What is the treatment plan for a pediatric patient with Dravet syndrome?

Treatment Plan for Pediatric Dravet Syndrome

First-Line Pharmacotherapy

Initiate treatment with sodium valproate plus clobazam as the foundational regimen, using a "start low, go slow" dosing approach to minimize adverse effects while achieving seizure control. 1, 2, 3

• Sodium valproate remains the cornerstone first-line agent for Dravet syndrome, demonstrating consistent efficacy across multiple studies 2, 3
• Clobazam should be added as the second first-line medication, as it provides synergistic benefit and is required for use with stiripentol 4, 2, 3
• Dose escalation must proceed gradually given the heightened sensitivity of Dravet patients to medication side effects 1

Second-Line Adjunctive Therapies

Add stiripentol as the first second-line agent if seizures remain inadequately controlled on valproate plus clobazam, as it has FDA approval and demonstrated >70% responder rates in controlled trials. 4, 3

• Stiripentol is FDA-approved for patients ≥6 months of age weighing ≥7 kg when used with clobazam 4
• In pivotal trials, 71% (Study 1) and 67% (Study 2) of patients achieved >50% seizure reduction, with 43% and 25% respectively becoming seizure-free during the 2-month treatment period 4
• Stiripentol must be administered during meals, either as whole capsules swallowed with water or as oral suspension mixed in water 4
• Monitor for somnolence (may require clobazam dose reduction), decreased appetite/weight loss, and obtain hematologic testing at baseline and every 6 months for neutropenia/thrombocytopenia 4

Consider cannabidiol as an alternative second-line adjunctive therapy, particularly for patients with inadequate response to stiripentol or those unable to tolerate it. 1, 5, 3

• Cannabidiol received FDA approval in 2018/2019 for Dravet syndrome and has documented efficacy in controlled trials 1, 5
• This represents a viable option when the stiripentol-clobazam-valproate combination proves insufficient 3

Additional Treatment Options

If seizures persist despite the above regimen, add topiramate or initiate the ketogenic diet as third-line interventions. 2, 3

• Topiramate has demonstrated benefit in Dravet syndrome without the seizure exacerbation seen with other sodium channel blockers 2, 3
• The ketogenic diet should be implemented with nutritionist support and has shown efficacy in medication-refractory cases 2, 3
• Levetiracetam may be considered as an additional option, though evidence is less robust than for the above agents 2
• Bromides can be utilized in highly resistant cases as a later-line option 2, 3

Critical Medications to Avoid

Never prescribe sodium channel blocking agents including carbamazepine, oxcarbazepine, phenytoin, or lamotrigine, as these consistently exacerbate seizures in Dravet syndrome. 2, 3

• These medications worsen seizure control due to the underlying SCN1A pathophysiology and represent a critical prescribing pitfall 2

Acute Seizure Management

Prescribe home rescue medication using intranasal, buccal, or intramuscular benzodiazepine formulations rather than rectal administration to manage prolonged seizures and prevent status epilepticus. 5, 3

• Modern rescue formulations (intranasal midazolam, buccal midazolam, intramuscular diazepam) provide more dignified and effective acute treatment 5
• Establish a clear status epilepticus protocol that can be implemented at the patient's local hospital 2
• Preventing status epilepticus and generalized tonic-clonic seizures may reduce sudden unexpected death in epilepsy (SUDEP) risk 5

Non-Pharmacologic Seizure Prevention

Counsel families to avoid known seizure triggers including hyperthermia, fever, hot baths, flashing lights, and visual patterns. 2

• Fever and hyperthermia are particularly potent triggers in Dravet syndrome and require aggressive management 2
• Families should maintain antipyretics readily available and use them promptly at fever onset 2

Multidisciplinary Care Requirements

Refer immediately to a multidisciplinary team including neurology, developmental specialists, physical therapy, occupational therapy, speech therapy, neuropsychology, and social work. 2, 6

• Dravet syndrome involves multiple comorbidities beyond seizures, including intellectual disability, behavioral problems, sleep disturbances, and crouch gait 2
• Physical, occupational, and speech therapy address motor impairments and developmental delays 2, 6
• Neuropsychology evaluates and manages cognitive and behavioral complications 2

Genetic Testing and Diagnosis

Obtain SCN1A genetic testing immediately upon clinical suspicion to confirm diagnosis and enable early targeted treatment. 7, 6

• Most Dravet syndrome cases result from pathogenic SCN1A mutations affecting voltage-gated sodium channels 7, 6
• Early genetic confirmation allows earlier initiation of appropriate therapy, potentially improving long-term cognitive, motor, and behavioral outcomes 5, 7
• Modern genetic testing enables diagnosis closer to disease onset, facilitating timely intervention 5, 7

Monitoring and Drug Interactions

Monitor closely for drug-drug interactions when using polypharmacy, particularly with stiripentol which affects hepatic metabolism. 5

• Most Dravet patients require multiple medications, necessitating awareness of pharmacokinetic interactions 5
• Stiripentol inhibits hepatic enzymes and can increase levels of clobazam and other medications 4, 5
• Therapeutic drug monitoring should be utilized when available to optimize dosing 5

Special Contraindications

Do not use stiripentol in patients with moderate-to-severe renal or hepatic impairment, as the drug and its metabolites are eliminated through these organs. 4

• Stiripentol metabolites are eliminated primarily renally, contraindicating use in moderate-to-severe renal impairment 4
• The drug undergoes hepatic metabolism, contraindicating use in moderate-to-severe hepatic impairment 4

Pregnancy and Vaccination Counseling

Counsel families that while vaccination may trigger seizures in the context of fever, the benefits of immunization outweigh risks, and fever should be managed aggressively during the vaccination period. 2, 7

• Vaccinations and infections can trigger seizures in Dravet syndrome, but this represents a controversial area requiring balanced counseling 5, 7
• For female patients of childbearing age, discuss pregnancy risks and encourage enrollment in the North American Antiepileptic Drug Pregnancy Registry if pregnancy occurs 4