What are the treatment options for patients with drug-resistant seizures?

Treatment Options for Drug-Resistant Seizures

For patients with drug-resistant epilepsy, treatment options include rational polytherapy with combinations of antiseizure medications, epilepsy surgery evaluation, and advanced neuroimaging techniques to identify the seizure focus. 1

Definition and Prevalence

• Drug-resistant epilepsy (DRE) is defined as failure to achieve seizure control after adequate trials of two appropriately chosen, well-tolerated antiseizure medications (ASMs), either as monotherapies or in combination 1, 2
• Approximately 30% of epilepsy patients develop drug resistance 3, 4
• Persistent seizures significantly impact quality of life and increase risk of injury and mortality 4

Pharmacological Options

Rational Polytherapy

• Combination therapy with ASMs having different mechanisms of action shows better outcomes than continued monotherapy trials in DRE 5
• Key medication options include:

1. Levetiracetam:

   • Effective for both focal and generalized seizures
   • Can be rapidly loaded at therapeutic doses
   • Monitor for behavioral side effects (irritability, depression, anxiety) 1, 6

2. Valproate:

   • Highly effective for generalized seizures
   • Can be administered IV at doses up to 30 mg/kg
   • Avoid in women of childbearing potential due to teratogenic risk 1, 3

3. Perampanel:

   • Non-competitive AMPA glutamate receptor antagonist
   • Indicated for partial-onset seizures and primary generalized tonic-clonic seizures
   • Starting dose: 2 mg once daily at bedtime, titrated by 2 mg increments weekly
   • Maintenance dose: 8-12 mg once daily
   • Monitor for psychiatric and behavioral reactions (aggression, irritability) 7

4. Other options:

   • Lamotrigine (requires slow titration)
   • Carbamazepine (for focal seizures)
   • Lacosamide, brivaracetam, cenobamate (newer agents) 1

Status Epilepticus Management

• For benzodiazepine-resistant status epilepticus, levetiracetam, fosphenytoin, or valproate are equally effective (approximately 45-47% efficacy) 3
• These medications can be administered intravenously for rapid effect 3

Non-Pharmacological Options

Epilepsy Surgery

• Epilepsy surgery should be considered early for suitable candidates with drug-resistant focal epilepsy 1
• Extended lesionectomy (excision of the lesion and abnormal dysplastic cortex) is preferred for epilepsy associated with structural abnormalities 1
• Surgical evaluation includes:
  • Video-EEG monitoring
  • High-resolution MRI
  • Neuropsychological testing
  • Advanced neuroimaging 3, 1

Advanced Neuroimaging

• PET and SPECT imaging can help identify the seizure onset zone when MRI is negative or inconclusive 3
• These molecular neuroimaging techniques are particularly valuable in the presurgical evaluation of patients with drug-resistant focal epilepsy 3

Treatment Algorithm

1. Confirm diagnosis and drug resistance:

   • Verify epilepsy diagnosis and seizure classification
   • Ensure adequate trials of at least two appropriate ASMs

2. Optimize current therapy:

   • Consider rational polytherapy with ASMs having complementary mechanisms
   • Monitor for drug interactions and adverse effects
   • Ensure medication adherence

3. Evaluate for epilepsy surgery:

   • Refer to comprehensive epilepsy center
   • Complete presurgical evaluation including video-EEG and neuroimaging

4. If surgery is not an option:

   • Trial additional ASM combinations
   • Consider perampanel or newer agents not previously tried
   • Maintain focus on quality of life and seizure reduction

Common Pitfalls and Caveats

• Medication adherence: Poor adherence is a common cause of apparent drug resistance
• Misdiagnosis: Ensure events are epileptic seizures, not psychogenic non-epileptic events
• Inadequate dosing: Subtherapeutic dosing may lead to false impression of drug resistance
• Drug interactions: ASMs may interact, reducing efficacy or increasing toxicity
• Behavioral side effects: Monitor closely for psychiatric adverse effects, especially with perampanel and levetiracetam 7, 6
• Women of childbearing age: Avoid valproate due to teratogenic risk; consider lamotrigine or levetiracetam 1

By following this structured approach to managing drug-resistant seizures, clinicians can optimize treatment outcomes and improve quality of life for patients with this challenging condition.