A Practical Guide to the Treatment of Dravet Syndrome with Anti-Seizure Medication

Abstract

Dravet syndrome is a severe developmental and epileptic encephalopathy characterised by refractory seizures and cognitive dysfunction. 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. Initial treatments include the broad-spectrum ASMs valproate (VPA), and clobazam (CLB) in some regions; however, they are generally insufficient to control seizures. 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. 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. 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. With a growing treatment landscape for Dravet syndrome, there can be practical challenges for clinicians, particularly with issues associated with polypharmacy. 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. 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. 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. Importantly, no signs of heart valve disease have been documented to date at the low doses used in patients with developmental and epileptic encephalopathies. In addition, potential drug-drug interactions and their consequences are a key consideration in everyday practice. 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. 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. In addition, CBD is associated with elevations of liver transaminases particularly in patients taking concomitant VPA. The interaction between FFA and STP requires a dose reduction of FFA. Furthermore,

Efficacy and safety of adjunctive antiseizure medications for dravet syndrome: A systematic review and network meta-analysis

“…The British National Institute of Clinical Practice guidelines and Chinese epilepsy diagnosis and treatment guidelines recommend valproic acid, topiramate, and/or clobazam as first-line treatment drugs for DS; stiripentol, levetiracetam, and zonisamide can be used as additional therapeutic drugs, while sodium channel blockers are not recommended for the treatment of DS ( Nunes et al, 2012 ). Because DS has no specific symptoms in the early stage, it is often misdiagnosed as other types of epilepsy, and the application of sodium channel inhibitors (carbamazepine, oxcarbazepine, and lamotrigine) and benzodiazepines may promote encephalopathy and worsen the condition ( Strzelczyk and Schubert-Bast, 2022 ). Despite reasonable multidrug therapy and ketogenic diets, approximately 45% of children experience more than four seizures per month due to limited drug options for DS ( Wheless et al, 2020 ).…”

“…The most common adverse reactions were loss of appetite and weight loss. Other common adverse reactions include diarrhea, fatigue, lethargy, fever, and upper respiratory tract infections ( Strzelczyk and Schubert-Bast, 2022 ).…”

“…However, antiseizure medication treatment remains the mainstay treatment for DS ( Chin et al, 2021 ). Valproic acid and clobazam are the first-line drugs for treating DS according to the practical guidelines for treating DS with anti-seizure medication ( Strzelczyk and Schubert-Bast, 2022 ). Medications that may exacerbate seizures, including sodium channel inhibitors (e.g., carbamazepine, oxcarbazepine, lamotrigine, and phenytoin) and the γ-aminobutyric acid (GABA) transaminase inhibitor vigabatrin, should be avoided ( Wirrell et al, 2017 ).…”

“…Recently, the U.S. Food and Drug Administration (FDA) approved medications for DS, which included stiripentol, fenfluramine, and cannabidiol ( Sharawat et al, 2021 ). Moreover, it was found that soticlestat, a new drug used to treat DS, showed promising efficacy and safety in a recently completed phase 2 clinical trial ( Strzelczyk and Schubert-Bast, 2022 ). These drugs act through different mechanisms.…”

The contribution of fenfluramine to the treatment of Dravet syndrome in Spain through Multi-Criteria Decision Analysis

“…In DS, as for other rare diseases, the decision for choosing a treatment not only depends on clinical experience, patient charac- teristics, and caregivers' preferences, but also depends on treatment availability [59]. Fenfluramine is undergoing pricing and reimbursement assessment in Spain and cannabidiol underwent a lengthy process.…”