Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut syndrome (LGS) is a severe epileptic and developmental encephalopathy that typically manifests in childhood between 2 and 7 years of age and persists into adulthood.¹ Most cases of LGS are secondary and can evolve from other conditions, such as West syndrome; brain abnormalities and genetic defects may also be identified as causes of the disease. A minority of LGS cases are idiopathic, with no known cause.¹

Diagnostic Guidelines

No specific international guidelines have been formulated for the diagnosis of LGS, but three diagnostic criteria were included in the original description of the disease and remain important in a classic diagnosis¹:

• Multiple seizure types: LGS is typically characterized by the presence of more than one type of seizure, including tonic, atonic, and atypical absence seizures
• Electroencephalography (EEG) findings: characteristic EEG abnormalities, such as slow spike-and-wave discharges during wakefulness and/or paroxysmal fast activity during sleep
• Cognitive impairment and developmental delay

Cognitive impairment or developmental delay is a characteristic feature of LGS, but it is not always present at the onset of disease. Five years after diagnosis, however, 75% to 95% of patients have cognitive impairment, and 50% of patients experience behavioral problems.¹ 

Neurological testing, such as EEG, can document the patient’s types of seizures, as well as their frequencies and intensities. EEGs can also track abnormal ictal and interictal activity. Other features of the disease may include epileptic spasms, nonconvulsive status epilepticus, focal seizures, and myoclonic seizures.¹

Read more about LGS diagnosis

According to expert opinion, recommended investigations in the diagnostic process include¹:

• Prolonged EEG, including sleeping, is considered mandatory for an LGS diagnosis to detect tonic seizures and/or paroxysmal fast rhythms
• Surface electromyography is recommended to detect stiffening as it can be subtle
• Magnetic resonance imaging to detect brain abnormalities
• Genetic testing to obtain information on the etiology of the disease

Read more about LGS testing

Management Guidelines

The management of seizures in patients with LGS can be challenging. Because most patients experience multiple types of seizures, and a single antiseizure medication (ASM) won’t treat all types of seizures that a patient is experiencing, it’s difficult to find a treatment plan that effectively minimizes or eliminates the patient’s seizures. Combination therapy of several ASMs is often required, but complete seizure control is attained infrequently.²

In 2004, the American Academy of Neurology reported management guidelines based on available information from randomized controlled trials regarding the efficacy and safety of various ASMs used to treat refractory epilepsy, including LGS.³ In these guidelines, Lamictal® (lamotrigine) and Topamax® (topiramate) were highlighted for the treatment of drop attacks, and Felbatol® (felbamate) was suggested to have a role in the treatment of LGS.³ In a more recent update of the guidelines, Banzel® (rufinamide) was included as an effective add-on therapy for adult and pediatric patients with LGS to reduce seizure frequency. Clobazam® (sold as Onfi® and Sympazan™) was also included as a possibly effective add-on therapy.⁴

Read more about LGS therapies

Other recommendations have been proposed following the results of randomized controlled clinical trials; however, these generally focus on the treatment of partial and generalized seizures, not LGS.⁵ 

For the management of LGS, several considerations are included⁵:

• At the onset of LGS and during early stages of the disease, when drop attacks are predominant, clinical data point toward the effective use of ASMs such as Depakote® (valproate), Lamictal, and benzodiazepines. These agents may also be effective in the management of atypical absence seizures.
• The excessive use of a combination of ASMs may facilitate the development of nonconvulsive status epilepticus or tonic status. The risk of adverse events may also be increased.
• Benzodiazepines can be used to treat all types of seizures, although with variable efficacy. 
• Felbatol, Lamictal, Banzel, and Topamax are indicated for the management of drop attacks.
• Patients with LGS must be cared for by a multidisciplinary medical team.

Read more about LGS treatment

References

1. Cross JH, Auvin S, Falip M, Striano P, Arzimanoglou A. Expert opinion on the management of Lennox-Gastaut syndrome: treatment algorithms and practical considerations. Front Neurol. 2017;8:505. doi:10.3389/fneur.2017.00505

2. Chin RF, Mingorance A, Ruban-Fell B et al. Treatment guidelines for rare, early-onset, treatment-resistant epileptic conditions: a literature review on Dravet syndrome, Lennox-Gastaut syndrome and CDKL5 deficiency disorder. Front Neurol. 2021;12:734612. doi:10.3389/fneur.2021.734612

3. French JA, Kanner AM, Bautista J et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62(8):1261-1273. doi:10.1212/01.wnl.0000123695.22623.32

4. Kanner AM, Ashman E, Gloss D et al. Practice guideline update summary: efficacy and tolerability of the new antiepileptic drugs II: treatment-resistant epilepsy: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018;91(2):82-90. doi:10.1212/WNL.0000000000005756

5. Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009;8(1):82-93. doi:10.1016/S1474-4422(08)70292-8

Reviewed by Debjyoti Talukdar, MD, on 2/28/2023.

---

Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.