Lennox-Gastaut syndrome (LGS) is a severe drug-resistant developmental and epileptic encephalopathy with slow spike and wave on EEG (DEE-SSW).1,2 It results from diverse etiologies, affects widespread cortical and subcortical regions, and impacts both children and adults.3 Approximately 95 % of patients with LGS experience moderate to severe cognitive dysfunction which negatively impacts quality of life.4 Patients with LGS may experience epilepsy related emergencies such as nonconvulsive status epilepticus and seizure clusters and have higher rates of premature mortality.5

In 1966 Gastaut described a severe type of intractable childhood epilepsy, characterized by frequent tonic seizures, atypical absence seizures, intellectual disability, and slow spike-and-wave discharges.6 This syndrome was designated “childhood epileptic encephalopathy with diffuse slow spike-waves” or “Lennox syndrome”.6 Initially recognizing this syndrome in 1989, the International League Against Epilepsy (ILAE) updated the criteria of DEE-SSW in 2022.7 This revised criteria included the following: (1) multiple types of drug-resistant seizures with onset prior to 18 years of age (one must be a tonic seizure); (2) cognitive and behavioral impairments; and (3) diffuse slow spike-and-wave and generalized paroxysmal fast activity on EEG.7 LGS often arises between 3 and 5 years of age and accounts for approximately 3-5 % of all childhood epilepsies.8,9

Patients with LGS rarely attain complete seizure control, and those who receive treatment early in the course of the LGS usually experience more favorable outcomes.4,8 Antiseizure medications (ASMs), in particular sodium valproate, are often the first-line treatment for patients with newly diagnosed LGS although are often associated with cognitive and behavioral side effects.2,4,9 While several ASMs (felbamate, lamotrigine, topiramate, rufinamide, clobazam, fenfluramine, and cannabidiol) have been approved by the United States (US) Food and Drug Administration (FDA),1,2,9 LGS is often drug-resistant which necessitates consideration of additional treatments. A ketogenic diet has been shown to be efficacious in the treatment of LGS by decreasing the frequency of seizures.4,10, 11, 12 Resective surgery is also promising for LGS in lesional cases. A meta-analysis reported that 76 % of patients with LGS who underwent resective surgery (lesionectomies and hemispherectomies) had a greater than 50 % seizure reduction at two or more years follow-up.13 A corpus callosotomy (CC) is a palliative option in LGS, especially to ameliorate drop attacks.4

Neuromodulation, comprised of vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), has emerged as a valuable modality in the management of drug-resistant epilepsy (DRE), in particular LGS.4,14, 15, 16 This treatment involves administering electrical stimulation to modulate abnormal brain activity causing seizures. The Pediatric Epilepsy Research Consortium (PERC) LGS Special Interest Group has recently provided guidance for clinicians about utilizing neuromodulation to treat patients with LGS.17,18 This same Special Interest Group has also reviewed the challenges associated with the myriad therapies used in LGS.2 The current focused review highlights the advantages and disadvantages of the three neuromodulation techniques as well as future directions of neuromodulation in LGS.