Seizures typically begin before the age of 1 year, in a formerly healthy infant, usually with tonic-clonic or clonic febrile seizures. First, DS is associated with multiple seizure types that evolve over time. Īs with other developmental and epileptic encephalopathies, the management of DS is challenging (Fig. Na V1.1 is a key sodium channel in the central nervous system that is highly expressed in many GABAergic inhibitory neurons, and the impairment of the production of this protein leads to hyperexcitability of the neuronal network. In the majority of cases, it is caused by heterozygous loss-of-function variants in the SCN1A gene, resulting in substantially decreased levels of the corresponding functional protein, the α-1 subunit of the neuronal, voltage-gated sodium channel Na V1.1. Finally, we briefly describe other ASMs used in Dravet syndrome, and current key clinical trials.ĭravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterised by drug-resistant seizures and cognitive dysfunction, negatively impacting on the quality of life of the patients and their families. Furthermore, concomitant administration of VPA with topiramate has been associated with encephalopathy and/or hyperammonaemia. The interaction between FFA and STP requires a dose reduction of FFA. In addition, CBD is associated with elevations of liver transaminases particularly in patients taking concomitant VPA. Cannabidiol has a bi-directional interaction with CLB producing an increase in plasma concentrations of 7-OH-CBD and norclobazam resulting in the potential for increased somnolence and sedation. Interactions that potentially require dosage adjustments to alleviate adverse events include the following: STP + CLB resulting in increased plasma concentrations of CLB and its active metabolite norclobazam may increase somnolence, and an interaction with STP and VPA may increase gastrointestinal adverse events. In addition, potential drug–drug interactions and their consequences are a key consideration in everyday practice. Importantly, no signs of heart valve disease have been documented to date at the low doses used in patients with developmental and epileptic encephalopathies. Regular cardiac monitoring is also important with FFA as it has previously been associated with cases of cardiac valve disease when used in adults at high doses (up to 120 mg/day) in combination with phentermine as a therapy for obesity. Standard laboratory and clinical parameters include blood counts, liver function tests, serum concentrations of ASMs, monitoring the growth of children, as well as weight loss and acceleration of behavioural problems. This practical guide provides an overview of these main ASMs including their indications/contraindications, mechanism of action, efficacy, safety and tolerability profile, dosage requirements, and laboratory and clinical parameters to be evaluated. With a growing treatment landscape for Dravet syndrome, there can be practical challenges for clinicians, particularly with issues associated with polypharmacy. Topiramate is also frequently used, with evidence of efficacy in Dravet syndrome, and there is anecdotal evidence of efficacy with bromide, which is frequently used in Germany and Japan. These “add-on” therapies (mostly to VPA/CLB) are used as escalation therapies, with the choice dependent on availability in different countries, patient characteristics and caregiver preferences. With this in mind, three adjunct ASMs have been approved specifically for the treatment of seizures in patients with Dravet syndrome: stiripentol (STP) in 2007 in the European Union and 2018 in the USA, cannabidiol (CBD) in 2018/2019 (in combination with CLB in the European Union) and fenfluramine (FFA) in 2020. Initial treatments include the broad-spectrum ASMs valproate (VPA), and clobazam (CLB) in some regions however, they are generally insufficient to control seizures. The treatment is challenging, not least because the seizures are highly drug resistant, requiring multiple anti-seizure medications (ASMs), while some ASMs can exacerbate seizures. Dravet syndrome is a severe developmental and epileptic encephalopathy characterised by refractory seizures and cognitive dysfunction.
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