What is Lennox-Gastaut (LGS) syndrome?

Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut syndrome is a severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types (including tonic seizures), abnormal electroencephalographic features with slow spike-wave discharges, and cognitive and behavioral impairments, typically beginning before 8 years of age. 1

Clinical Characteristics

• Multiple seizure types that typically include:

  • Tonic seizures (required for diagnosis)
  • Atonic seizures (causing dangerous drop attacks)
  • Absence seizures
  • Myoclonic seizures
  • Generalized tonic-clonic seizures

• Electroencephalographic (EEG) features:

  • Generalized slow (<3 Hz) spike-wave discharges
  • Paroxysmal fast rhythms during sleep

• Cognitive and developmental issues:

  • Intellectual disability (varying severity)
  • Behavioral problems
  • Developmental regression

Epidemiology and Etiology

LGS typically begins in early to mid-childhood with peak onset between 3-5 years of age, though it persists throughout life 2. The syndrome can have various etiologies:

• Structural brain abnormalities
• Genetic mutations
• Metabolic disorders
• Previous brain injuries
• Evolution from other epilepsy syndromes
• Idiopathic (unknown cause)

Diagnosis

Diagnosis is based on the triad of:

1. Multiple seizure types (must include tonic seizures)
2. Characteristic EEG pattern with slow spike-wave discharges
3. Cognitive impairment

Accurate diagnosis is critical but can be challenging, especially in adults where the clinical and EEG features may evolve over time 2.

Treatment Approach

Treatment of LGS is challenging due to drug resistance and associated comorbidities. A comprehensive approach is necessary:

First-line Pharmacological Treatment:

• Valproate is recommended as first-line monotherapy 1, 3

Second-line (if valproate is ineffective as monotherapy):

• Lamotrigine as first adjunctive therapy
• Rufinamide as second adjunctive therapy 1

Additional Pharmacological Options:

• Cannabidiol
• Clobazam
• Felbamate
• Fenfluramine
• Topiramate 1

Non-pharmacological Approaches:

• Ketogenic diet therapy
• Vagus nerve stimulation
• Corpus callosotomy 1, 4

Medication Considerations

Rufinamide has shown specific efficacy in LGS clinical trials. In a double-blind, placebo-controlled study, rufinamide demonstrated:

• 32.7% median reduction in total seizure frequency
• 42.5% median reduction in tonic-atonic seizure frequency
• Significant improvement in seizure severity ratings 5

Important medication interactions to note with rufinamide:

• Valproate may increase rufinamide levels by up to 70% in pediatric patients
• Rufinamide is a weak inducer of CYP3A4 enzymes and may decrease levels of medications metabolized through this pathway 5

Long-term Management

LGS is a lifelong condition requiring ongoing management:

• Regular review by experienced neurologists (at least annually)
• Monitoring for medication side effects
• Addressing cognitive and behavioral issues
• Supporting transition from pediatric to adult care
• Managing comorbidities including sleep disturbances and physical disabilities 2

Prognosis

The prognosis for complete seizure control in LGS remains poor despite multiple treatment options 4. Most patients continue to have seizures into adulthood and require lifelong care and support. Cognitive impairment typically persists, though early and effective seizure management may help limit developmental impact.

Research Priorities

Current research priorities include:

• Development of disease-modifying therapies
• Better understanding of LGS pathophysiology
• Standardization of treatment approaches
• Incorporation of patient-centered outcomes in clinical trials 6

Common Pitfalls in Management

• Failure to recognize LGS in adults due to evolution of clinical and EEG features
• Excessive polypharmacy (ideally no more than two antiseizure medications should be used together) 1
• Focusing solely on seizure control without addressing quality of life and comorbidities
• Inadequate transition from pediatric to adult care

LGS represents one of the most challenging epilepsy syndromes to manage, requiring a comprehensive approach to treatment that extends beyond seizure control to address the multiple aspects of this complex condition.