Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy that begins in childhood.1,2 LGS is characterized by multiple seizure types, characteristic electroencephalographic (EEG) patterns, and cognitive disability.1,3 Malformations of the brain, perinatal asphyxia, severe head injury, central nervous system infections, and inherited degenerative metabolic conditions are possible underlying causes of this syndrome.1 

Currently, there are several pharmacological and nonpharmacological therapies available for the management of LGS. The ultimate goal of treatment is to control or eliminate a patient’s seizure activity. However, as most patients experience multiple types of seizures, it is difficult to attain a level of seizure control with any single antiseizure medication (ASM) or even combination therapy of ASMs. Because of this, antiseizure medication therapy is used with the goal of reducing the frequency of seizures that are most incapacitating and prone to cause injury. 2,3


Depakote® (valproate or valproic acid) is an ASM manufactured by AbbVie that is commonly used in the management of LGS. Sometimes sold as Depakene®, this drug remains a mainstay in the treatment of LGS due to its broad-spectrum anticonvulsant activity and effectiveness in reducing seizures, particularly myoclonic, atypical absence, and atonic.2-4 

Depakote works via several mechanisms, both by increasing GABA levels and modifying sodium and calcium channel activity in the brain.2 Common adverse effects following the use of Depakote include gastrointestinal upset and weight gain. Although rare, hepatotoxicity and pancreatitis can also develop.3

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Topamax® (topiramate) is a fructose derivative commercialized by Janssen Pharmaceuticals. Topamax is approved for the treatment of seizures associated with LGS in patients 2 years of age and older.5 It is a broad-spectrum ASM that prevents the onset of multiple seizure types.2,5 Preclinical data indicate that this medication is capable of blocking voltage-dependent sodium channels, increasing the activity of GABA, antagonizing the AMPA/kainate subtype of the glutamate receptor, and inhibiting the carbonic anhydrase enzyme.5

The efficacy of Topamax in patients with LGS was shown in a double-blind, placebo-controlled clinical trial. This trial included 98 patients who were treated with Topamax for 11 weeks. The average monthly rates of major seizures (drop attacks and tonic-clonic seizures) in the Topamax-treated group were decreased compared to those of the placebo-treated group. In addition to reducing the frequency of seizures, the drug also reduced their severity.6

Adverse events observed with the use of Topamax include paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever.5


Felbatol® (felbamate) is an antiseizure drug marketed in the United States by Medpointe Pharmaceuticals.7 Its mechanism of action involves the reduction of glutamatergic transmission and the inhibition of GABA-receptor binding and voltage-gated sodium and calcium channels.2 

Particularly effective against generalized tonic-clonic or partial seizures, the approval of Felbatol followed a double-blind, placebo-controlled clinical trial that included 73 patients with LGS.8 The administration of Felbatol led to a 34% reduction in the frequency of atonic seizures. Other types of seizures were also reduced with the treatment, with a reported total decrease of 19%, while the placebo group experienced an increase in frequency of 4%.8 

An open-label follow-up study included 70 patients who completed the previous clinical trial and demonstrated a relative long-term efficacy of the medication with no tolerance development. In this extension study, the control of atonic seizure frequency was maintained and 51% of the patients maintained at least a 50% reduction in total seizure frequency after 12 months.2 

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Lamictal® (lamotrigine) is an antiseizure medication commercialized by GlaxoSmithKline that is indicated for adjunctive therapy of generalized seizures in patients with LGS aged 2 years and older.9 This medication is effective in the reduction of all major seizures including tonic-clonic seizures and drop attacks.2

The mechanism of action of Lamictal is not completely understood, but it may involve the stabilization of voltage-sensitive sodium channels.2 Approval in the United States and the European Union followed the results of a double-blind, placebo-controlled clinical trial with 169 patients. A median reduction of 32% was observed for all major seizures in the treatment group compared to 9% in the placebo group.2,10

The most common adverse reactions with the use of Lamictal include dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, pharyngitis, and rash. In children, other adverse events may be observed, such as vomiting, infection, fever, diarrhea, and abdominal pain.9


Banzel® (rufinamide) is a medication distributed and marketed by Eisai that is indicated for the adjunctive treatment of seizures associated with LGS in patients aged 1 year and older.11 Rufinamide, the active ingredient of Banzel, is a triazole derivative that modulates the activity of sodium channels. It is effective in reducing the frequency of generalized tonic-clonic, tonic, atonic, and focal seizures.2,3

US and EU approval of Banzel for use in LGS derived from the phase 3, double-blind, placebo-controlled clinical trial, Study 022, which was followed by an open-label single-arm extension study (Study 022E) for up to 3 years.2 Study 022 involved 138 patients and included a baseline period of 4 weeks and a treatment period of 12 weeks. This study reported significant reductions in total seizure frequency and drop seizures in the Banzel-treated group when compared to those of the placebo-treated group.2 In the extension study, the efficacy of Banzel was sustained.2

Banzel is usually well tolerated; common adverse events include headache, dizziness, fatigue, somnolence, and nausea.11

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Onfi® (clobazam) is a medication marketed by Lundbeck that is indicated for the adjunctive treatment of seizures in patients with LGS aged 2 years and over.12 The active ingredient of Onfi is a benzodiazepine with an improved safety and tolerability profile compared to that of other molecules from the same class.2

Onfi decreases the likelihood of seizures by binding to postsynaptic GABA receptors, allowing an increase in action potential threshold and a reduction in the frequency of the action potentials.2

The tolerability of Onfi was determined in a phase 2 clinical trial. This trial also reported a reduction in the weekly rates of drop and nondrop seizures in patients.13 The safety and efficacy of the drug were studied in a phase 3 double-blind, placebo-controlled clinical trial. Results showed a decrease in the average weekly rate of total seizures and an increase in the rate of responders with an increase in dosage.14

Adverse reactions reported with the use of Onfi include constipation, somnolence or sedation, pyrexia, lethargy, and drooling.12


Epidiolex® is an oral cannabidiol (CBD) solution commercialized by Jazz Pharmaceuticals that is indicated for the treatment of seizures associated with LGS in patients aged 1 year and older.15 The mechanism of action of Epidiolex for the control of seizures is not known, although its affinity for targets that decrease neuronal excitability and are related to the pathological mechanisms of the disease has been reported.2 

Approval of Epidiolex by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in patients with LGS followed data from two phase 3 double-blind, placebo-controlled clinical trials, GWPCARE3 and GWPCARE4.16-19 Results from these trials show a significant decrease in seizure frequency with Epidiolex treatment when compared to that with a placebo. Significantly higher percentages of patients in the cannabidiol-treatment groups achieved at least 50% reductions in the monthly frequency of drop seizures compared to patients in the placebo group.16,17 An open-label extension study reported sustained reductions in seizures.2

The most common adverse reactions with the use of Epidiolex include somnolence, decreased appetite, diarrhea, fatigue, rash, and infections.15

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Fintepla® (fenfluramine) is a medication marketed by Zogenix Inc (part of the UCB Group of Companies) that is indicated for the treatment of seizures associated with LGS in patients aged 2 years and above.20 The active ingredient in Fintepla is fenfluramine, a derivative of amphetamine. Fintepla increases serotonin levels and demonstrates agonist activity at serotonin 5HT-2 receptors.2

The efficacy of this medication was studied in a phase 3 multicenter, global, double-blind, placebo-controlled study, Study 1601.21 This trial included 263 patients with LGS with pharmacologically uncontrolled seizures. Fintepla led to a significant reduction in the frequency of seizures.2 

Common adverse reactions to Fintepla include diarrhea, fatigue, decreased appetite, and vomiting.20


1. Lennox-Gastaut syndrome: about the disease. Genetic and Rare Diseases Information Center (GARD). Updated February 2023. Accessed February 13, 2023.

2. Strzelczyk A, Schubert-Bast S. Expanding the treatment landscape for Lennox-Gastaut syndrome: current and future strategies. CNS Drugs. 2021;35(1):61-83. doi:10.1007/s40263-020-00784-8

3. Asadi-Pooya AA. Lennox-Gastaut syndrome: a comprehensive review. Neurol Sci. 2018;39(3):403-414. doi:10.1007/s10072-017-3188-y

4. Cherian KA. Lennox-Gastaut syndrome medication. Medscape. Updated August 6, 2020. Accessed February 13, 2023.

5. Topamax. Prescribing information. Janssen Pharmaceuticals, Inc; 2022. Accessed February 13, 2023.

6. Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G; Topiramate YL Study Group. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Neurology. 1999;52(9):1882-1887. doi:10.1212/wnl.52.9.1882

7. Felbamate. Epilepsy Foundation. Updated November 3, 2022. Accessed February 13, 2023.

8. Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med. 1993;328(1):29-33. doi:10.1056/NEJM199301073280105

9. Lamictal. Prescribing information. GlaxoSmithKline; 2023. Accessed February 13, 2023.

10. Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, Manasco P; Lamictal Lennox-Gastaut Study Group. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N Engl J Med. 1997;337(25):1807-1812. doi:10.1056/NEJM199712183372504

11. Banzel. Prescribing information. Eisai Inc; 2021. Accessed February 13, 2023.

12. Onfi. Prescribing information. Lundbeck; 2023. Accessed February 13, 2023.

13. Conry JA, Ng YT, Paolicchi JM, et al. Clobazam in the treatment of Lennox-Gastaut syndrome. Epilepsia. 2009;50(5):1158-1166. doi:10.1111/j.1528-1167.2008.01935.x

14. Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011;77(15):1473-1481. doi:10.1212/WNL.0b013e318232de76

15. Epidiolex. Prescribing information. Jazz Pharmaceuticals, Inc; 2023. Accessed February 13, 2023.

16. Devinsky O, Patel AD, Cross JH, et al; GWPCARE3 Study Group. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378(20):1888-1897. doi:10.1056/NEJMoa1714631

17. Thiele EA, Marsh ED, French JA, et al; GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085-1096. doi:10.1016/S0140-6736(18)30136-3

18. Efficacy and safety of GWP42003-P for seizures associated with Lennox-Gastaut syndrome in children and adults (GWPCARE3). ClinicalTrials.gov. August 25, 2014. Updated September 28, 2022. Accessed February 14, 2023.

19. A study to investigate the efficacy and safety of cannabidiol (GWP42003-P; CBD) as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in children and adults (GWPCARE4). ClinicalTrials.gov. August 25, 2014. Updated September 28, 2022. Accessed February 14, 2023.

20. Fintepla. Prescribing information. Zogenix Inc; 2023. Accessed February 13, 2023.

21. A study to investigate the efficacy and safety of ZX008 (fenfluramine hydrochloride) as an adjunctive therapy in children and adults with Lennox-Gastaut syndrome. ClinicalTrials.gov. November 28, 2017. Updated January 30, 2023. Accessed February 14, 2023.

Reviewed by Harshi Dhingra, MD, on 2/21/2023.