What is the management approach for Dravet syndrome?

Management Approach for Dravet Syndrome

Stiripentol in combination with valproate and clobazam is the most effective evidence-based treatment for Dravet syndrome, with proven efficacy in randomized controlled trials showing 71% responder rates compared to 5% with placebo. 1, 2

First-Line Treatment

• Valproate should be initiated at the first onset of complicated febrile seizures in Dravet syndrome patients as a first-line agent to prevent seizure recurrence 2, 3
• Oral/nasal/rectal benzodiazepines should be used for any long-lasting seizures as rescue medication 2
• When seizures persist despite valproate monotherapy, clobazam should be added as a second agent 3

Second-Line Treatment (Add-on Therapy)

• Stiripentol (Diacomit) should be added when seizures remain inadequately controlled on valproate and clobazam 1, 2
  • Approved as an orphan drug for Dravet syndrome in Europe (2007) and the US (2018) 2, 4
  • Dosage: 50mg/kg/day up to 2500mg/day 5
  • Mechanism: Acts as a GABAergic agent, mainly via the α3 subunit of GABA(A) receptors 2, 3
  • Clinical evidence: Two independent randomized placebo-controlled trials showed significant efficacy 1, 2
    • 71% responder rate (>50% seizure reduction) with stiripentol vs. 5% with placebo 1
    • 43% of patients reported no generalized clonic or tonic-clonic seizures during the study period 1

Important Medication Considerations

• "Start low, go slow" approach is recommended for medication dosing in Dravet syndrome 6
• When adding stiripentol, doses of valproate and clobazam should be reduced to minimize side effects due to pharmacokinetic interactions 2, 4
• Common side effects of stiripentol include:
  • Somnolence (67%) 1
  • Decreased appetite (45%) 1
  • Weight decrease (27%) 1
  • Ataxia (27%) 1
  • Hypotonia (24%) 1

Alternative and Adjunctive Therapies

• For patients with inadequate response to the above regimen, consider:
  • Topiramate (substantial efficacy as adjunctive therapy) 2, 4, 3
  • Levetiracetam (may provide additional seizure control) 2, 3
  • Cannabidiol (FDA-approved for Dravet syndrome in 2018/2019) 6, 4
  • Fenfluramine (FDA-approved for Dravet syndrome in 2020) 4, 7
  • Ketogenic diet (non-pharmacological option with proven efficacy) 2, 4, 3
  • Bromide (used in Germany and Japan with anecdotal evidence of efficacy) 4, 3

Medications to Avoid

• Lamotrigine, carbamazepine, and high doses of intravenous phenobarbital should be avoided as they may worsen seizures in Dravet syndrome 2, 3

Long-term Monitoring

• Regular laboratory monitoring is essential:
  • Complete blood counts (neutropenia and thrombocytopenia risk with stiripentol) 1
  • Liver function tests 4
  • Serum drug concentrations 4
  • Growth parameters (weight and height) 4
• Monitor for behavioral changes and cognitive function 4, 7
• Early detection and prompt treatment of seizures is crucial to potentially improve long-term cognitive outcomes 2, 7

Acute Seizure Management

• New rescue medication formulations via intranasal, buccal, and intramuscular routes are preferred over rectal administration 7
• Preventing status epilepticus and generalized tonic-clonic seizures is critical to potentially lower the risk of sudden unexpected death in epilepsy 7

Prognosis and Outcomes

• Early diagnosis and treatment with appropriate medications may improve long-term outcomes, including less severe cognitive, motor, and behavioral impairments 7
• Despite optimal treatment, most patients will require polypharmacy due to the pharmacoresistant nature of Dravet syndrome 2, 4