Management of Dravet Syndrome
Initiate valproate at the first onset of complicated febrile seizure, add clobazam for seizure recurrence, and escalate to stiripentol as the preferred third agent when seizures remain uncontrolled. 1, 2
First-Line Therapy
- Valproate (sodium valproate/valproic acid) is the foundational first-line agent and should be started immediately upon clinical diagnosis or at the first complicated febrile seizure in suspected Dravet syndrome 1, 3, 2
- Clobazam should be added as the second agent when valproate alone proves insufficient for seizure control 3, 4, 5
- Use a "start low, go slow" dosing approach for all medications in Dravet syndrome to minimize adverse effects 6
Second-Line/Escalation Therapy
When valproate and clobazam fail to control seizures, stiripentol is the preferred add-on agent based on the strongest evidence:
- Stiripentol (FDA-approved 2018 in USA, 2007 in EU) is the only medication proven effective through two independent randomized, placebo-controlled trials specifically in Dravet syndrome 7, 1, 2
- Stiripentol demonstrated a 71% responder rate (>50% seizure reduction) versus 5% with placebo in Study 1, and 67% versus 9.1% in Study 2 7
- Critical dosing consideration: Reduce doses of both valproate and clobazam when adding stiripentol due to potent cytochrome P450 inhibition that increases plasma concentrations of both medications, which can cause excessive somnolence and gastrointestinal adverse events 1, 4, 2
- Stiripentol acts through GABAergic mechanisms via the α3 subunit of GABA-A receptors 1, 2
Alternative Second-Line Options
When stiripentol is unavailable or not tolerated:
Cannabidiol (FDA-approved 2018/2019) as adjunctive therapy for inadequate response to other regimens 6, 4, 5
Topiramate has demonstrated efficacy in Dravet syndrome and is frequently used 1, 3, 4, 5
- Caution: Concomitant valproate may cause encephalopathy and/or hyperammonemia 4
Ketogenic diet provides substantial efficacy as adjunctive therapy 1, 3, 5, 2
Fenfluramine (FDA-approved 2020) is a newer option with proven efficacy in clinical trials 4, 5
Later-Line Options for Refractory Cases
- Bromides (particularly used in Germany and Japan) for highly resistant cases 1, 3, 4, 5
- Levetiracetam may be considered 1, 3
- Vagus nerve stimulation for medically refractory patients 3
Medications to AVOID
These agents typically exacerbate seizures and should be strictly avoided:
- Carbamazepine 1, 3, 2
- Oxcarbazepine 3
- Phenytoin 3
- Lamotrigine 1, 3, 2
- High-dose intravenous phenobarbital 1, 2
Acute Seizure Management
- All patients require home rescue medication (oral/nasal/rectal benzodiazepines) for prolonged seizures 5, 2
- Establish a status epilepticus protocol executable at the local hospital 3, 5
Monitoring Requirements
- Hematologic testing (blood counts) prior to starting treatment and every 6 months due to risk of neutropenia and thrombocytopenia 7
- Liver function tests regularly, especially with valproate and cannabidiol combinations 4
- Monitor weight and appetite closely, as decreased appetite (45% incidence) and weight loss (27% incidence) are common with stiripentol 7, 4
- Cardiac monitoring with fenfluramine 4
- Serum concentrations of antiseizure medications to guide dosing adjustments 4
- Growth monitoring in children 4
Non-Pharmacologic Strategies
- Counsel families on trigger avoidance: hyperthermia, flashing lights, patterns 3
- Multidisciplinary team involvement: physical therapy, occupational therapy, speech therapy, neuropsychology, social work 3
Common Pitfalls
- Failing to reduce clobazam and valproate doses when adding stiripentol leads to excessive somnolence and other adverse effects due to drug-drug interactions 1, 4, 2
- Using sodium channel blockers (carbamazepine, lamotrigine, phenytoin, oxcarbazepine) will worsen seizures 1, 3, 2
- Abrupt withdrawal of medications increases risk of status epilepticus 7