Treatment-resistant Lennox-Gastaut syndrome: therapeutic trends, challenges and future directions

Abstract

Lennox-Gastaut syndrome is a severe, childhood-onset electroclinical syndrome comprised of multiple seizure types, intellectual and behavioral disturbances and characteristic findings on electroencephalogram of slow spike and wave complexes and paroxysmal fast frequency activity. Profound morbidity often accompanies a common and severe seizure type, the drop attack. Seizures often remain refractory, or initial treatment efficacy fades. Few individuals are seizure free despite the development of multiple generations of antiseizure medications over decades and high-level evidence on several choices. Approved medications such as lamotrigine, topiramate, rufinamide, felbamate and clobazam have demonstrated efficacy in reducing seizure burden. Cannabidiol has emerged as a promising investigational therapy with vast social interest yet lacks a standard, approved formulation. Palliative surgical procedures, such as vagal nerve stimulation and corpus callosotomy may provide reduction in total seizures and drop attacks. Emerging evidence suggests that complete callosotomy provides greater improvement in seizures without additional side effects. Etiologies such as dysplasia or hypothalamic hamartoma may be amenable for focal resection and thus offer potential to reverse this devastating epileptic encephalopathy.

Keywords: Lennox-Gastaut syndrome; cannabidiol; epilepsy; epilepsy surgery; epileptic encephalopathy.

Figure 1

Electroencephalographic findings in Lennox-Gastaut syndrome. Notes: Individuals with Lennox-Gastaut syndrome typically exhibit (A) generalized or diffuse slow spike and wave complexes and (B) generalized paroxysmal fast activity. (C) Lateralized predominance of epileptiform activity may be indicative of a focal lesion. (D) Generalized tonic seizures may arise from the background abnormalities.

Figure 2

Total seizure efficacy. Notes: Percentage of reduction in total seizures in patients with Lennox-Gastaut syndrome noted from class I or class II studies of approved antiseizure medications. Dark bars represent study drug results, with corresponding placebo response in light bars. Modified from Pediatr Neurol, 47(3), VanStraten AF, Ng YT. Update on the management of Lennox-Gastaut syndrome. 153–161, Copyright © 2012 Elsevier Inc. All rights reserved, with permission from Elsevier. Abbreviation: NS, not significant.

Figure 3

Drop seizure efficacy. Notes: Percentage of reduction in drop seizures in patients with Lennox-Gastaut syndrome noted from class I or class II studies of approved antiseizure medications. Dark bars represent study drug results, with corresponding placebo response in light bars. Modified from Pediatr Neurol, 47(3), VanStraten AF, Ng YT. Update on the management of Lennox-Gastaut syndrome. 153–161, Copyright © 2012 Elsevier Inc. All rights reserved, with permission from Elsevier.

Figure 4

Drop seizure responders. Notes: Percentage of subjects with a greater than 50% reduction in drop seizures in patients with Lennox-Gastaut syndrome noted from class I or class II studies of approved antiseizure medications. The results from a meta-analysis of VNS and CC are in the box to the right. Dark bars represent study intervention results, with corresponding placebo response in light bars. Abbreviations: VNS, vagal nerve stimulator; CC, corpus callosotomy.

Figure 5

Complete corpus callosotomy. Note: Magnetic resonance imaging (A) before and (B) after complete corpus callosotomy in an individual with Lennox-Gastaut syndrome.

Figure 6

Proposed management of Lennox-Gastaut syndrome. Notes: First-tier preferred medications are in bold. *Commonly used medications without level 1 or 2 evidence. Abbreviations: CC, corpus callosotomy; EEG, electroencephalogram; VNS, vagal nerve stimulator.