What is the management of Lennox-Gastaut (LGS) syndrome?

Management of Lennox-Gastaut Syndrome

Valproate should be used as first-line treatment for newly diagnosed Lennox-Gastaut syndrome, followed by adjunctive therapy with lamotrigine and then rufinamide if seizure control remains inadequate. 1

Overview of Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut syndrome is a severe developmental and epileptic encephalopathy characterized by:

• Multiple drug-resistant seizure types (must include tonic seizures)
• Classical onset before 8 years of age
• Abnormal EEG with slow spike-wave complexes and paroxysmal fast rhythms
• Cognitive and behavioral impairments
• Poor responsiveness to antiepileptic medication 2, 1

Pharmacological Management Algorithm

First-Line Treatment

• Valproate monotherapy 1, 3
  • Considered the most effective first-line option
  • Addresses multiple seizure types common in LGS

Second-Line (Add-on) Treatment

If valproate alone is ineffective:

• Add lamotrigine 1, 4
  • Effective for multiple seizure types in LGS
  • Monitor for potential drug interactions with valproate

Third-Line (Add-on) Treatment

If valproate + lamotrigine combination is inadequate:

• Add rufinamide 1, 5
  • FDA-approved for LGS in patients ≥1 year of age
  • Clinical trials showed 32.7% median reduction in total seizure frequency and 42.5% reduction in tonic-atonic seizures 5
  • Target dosage: approximately 45 mg/kg/day (up to 3200 mg in adults >70 kg)

Fourth-Line Options (if seizure control remains suboptimal)

Consider one of the following as adjunctive therapy:

• Cannabidiol 1, 6
• Clobazam 1, 3
• Topiramate 7, 3
  • FDA-approved for LGS
  • Effective for multiple seizure types
• Felbamate 1, 3
  • Requires careful monitoring due to risk of aplastic anemia and hepatotoxicity
• Fenfluramine 1, 6

Non-Pharmacological Interventions

These should be considered concurrently with medication therapy:

1. Ketogenic Diet

   • Consider early in treatment course
   • Particularly effective for drug-resistant epilepsies 1, 4

2. Vagus Nerve Stimulation (VNS)

   • Offers reasonable seizure improvement
   • Consider when multiple medications have failed 8, 4

3. Corpus Callosotomy

   • Palliative surgical procedure
   • Primarily aimed at controlling drop attacks (tonic or atonic seizures) 8, 4

4. Advanced Neuroimaging

   • [18F]FDG PET may be valuable in surgical treatment planning for patients with unilateral focal hypometabolism 2
   • Helps identify the epileptogenic zone when MRI findings are inconclusive

Practical Management Considerations

Medication Optimization

• Limit polypharmacy: Whenever possible, use no more than two antiseizure medications concurrently 4
• Individualize maintenance regimens: Titrate treatment to maintain symptom control and prevent scarring
• Monitor for adverse effects: Sedation, cognitive impairment, and behavioral changes are common

Follow-up and Monitoring

• Patients should be followed up regularly to assess response to treatment 1
• Annual review by a neurologist specialized in epilepsy is recommended 4
• Reassess diagnosis and treatment plan periodically, as LGS features evolve over time

Special Considerations

• Treatment goals: Focus on reducing the most disabling seizures (drop attacks and tonic-clonic seizures) rather than achieving complete seizure freedom 8
• Comorbidity management: Address cognitive impairment and behavioral disorders alongside seizure control
• Long-term outlook: Prepare patients/caregivers for typically poor long-term outcomes regarding intellectual development and independent living 8

Pitfalls and Caveats

• Avoid frequent medication changes without adequate trial periods
• Be vigilant for treatable etiologies that may be underlying LGS
• Recognize that seizure types and EEG features evolve over time, potentially changing the diagnosis
• Complete seizure control with resolution of intellectual dysfunction is often not achievable; focus on improving quality of life 8
• Diagnostic neuroimaging tools like [18F]FDG PET may show different tracer uptake patterns in LGS and should be interpreted carefully 2

The management of LGS requires a comprehensive approach targeting seizure reduction while optimizing cognitive function and quality of life. Early intervention with appropriate medication and consideration of non-pharmacological options offers the best chance for improved outcomes in this challenging syndrome.