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Dravet Syndrome (DS)

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Therapies

Dravet syndrome (DS) is a rare and severe epilepsy disorder with an onset in the first year of life. DS is characterized by recurrent seizures that are often prolonged and hemiclonic or generalized tonic-clonic. Development is usually normal when the disease begins, but with time, patients develop cognitive impairment.1

Currently, there is no cure for DS. Pharmacological treatment is the first line of therapy; however, this epilepsy is highly resistant to drug treatment.2 Several antiseizure medications (ASMs) are available as therapies for DS, including Depakote® (valproate), Onfi® (clobazam), and Diacomit® (stiripentol).1 

Treatment often begins with a combination of multiple ASMs, such as Depakote and Onfi, however, even with the use of these medications, seizure control is challenging.2,3 Adjunctive therapies have therefore been developed, mainly with Depakote and Onfi, such as Diacomit, Epidiolex® (cannabidiol), and Fintepla® (fenfluramine).2

Depakote

Depakote is one of the most commonly used ASMs for DS.3 It is a broad-spectrum ASM effective in treating focal and generalized seizure types, including tonic-clonic, myoclonic, tonic, and absence seizures. Depakote works by modulating the level of gamma-aminobutyric acid (GABA), which helps to reduce the frequency and severity of seizures.2

Depakote is available in different formulations, including tablets, granules, oral solutions (liquid and syrup), and solutions for injection or infusion. Although it has an acceptable safety profile, Depakote can have side effects, such as gastrointestinal issues, lethargy, and somnolence. In addition, long-term Depakote use can increase the risk of liver damage.2

Read more about DS treatment

Onfi

Onfi is another ASM commonly used for treating DS.3 In the United States, Onfi has been approved as an adjunctive treatment of seizures in Lennox–Gastaut syndrome (LGS) and is often used off label in DS.4 This medication is orally administered as tablets and oral suspensions in the European Union and United States. An oral soluble film was also approved in the United States in 2018.2

Onfi works by different mechanisms, including enhancing the activity of GABA in the brain. It is often used in combination with other ASMs, such as Depakote. In this combination, an increase in plasma valproate levels can occur, requiring careful monitoring of these patients.2 

Side effects of Onfi include somnolence, pyrexia, upper respiratory infections, lethargy,

drooling, and constipation.2

Read more about DS complications

Diacomit

Diacomit was approved by the US Food and Drug Administration (FDA) in 2018 as the first therapy indicated for the treatment of seizures in patients with DS in combination with Onfi (and with Depakote and Onfi in the European Union).2,3 Diacomit works by enhancing the activity of GABA in the brain and inhibiting the breakdown of other ASMs, such as Depakote and Onfi.5,6 

Diacomit is available as hard capsules or a powder for oral suspension. Side effects of this medication include reduced appetite and changes in blood counts.2

Epidiolex

Epidiolex is a nonpsychoactive compound found in the cannabis plant that has been shown to have antiepileptic properties. It was approved by the FDA in 2018 as an adjunctive therapy for seizures in patients with DS aged 1 year and over.2,3

Epidiolex is usually administered orally and has been shown to reduce the frequency and severity of seizures in some patients with DS. However, adverse effects may be observed, including decreased appetite, fatigue, and diarrhea.2

Read more about DS experimental therapies

Fintepla

Fintepla is an add-on therapy indicated for the treatment of seizures in DS. It was approved by the FDA in 2020.2,3 It is administered orally, and its mechanism of action relies on targeting the serotonergic system and modulating the sigma-1 receptor.2

Fintepla is well tolerated, and adverse events include diarrhea, fatigue, lethargy, pyrexia, and upper respiratory tract infections.2

Topamax

Topamax® (topiramate) is a broad-range ASM that is indicated as an adjunctive therapy in patients aged 2 years and above who present with partial-onset seizures with or without secondary generalization or primary generalized tonic-clonic seizures.2

The mechanism of action of Topamax includes the blockage of voltage-dependent sodium channels and enhancement of the GABAergic pathway. This medication is available as capsules, film-coated tablets, an oral solution, and sprinkle capsules.2

The safety profile of Topamax is acceptable, and the most common adverse events following its administration include somnolence, fatigue, nausea, dizziness, ataxia, anorexia, paresthesia, weight loss, and cognitive/neuropsychiatric problems such as nervousness, psychomotor slowing, memory difficulties, speech disorders/related speech problems, and personality disorders.2

Read more about DS prognosis

References

1. Wirrell EC, Nabbout R. Recent advances in the drug treatment of Dravet syndrome. CNS Drugs. 2019;33(9):867-881. doi:10.1007/s40263-019-00666-8

2. Strzelczyk A, Schubert-Bast S. A practical guide to the treatment of Dravet syndrome with anti-seizure medication. CNS Drugs. 2022;36(3):217-237. doi:10.1007/s40263-022-00898-1

3. Dravet syndrome. National Organization for Rare Disorders (NORD). Updated July 24, 2020. Accessed March 27, 2023.

4. Onfi® (clobazam). Prescribing information. Lundbeck; 2016. Accessed March 27, 2023.

5. Giraud C, Treluyer JM, Rey E, et al. In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism. Drug Metab Dispos. 2006;34(4):608-611. doi:10.1124/dmd.105.007237

6. Wirrell EC, Laux L, Franz DN, et al. Stiripentol in Dravet syndrome: results of a retrospective U.S. study. Epilepsia. 2013;54(9):1595-1604. doi:10.1111/epi.12303

Reviewed by Harshi Dhingra, MD, on 3/29/2023.

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