What is Dravet syndrome?

Dravet syndrome — formerly known as severe myoclonic epilepsy of infancy (SMEI) — is a genetic epilepsy, characterized by temperature-sensitive/febrile seizures, treatment-resistant epilepsy that begins in the first year of life, and differences in childhood development. Before the onset of seizures, children with Dravet syndrome reach developmental milestones on time. However, with symptom onset, children exhibit developmental delays and features of autism spectrum disorder. Most children with Dravet syndrome (approximately 90%) have a pathogenic variant (“mutation”) in the SCN1A gene, which affects the function of brain cells (neurons).

A more detailed description can be found in the references below or can be provided in the context of an ENGIN Clinic visit.

Symptoms of Dravet syndrome

Seizures, usually starting between the ages of 4 months and 12 months, are the first sign of Dravet syndrome. These first seizures often occur with a fever (called febrile seizures). They may be tonic-clonic seizures (also called “grand mal” seizures), which involves convulsive movements (shaking) of the entire body. In many children with Dravet syndrome, the first seizure is a hemiclonic seizure, with jerking movements affecting only one side of the body. The seizures often do not stop on their own and may occur in clusters.

After the first febrile seizure, additional seizures may occur without a fever. Some may be triggered by slight changes in body temperature, as from hot weather or a warm bath.

Additional types of seizures may subsequently appear. Behavioral and developmental delays may start to appear at around age 1-2 years, as well as movement and balance issues (ataxia), sleep problems, and features of autism spectrum disorder.

Diagnosis of Dravet syndrome

The appearance of prolonged tonic-clonic or hemiclonic seizures in the first year of life in a previously well child, particularly if triggered by fever, is a strong indication of Dravet syndrome.

Electroencephalogram (EEG) and magnetic resonance imaging (MRI) test results are often normal when seizures first appear, which can sometimes delay diagnosis.

When Dravet syndrome is suspected, genetic testing may be done to look for a pathogenic variant in the SCN1A gene. If found, this can confirm the diagnosis, in the larger context of clinical features consistent with Dravet syndrome. Earlier diagnosis may improve long-term outcomes for children with Dravet syndrome.

If no pathogenic SCN1A variant is found, diagnosis may be made based purely on symptoms. Such patients may be candidates for research studies investigating novel genetic causes or mechanisms of Dravet syndrome.

Dravet syndrome genetics

About 90% of children with Dravet syndrome have a pathogenic variant (“mutation”) in the gene SCN1A, which encodes the instructions to make a protein in the brain called a sodium channel. Genetic variants that affect the SCN1A sodium channel impair the flow of sodium ions into neurons in the brain and lead to overactivity of neurons. This overactivity causes seizures and epilepsy.

In most children with Dravet syndrome, the pathogenic SCN1A variant occurred spontaneously (de novo) and was not inherited from either parent. In some cases, the pathogenic SCN1A variant has been passed on from an asymptomatic parent due to parental mosaicism. Just like a mosaic piece of art, in which each tile is different, a mosaic parent has distinct cell types. Most cells of a mosaic parent do not carry the pathogenic SCN1A variant. However, a small proportion of cells do carry the pathogenic SCN1A variant in very low levels that may be difficult or impossible to detect.

In rare cases, the pathogenic SCN1A variant has been inherited from a parent who also has a history of seizures or epilepsy. A family history of epilepsy or fever-related seizures may suggest an inherited SCN1A variant in these families.

In cases where a pathogenic variant in the SCN1A gene is not found, the exact cause of the condition is unknown, but other genes are likely to be the cause.

Treatment for Dravet syndrome

The primary goal of treatment for Dravet syndrome is to reduce or eliminate seizures, improve cognition, and reduce risk of sudden unexpected death in epilepsy (SUDEP). Early and effective control of the seizures may improve the child’s long-term outlook.

• A combination of medications is typically used to control the different seizure types. Medications may include:
  • Sodium valproate or clobazam, which are considered first line treatments for Dravet syndrome based on a recent North American Consensus Panel (Wirrell et al., 2017)
  • Topiramate and Stiripentol (Diacomit®; an anti-convulsant drug approved specifically for the treatment of Dravet syndrome) are considered second-line agents.
  • Epidiolex®, a purified form of cannabidiol (CBD), which was approved by the FDA in 2018 specifically for the treatment of Dravet syndrome. CHOP and ENGIN team members were involved in the early clinical studies of Epidiolex.
• Dietary therapy, such as the ketogenic diet, can be highly effective in some cases.
• Vagus nerve stimulation may be considered when medications are not effective in controlling seizures.

Sodium channel blocking medications, such as lamotrigine, phenytoin, carbamazepine and oxcarbazepine, should be avoided, especially in younger patients, as these can worsen seizures in people with Dravet syndrome.

Family counseling and support is a key element in a successful treatment plan. Parents and caregivers must know how to treat a fever or illness in a child with the condition, how to watch for and respond to seizures, and how to administer rescue medication.

Dravet syndrome treatment will generally include physical therapy, occupational therapy and speech therapy.

Why choose CHOP for care of a child with Dravet syndrome?

The Dravet Syndrome Foundation has recognized the Epilepsy Neurogenetics Initiative (ENGIN) at Children’s Hospital of Philadelphia as a Dravet Comprehensive Care Center, recognizing the expertise of our providers in delivering comprehensive care for children with Dravet syndrome.

Children with Dravet syndrome who are cared for at CHOP will receive cutting-edge genetic testing to confirm the underlying cause of the child’s epilepsy, as well as parental testing to confirm the diagnosis and inform recurrence risk with a subsequent pregnancy. Patients will be evaluated for: genetic testing; epilepsy management; physical, occupational and speech therapy needs; dysautonomia and cardiac issues; ophthalmological issues; gastrointestinal issues; and SUDEP risk reduction.

ENGIN team members are leaders in basic, translational and clinical research investigating mechanisms of and novel therapies for Dravet syndrome.

ENGIN integrates genetic testing into the diagnosis and treatment of children with difficult-to-treat or unexplained epilepsies, genetic epilepsy syndromes and other genetic neurodevelopmental disorders. We combine cutting-edge clinical care and advanced genetic testing with innovative research to identify the underlying cause of a child’s epilepsy and develop an individualized approach to treatment and management.

Families come to our ENGIN Clinic from all over the world. Through ENGIN, your child will have access to any other medical specialists they may need, as well as a full range of epilepsy therapies provided through CHOP’s Pediatric Epilepsy Program, including medication, dietary treatment and epilepsy surgery. They will also have access to cutting edge research and clinical trials, as well as ongoing follow-up care.