Lennox-Gastaut syndrome (LGS) is a form of severe epilepsy with a prevalence of 1 to 2 per 100,000 individuals that is diagnosed in childhood, with seizures usually beginning before the age of 4, although they can first present at any time during childhood.

Lennox-gastaut syndrome. National Institute of Neurological Disorders and Stroke.

 

The treatment of LGS is often difficult due to the high probability of resistance to anti-epileptic drugs, per the authors of a retrospective study published in the Journal of Clinical Medicine.

Falcicchio G, Lattanzi S, Negri F, et al. Treatment with cenobamate in adult patients with lennox–gastaut syndrome: a case series. J Clin Med. 2022;12(1):129.

 

 

Drug resistance in patients with LGS

 

• Drug-resistant seizures of varying types

• Changes on EEG showing bursts of slow spike-wave complexes or generalized paroxysmal fast activity

• Cognitive and behavioral impairment

 

The formidable challenge of drug resistance in treating LGS often results in fleeting positive outcomes. Treatment objectives commonly revolve around diminishing seizure frequency, enhancing overall quality of life, and tackling behavioral and cognitive challenges. While antiepileptic drugs (AEDs) like valproic acid, lamotrigine, and rufinamide are frequently employed, they may offer only limited seizure control.

Fortunately, ongoing and promising research in this field continues to drive progress.

 

Milestones in LGS treatment research

 

Presently, first-line pharmacological therapies for LGS encompass valproate, lamotrigine, and topiramate, while second-line options include rufinamide, clobazam, and felbamate. Notably, the range of potential adjuvant medications for LGS is expanding.

 

Non-pharmacological management, such as the ketogenic diet, surgical procedures such as the corpus callosotomy, and the innovative approach of vagus nerve stimulation, are vital considerations for refractory patients.

Vagus nerve stimulation involves implanting a device under the skin, which is connected to the vagus nerve and sends regular impulses to the brain via this nerve.

Vagus nerve stimulation (Vns) therapy. Epilepsy Foundation.

The goal is to reduce the frequency of seizures that resist pharmacological therapy.

 

This treatment is approved and utilized for drug-resistant epilepsy in patients aged 4 years and older. A 2020 meta-analysis reported that 54% of LGS patients treated with vagus nerve stimulation as an adjunctive therapy responded well and tolerated it effectively.

Dibué M, Greco T, Spoor JKH, et al. Vagus nerve stimulation in patients with Lennox‐Gastaut syndrome: A meta‐analysis. Acta Neurol Scand. 2021;143(5):497-508.

 

 

What else is in the pipeline

 

Perampanel

Perampanel is an AMPA receptor antagonist that works by reducing the excitability of neurons in the brain. In a recent multicentre retrospective study published in Epilepsia, perampenel was found to be effective as an adjuvant therapy for the treatment of seizures associated with LGS.

Matricardi S, Cesaroni E, Bonanni P, et al. Long‐term effectiveness of add‐on perampanel in patients with Lennox–Gastaut syndrome: A multicenter retrospective study. Epilepsia. 2023;64(6).

The study found that about 41% of patients were responders, having a decreased amount of all types of seizures. About two-thirds of the responders saw continued benefit long term.

 

Carisbamate

Carisbamate is thought to work by modulating the activity of neurotransmitters in the brain, particularly gamma-aminobutyric acid, which plays a role in inhibiting excessive neuronal activity. Currently undergoing phase 3 clinical trials, carisbamate is being investigated for the efficacy and safety as an adjuvant therapy for seizures associated with LGS in both children and adults.

Investigate efficacy and safety of carisbamate as adjunctive treatment for seizures associated with lgs in children and adults. ClinicalTrials.gov. February 2, 2022.

 

Soticlestat

Soticlestat (formerly known as OV935) is designed to inhibit the enzyme cholesterol 24-hydroxylase (CH24H). This enzyme plays a role in the conversion of cholesterol to 24S-hydroxycholesterol (24HC) in the brain. Elevated levels of 24HC have been associated with increased excitability and neuronal hyperactivity, which can contribute to seizures. Soticlestat is showing promise in phase 2 clinical trials, and is still under investigation as an adjuvant therapy for seizure control in patients with LGS or Dravet syndrome.

Hahn CD, Jiang Y, Villanueva V, et al. A phase 2, randomized, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox–Gastaut syndrome (Elektra). Epilepsia. 2022;63(10):2671-2683.

 

 

LP352

The PACIFIC study is currently in progress, evaluating the safety, tolerability, efficacy, and pharmacokinetics of adjunctive therapy of LP352 in adults and adolescents with developmental and epileptic encephalopathies, including Dravet syndrome and LGS.

Study to investigate lp352 in subjects with developmental and epileptic encephalopathies. ClinicalTrials.gov. May 6, 2022.

 

 

What’s new in non-pharmacological management

 

Responsive neurostimulation (RNS)

RNS is an implantable neurostimulation system designed to treat epilepsy by continuously monitoring brain activity and delivering electrical stimulation in response to detected abnormal electrical patterns or seizure onsets, analogous to a pacemaker for the heart.

The RNS system consists of a neurostimulator device implanted in the skull and one or more leads (thin wires with electrodes) that are placed directly on or within the brain tissue in areas associated with seizure activity.

RNS is not currently approved for LGS, but has shown to be beneficial in drug resistant, multifocal epilepsy.

Keen K. Responsive neurostimulation (RNS). LGS Foundation.

 

RNS is currently undergoing evaluation on safety and efficacy for brain-responsive neurostimulation of thalamocortical networks as adjuvant therapy for patients who are refractory to medication. The study is designed for LGS patients 12 years and older.

RNS system clinical trials. NeuroPace, Inc.

Like many invasive therapies, we may see the approved age reduced to include younger, medication-refractory patients, once it is proven effective and safe.