Current and emerging pharmacotherapy for the treatment of Lennox-Gastaut syndrome

ABSTRACT

Introduction

Lennox-Gastaut syndrome (LGS) is a severe childhood-onset epileptic encephalopathy, characterized by multiple seizure types, generalized slow spike-and-wave complexes in the EEG, and cognitive impairment. Seizures in LGS are typically resistant to treatment with antiseizure medications (ASMs). Tonic/atonic (‘drop’) seizures are of particular concern, due to their liability to cause physical injury.

Areas covered

We summarize evidence for current and emerging ASMs for the treatment of seizures in LGS. The review focuses on findings from randomized, double-blind, placebo-controlled trials (RDBCTs). For ASMs for which no double-blind trials were identified, lower quality evidence was considered. Novel pharmacological agents currently undergoing investigation for the treatment of LGS are also briefly discussed.

Expert opinion

Evidence from RDBCTs supports the use of cannabidiol, clobazam, felbamate, fenfluramine, lamotrigine, rufinamide, and topiramate as adjunct treatments for drop seizures. Percentage decreases in drop seizure frequency ranged from 68.3% with high-dose clobazam to 14.8% with topiramate. Valproate continues to be considered the first-line treatment, despite the absence of RDBCTs specifically in LGS. Most individuals with LGS will require treatment with multiple ASMs. Treatment decisions should be individualized and take into account adverse effects, comorbidities, general quality of life, and drug interactions, as well as individual efficacy.

KEYWORDS:

• Antiseizure medication
• cannabidiol
• drop seizure
• epilepsy
• fenfluramine
• Lennox-gastaut
• pharmacotherapy
• soticlestat

Article highlights

• Lennox-Gastaut syndrome is associated with multiple seizure types that are often resistant to treatment.

• There are relatively few randomized, double-blind, placebo-controlled trials of pharmacological treatment options for seizures in LGS.

• Seven ASMs, cannabidiol, clobazam, felbamate, fenfluramine, lamotrigine, rufinamide, and topiramate, are licensed as adjunct treatments in the US (clobazam, felbamate, and fenfluramine are not licensed for LGS in the EU or UK).

• Cannabidiol and fenfluramine are licensed as monotherapy in the US despite the absence of supporting efficacy data. There are currently no approved monotherapies in the EU or UK.

• Treatment decisions should be taken on an individual basis, in consultation with patients and their families, and considering adverse effects, comorbidities, and general wellbeing, as well as efficacy.

Declaration of interest

R F M Chin was a principal investigator in a GW Pharma sponsored trial of cannabidiol for the treatment of Lennox Gastaut Syndrome. He has provided paid consultancy for GW Pharma and Zogenix, and received travel grants from GW Pharma, Zogenix, Esai and UCB. He has shares in RIZE Medical Cannabis & Life Sciences UCITS ETF.

F M C Besag was an author on some of the original studies of lamotrigine in children.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors contributed to the literature review, drafting, and final production of the review, and approved the final manuscript.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14656566.2023.2215924.

Additional information

Funding

This paper was not funded.