) - et al.
Clinical course of young patients with Dravet syndrome after vagal nerve stimulation
Eur. J. Paediatr. Neurol.
(2011) - et al.
A long-term follow-up study of Dravet syndrome up to adulthood
Epilepsia
(2010)
Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome
Brain
Nonpharmacologic treatments of Dravet syndrome: focus on the ketogenic diet
Epilepsia
Ketogenic diet in patients with Dravet syndrome
Epilepsia
Vagus nerve stimulation: effectiveness and tolerability in 64 paediatric patients with refractory epilepsies
Epileptic Disord.
Current therapeutic procedures in Dravet syndrome
Dev. Med. Child Neurol.
Protective effect of the ketogenic diet in Scn1a mutant mice
Epilepsia
Status epilepticus: risk factors and complications
Epilepsia
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