What is the treatment for Dravet syndrome?

Treatment of Dravet Syndrome

Initiate treatment with valproate as first-line therapy, followed by addition of clobazam, and then escalate with stiripentol, cannabidiol, or fenfluramine as adjunctive therapies when seizures remain uncontrolled. 1, 2, 3

First-Line Pharmacotherapy

Valproate (VPA) should be started at the first onset of complicated febrile seizures in Dravet syndrome patients. 2 Use a "start low, go slow" dosing approach to minimize adverse effects. 4

• When valproate alone proves insufficient (which is typical), add clobazam (CLB) as the second agent. 2, 3
• This combination of VPA + CLB forms the foundation upon which additional therapies are built. 3

Second-Line/Adjunctive Therapies

When first-line therapy fails to control seizures, escalate with one of three FDA-approved adjunctive medications:

Stiripentol (STP)

• FDA-approved for patients ≥6 months of age weighing ≥7 kg, used in combination with clobazam. 1
• Demonstrated efficacy in two independent double-blind controlled trials specifically in Dravet syndrome. 2
• Critical drug interaction management required: Reduce doses of both VPA and CLB when adding stiripentol due to cytochrome P450 inhibition. 2, 3
  • STP + CLB interaction increases plasma concentrations of CLB and norclobazam, potentially causing increased somnolence. 3
  • STP + VPA interaction may increase gastrointestinal adverse events. 3
• Monitor for decreased appetite and weight loss, the most common side effects. 1, 2
• Over 500 Dravet patients have been successfully treated with this combination. 2

Cannabidiol (CBD)

• FDA-approved in 2018/2019 as adjunctive therapy for inadequate response to other regimens. 4, 3
• In the EU, approved specifically in combination with clobazam. 3
• Bidirectional interaction with CLB: Increases plasma concentrations of 7-OH-CBD and norclobazam, potentially causing increased somnolence and sedation. 3
• Monitor liver transaminases closely, particularly when used with concomitant VPA, as CBD is associated with hepatic enzyme elevations. 3

Fenfluramine (FFA)

• FDA-approved in 2020 as adjunctive therapy. 3
• Requires cardiac monitoring due to historical association with cardiac valve disease at high doses (though no cases documented at low doses used in epilepsy). 3
• Dose reduction of FFA required when combined with stiripentol. 3

Additional Treatment Options

Topiramate (TPM)

• Frequently used with evidence of efficacy in Dravet syndrome. 3, 5
• Caution: Concomitant VPA + TPM has been associated with encephalopathy and/or hyperammonemia. 3

Other Agents

• Levetiracetam shows substantial efficacy as adjunctive therapy. 2, 5
• Bromide provides efficacy and is frequently used in Germany and Japan. 2, 3
• Ketogenic diet demonstrates substantial efficacy as an adjunctive procedure. 2, 5

Medications to AVOID

Sodium channel-blocking anticonvulsants are contraindicated and can aggravate seizures: 2, 3, 5

• Lamotrigine
• Carbamazepine
• High-dose intravenous phenobarbital

Monitoring Parameters

Standard Laboratory Monitoring

• Complete blood counts (monitoring for neutropenia and thrombocytopenia with stiripentol). 1
• Liver function tests (especially with CBD + VPA combination). 3
• Serum concentrations of antiseizure medications. 3
• Growth parameters and weight monitoring in children (particularly with stiripentol). 1, 3

Cardiac Monitoring

• Required with fenfluramine therapy. 3

Behavioral Monitoring

• Watch for acceleration of behavioral problems. 3
• Monitor for suicidal thoughts/behavior with all antiepileptic drugs. 1

Treatment Algorithm

1. Start VPA immediately upon diagnosis or first complicated febrile seizure. 2
2. Add CLB when VPA monotherapy fails (which is expected). 2, 3
3. Escalate with one of the three approved adjunctive therapies (STP, CBD, or FFA) based on:
   • Regional availability 3
   • Patient age (stiripentol approved from 6 months) 1
   • Anticipated drug interactions 3
   • Caregiver preferences 3
4. Consider topiramate, levetiracetam, bromide, or ketogenic diet as alternatives in pharmacoresistant cases. 2, 3

Common Pitfalls

• Failing to reduce VPA and CLB doses when adding stiripentol leads to excessive side effects from drug accumulation. 2, 3
• Missing hepatotoxicity with CBD + VPA combination requires vigilant liver function monitoring. 3
• Using sodium channel blockers (lamotrigine, carbamazepine) can paradoxically worsen seizures. 2, 5
• Inadequate cardiac monitoring with fenfluramine despite low documented risk at epilepsy doses. 3