Research update: The latest news in LGS treatment

By Courtney Manser, MD, CCFP (PC) | Medically reviewed by Moody Kassem, MD, MBA
Published September 5, 2023

Key Takeaways

  • Drug resistance is common in Lennox-Gastaut syndrome (LGS), meaning treatment can be difficult.

  • Cannabidiol and fenfluramine are the two most recent medications that have been approved by the FDA for LGS.

  • There is exciting new research and several medications and non-pharmacological treatments in the pipeline for the management of LGS, including perampanel, carisbamate, soticlestat, LP352, and responsive neurostimulation, among others.

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.[]

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.[]

Drug resistance in patients with LGS

Due to the differing presentations of LGS, there is no universally accepted definition. However, it is often described by the following three key features:

  • 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

Related: Spotting the elusive signs of Lennox-Gastaut syndrome in young patients

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.

Non-pharmacological avenues, including surgical procedures, ketogenic diet therapy, and vagus nerve stimulation (VNS), can be highly beneficial for select cases.

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.

In 2018, a pivotal milestone was reached when cannabidiol (CBD) received FDA approval for LGS treatment. More recently, in 2022, fenfluramine hydrochloride was added to the list of approved treatments.[]

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.[] 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.[]

While not a new treatment, the demonstrated efficacy, and safety data suggest that vagus nerve stimulation may be an underutilized tool in managing drug-resistant LGS.

What else is in the pipeline


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.[] 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 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.[]


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.[]

Related: Unique approaches to Lennox-Gastaut and Dravet syndromes


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.[]

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.

When abnormal activity is detected, the neurostimulator delivers brief electrical pulses to the affected brain area, aiming to disrupt the seizure activity and prevent the spread of the seizure to other parts of the brain.

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

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

What this means for you

LGS presents a formidable treatment challenge, primarily due to the frequent resistance to conventional antiepileptic drugs. However, there's reason for optimism. It's crucial to be aware of available options, especially for patients who have not responded to initial or secondary treatments. Exploring non-pharmacological approaches can open new avenues of hope, and ongoing research promises innovative therapeutic breakthroughs, offering a glimmer of optimism for patients and their caregivers.

Read Next: As a pediatric neuroimmunologist, here’s what excites me in Lennox-Gastaut syndrome research

Share with emailShare to FacebookShare to LinkedInShare to Twitter