Dravet Syndrome (DS)

Dravet syndrome (DS) was originally known as severe myoclonic epilepsy of infancy (SMEI).¹ The condition was first described in 1978 by Dr. Charlotte Dravet,¹ a French epileptologist who worked from 1965 to 2000 at the Centre St. Paul at the University of Marseille alongside notable colleagues, including Henri Jean Pascal Gastaut.² 

First Description of Dravet Syndrome

Dr. Dravet first described the syndrome in a paper, “Les épilepsies graves de l’enfant,” that was published in a small French medical journal. Dravet and colleagues later published a case series detailing the clinical features of 42 individuals with the syndrome at the 13th Epilepsy International Symposium in Kyoto, Japan.¹

Classification of DS

In 1983, members of the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE), including Dr. Dravet, organized an international workshop in Marseille, France, specifically to classify the different types of epilepsy that occur in infancy, childhood, and adolescence. Their determinations were published in French in 1984 and in English in 1985.¹

In 1989, SMEI and borderline cases of SMEI were eponymously renamed Dravet syndrome by the ILAE to reflect the lifelong nature of the syndrome.^3,4 In comparison with SMEI, borderline cases of SMEI are characterized by less-frequent seizures and atypical clinical features.³

Read more about DS clinical features

Shaping of DS Criteria

At the 1983 workshop, members also worked to define criteria for SMEI, which soon became known as DS. A 2011 review by Dr. Dravet confirmed the validity of the criteria with minor revisions. According to Dr. Dravet, the electro-clinical criteria required for a diagnosis of typical DS included¹:

• Family history of febrile convulsions or epilepsy, which is variably associated with DS
• No previous personal history of disease
• Initial seizures occurring within the first year of life, often generalized or unilateral clonic seizures but possibly focal or myoclonic
• Initial seizures that are not always febrile and clonic seizures that usually progress to status epilepticus
• Secondary onset of myoclonic seizures, partial seizures, atypical absences, and obtundation status 
• Refractoriness to all forms of treatment
• Variable degrees of cognitive and behavioral impairment
• Delayed developmental growth manifesting by age 2
• Frequently observed neurological symptoms, including ataxia (60%), pyramidal signs (20%), and interictal myoclonus (36%-85%)
• Generalized spike-wave and polyspike-wave findings on electroencephalography (EEG)
• Normal magnetic resonance imaging (MRI) findings at seizure onset
• Early photosensitivity with possible pattern-sensitivity associations and focal abnormalities
• Progressive cognitive impairment and behavioral challenges that vary from slight to severe, exhibiting by age 5

Read more about DS guidelines

Discovery of the Genetic Basis of DS

As studies on the influence of genetics proliferated, researchers began to search for genetic mutations associated with DS. In 2001, Lieve Claes and his colleagues in Belgium discovered de novo mutations in the SCN1A gene, which encodes a sodium channel protein, in 7 children with DS.^1,5

Following this seminal publication, other researchers confirmed the findings, determining that approximately 80% of patients with DS carry SCN1A mutations affecting biosynthesis of the type 1 voltage-gated sodium channel alpha subunit protein (NA_V1.1).⁶

More recently, researchers have discovered mutations in the PCDH19 gene in a small group of female patients with borderline forms of DS.^1,7

Read more about DS genetics

Evolution of Treatment for Dravet Syndrome

As the etiology of DS became clearer, researchers began to develop and test targeted therapies specifically intended for DS.⁴ 

In 2018, the US Food and Drug Administration (FDA) approved Diacomit® (stiripentol) to treat individuals aged 2 and older with DS.^4,8 Diacomit is often used in combination with Depakote® (valproate) and/or Onfi® (clobazam) to treat seizures in DS.⁸ 

Also in 2018, the FDA approved Epidiolex® (cannabidiol) to treat individuals aged 1 or older with DS.^4,9 

In 2020, the FDA approved Fintepla® (fenfluramine) to treat individuals aged 2 or older with DS.^4,10

Read more about DS therapies

References

1. Dravet C. Dravet syndrome history. Dev Med Child Neurol. 2011;53(s2):1-6. doi:10.1111/j.1469-8749.2011.03964.x
2. Charlotte Dravet. Whonamedit? Accessed March 23, 2023.
3. Millichap JJ, Koh S, Laux LC, Nordli DR. Child neurology: Dravet syndrome: when to suspect the diagnosis. Neurology. 2009;73(13):e59-e62. doi:10.1212/wnl.0b013e3181b9c880
4. History of Dravet syndrome. Dravet Syndrome Foundation. Accessed March 23, 2023.
5. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68(6):1327-1332. doi:10.1086/320609
6. Bender AC, Morse RP, Scott RC, Holmes GL, Lenck-Santini PP. SCN1A mutations in Dravet syndrome: impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav. 2012;23(3):177-186. doi:10.1016/j.yebeh.2011.11.022
7. Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet. 2009;5(2):e1000381. doi:10.1371/journal.pgen.1000381
8. Stiripentol. Epilepsy Foundation. Accessed March 23, 2023.
9. Epidiolex. Jazz Pharmaceuticals. Accessed March 23, 2023.
10. Fenfluramine. Epilepsy Foundation. Accessed March 23, 2023.

Reviewed by Hasan Avcu, MD, on 3/27/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.