What is the first-line treatment for Dravet syndrome?

First-Line Treatment for Dravet Syndrome

The first-line treatment for Dravet syndrome is valproate, typically combined with clobazam, with stiripentol added as the most evidence-based adjunctive therapy when seizures persist. 1, 2, 3

Initial Treatment Approach

First-Line Medications

• Valproate: Should be initiated at the first onset of complicated febrile seizures in Dravet patients 2
• Clobazam: Added when seizures persist despite valproate therapy 2, 3

When Initial Treatment Is Insufficient

When seizures are not adequately controlled with valproate and clobazam (which is common in this highly pharmaco-resistant epilepsy syndrome), the evidence strongly supports adding stiripentol:

• Stiripentol (Diacomit): The only medication specifically approved for Dravet syndrome that has demonstrated efficacy in two independent double-blind controlled trials 1, 2
  • FDA-approved for treatment of seizures associated with Dravet syndrome in patients taking clobazam who are 6 months of age and older and weighing 7 kg or more 1
  • Important note: Not indicated for monotherapy in Dravet syndrome 1

Evidence Supporting Stiripentol

Stiripentol has the strongest evidence base among adjunctive therapies:

• Demonstrated efficacy in two multicenter placebo-controlled double-blind randomized studies 1
• In clinical trials, the responder rate (>50% reduction in seizures) was significantly greater for stiripentol than for placebo:
  • Study 1: 71% for stiripentol vs. 5% for placebo (p<0.0001) 1
  • Study 2: 67% for stiripentol vs. 9.1% for placebo (p=0.0094) 1
• 43% and 25% of patients in Studies 1 and 2 respectively reported no generalized clonic or tonic-clonic seizures for the duration of the study 1
• Long-term safety and efficacy have been confirmed in Japanese studies with responder rates of 54% 4

Dosing and Administration of Stiripentol

• Fixed dose of 50 mg/kg/day in divided doses 1
• When adding stiripentol to valproate and clobazam, doses of these medications should be reduced to minimize side effects 2, 5
• Main side effects include:
  • Loss of appetite (67%)
  • Somnolence (79%)
  • Ataxia (58%)
  • Elevated liver enzymes (38%) 4

Alternative or Additional Therapies

If the combination of valproate, clobazam, and stiripentol is insufficient or not tolerated:

• Topiramate: Effective adjunctive therapy with evidence of efficacy 2, 5, 6
• Ketogenic diet: Alternative in pharmacoresistant cases 2, 3
• Levetiracetam: May provide substantial efficacy as adjunctive therapy 2, 3
• Bromide: Used in Germany and Japan with anecdotal evidence of efficacy 5
• Cannabidiol: Approved specifically for Dravet syndrome in 2018/2019 5
• Fenfluramine: Approved for Dravet syndrome in 2020 5

Medications to Avoid in Dravet Syndrome

Certain medications can worsen seizures in Dravet syndrome and should be avoided:

• Lamotrigine
• Carbamazepine
• High doses of intravenous phenobarbital 2, 3

Practical Management Algorithm

1. Initial treatment: Start with valproate
2. If seizures persist: Add clobazam
3. If inadequate control: Add stiripentol (most evidence-based approach)
4. If still inadequate: Consider topiramate, ketogenic diet, or other approved therapies (cannabidiol, fenfluramine)
5. For acute seizure management: Use benzodiazepines for prolonged seizures

Monitoring Recommendations

• Regular monitoring of:
  • Blood counts
  • Liver function tests
  • Serum drug concentrations
  • Growth parameters in children
  • Behavioral changes 5

The treatment of Dravet syndrome requires careful medication selection and monitoring, with stiripentol being the most evidence-based adjunctive therapy when valproate and clobazam are insufficient.