Dravet Syndrome (DS)

The guidelines for the diagnosis and treatment of Dravet Syndrome (DS) have been developed by the Dravet Syndrome Foundation¹ based on information from the 2017 North American Consensus Panel study,² the 2021 International Consensus Panel Study,³ and the 2022 International League Against Epilepsy (ILAE) Classification and Definition for Dravet Syndrome.⁴

Diagnostic Guidelines for the Initial Onset of DS

Age at Seizure Onset

Most individuals experience the first seizure between the age of 2 months to 15 months. In rare cases, seizures may appear earlier than 2 months or as late as the age of 20 months.^1,3 

Types of Seizures

Initial Seizures

The patient’s initial seizures are typically focal clonic (usually hemiclonic, affecting one side of the body), generalized clonic, and/or focal to bilateral tonic-clonic. These seizures are recurrent, often prolonged, and may or may not be accompanied by fever.^1,3

Additional Seizures

As the child ages, around 12 months to 60 months, patients experience additional types of seizures, of which focal impaired awareness and myoclonic seizures are more frequent. Other less-frequent seizure types include atonic seizures (in less than half of the cases), atypical absence seizures and nonconvulsive status epilepticus. Tonic and tonic-clonic seizures may occur during sleep in concurrent clusters.^1,3

Epileptic spasms and typical absence seizures are rarely experienced by patients with DS.^1,3

Read more about DS diagnosis

Seizure Triggers

The most common trigger of seizures in patients with DS is abnormally elevated body temperature (hyperthermia), which may be caused by illness or vaccination. Seizures may also be triggered by bathing, eating, overexertion, visual patterns, and flashing lights.^1,3

Diagnostic Testing

At the onset of DS, development is usually normal with normal findings observed in neurological examination, magnetic resonance imaging (MRI) and electroencephalographic (EEG) imaging.^1,3

As patients age, development slows, with the delay in developmental milestones becoming evident between 1 year and 5 years after the first seizure.^1,3

Diagnostic Guidelines for Late Presentation of DS in Adolescents and Adults

Late Seizures

Many types of seizures persist in older children and adults with DS. These include focal convulsive seizures, generalized convulsive seizures, focal seizures, myoclonic seizures, atypical absence seizures, and tonic seizures. However, some types of seizures, such as recurrent status epilepticus and obtundation, occur less frequently as patients reach adolescence or adulthood. In addition, hyperthermia may not trigger seizures in adolescents and young adults, but seizures may become exacerbated by sodium channel blockers.^1,3

Diagnostic Testing

As patients reach the age of 3 to 4 years, the neurological findings become typically abnormal, with clinical features such as hypotonia, incoordination, crouched gait, and mobility impairment. Intellectual disability is typically evident by the age of 18 months to 5 years.^1,3

By the age of 5, most patients exhibit slow background and interictal epileptiform discharges on EEG testing. MRI findings are generally normal, but with disease progression, mild generalized atrophy may evolve. Few cases may show hippocampal sclerosis in MRI imaging.^1,3

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Genetic Testing

If a diagnosis of DS is suspected, genetic testing should be performed (irrespective of the patient’s age). Most patients with a clinical diagnosis of DS carry variants of the SCN1A gene, which occur spontaneously in most cases. However, the absence of a known genetic variant should not preclude a diagnosis of DS.^3-5 

Guidelines recommend that genetic testing should be performed for young children with normal development who experience unexplained initial seizures between the ages of 2 months and 15 months, especially if they are prolonged seizures, which may be hemiclonic, tonic-clonic, or status epilepticus. These seizures may or may not be in the context of fever or vaccination.¹

Genetic testing is particularly important in adults, who may have difficulty providing a detailed history of presentation in infancy. The recommended genetic tests include simple SCN1A sequencing, multiplex ligation-dependent probe amplification (to detect intragenic deletions or duplications), whole-exome sequencing, whole-genome sequencing, and an epilepsy gene panel analysis⁶ (based on next-generation sequencing).^3-5

SCN1A mutations are also found in other epilepsy types, such as generalized epilepsy with febrile seizures plus (GEFS+) and early infantile SCN1A encephalopathy with profound impairment. Thus, the presence of SCN1A variants should be interpreted with caution.^3-5

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The Importance of Early Diagnosis

On the basis of clinical experience, experts agree that an early diagnosis may improve the long-term outcome, increasing seizure control and minimizing cognitive degeneration. An accurate and timely diagnosis can help avoid inappropriate therapies, such as sodium channel blockers, which have been shown to worsen outcomes in patients with DS.³

Treatment Guidelines for DS

Patients with DS should be managed by a multidisciplinary team, including pediatric or adult neurologists, neuropsychologists, physiotherapists, nurses, and patient advocates.^1,3  

Therapy Recommendations

For the management of seizures in DS, a therapeutic algorithm for maintenance therapies was developed on the basis of consensus from physicians and caregivers.³ Depakote^® (valproic acid) is the drug of choice as first-line treatment in DS; it can decrease the number and severity (duration) of seizures. Onfi^® (clobazam), Fintepla^® (fenfluramine), and Diacomit^® (stiripentol) can be considered as first- or second-line antiseizure medications. Pharmaceutical-grade Epidiolex^® (cannabidiol) can be used as a first- or second-line treatment. The consensus of caregivers was that Topamax^® (topiramate) can be used as a first-, second-, or third-line treatment.^1,3

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Contraindicated Therapies

In patients with a confirmed diagnosis of DS, sodium channel blockers such as Tegretol^® (carbamazepine), Trileptal^® (oxcarbazepine), Lamictal^® (lamotrigine), Banzel® (rufinamide), Cerebyx® (fosphenytoin), and Dilantin^® (phenytoin) must be avoided; these have been shown to worsen seizure rates and cognitive outcomes. Other drugs that must be avoided include Sabril^® (vigabatrin) and Gabitril^® (tiagabine), as they may increase the frequency of myoclonic seizures.^1,3,7

Dietary Therapy for DS

When treatment with 3 or 4 antiseizure medications has failed, dietary therapy should be considered. While the classic ketogenic diet is recommended for children 6 years old or younger, the modified Atkins diet is the recommended option for adolescents and adults.³

The use of vagus nerve stimulation (VNS) for drug-resistant seizures in patients with DS requires further investigation. This option may be considered only after other therapies have failed, including Depakote, Onfi, Diacomit, Fintepla, Epidiolex, Topamax, and the ketogenic diet.³

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Treatment of Specific Seizure Types 

According to physicians’ consensus, Depakote, Onfi, Diacomit, and Fintepla were the most efficacious for the treatment of focal or generalized convulsive seizures. Further, they agreed that both Depakote and Zarontin^® (ethosuximide) were highly effective for the treatment of absence seizures and Depakote was the most effective for the treatment of myoclonic seizures.³

Treatment of Seizure Emergencies

Because patients with DS experience prolonged seizures that may require emergency interventions, a personalized emergency protocol should be in place, including a plan for rescue therapy at home. Guidelines recommend an age-appropriate dose of a benzodiazepine that can be administered via rectal, buccal, or nasal route, such as Diastat^® (diazepam) rectal gel, Valtoco^® (diazepam) nasal spray, or Nayzilam^® (midazolam) nasal spray and a ‘seizure action plan’ (developed with the help of a neurologist) for the management of convulsive seizures lasting 5 minutes or more.⁸

If a convulsive seizure persists despite benzodiazepine treatment, then intravenous Depakote or Keppra^® (levetiracetam) should be considered as the next option.^1,3

If a seizure persists (status epilepticus) after the above-mentioned interventions, intravenous Dilantin or Cerebyx can be considered.^1,3

Read more about DS treatment

References

1. Diagnosis and treatment. Dravet Syndrome Foundation. Accessed March 23, 2023. 
2. Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American Consensus Panel. Pediatr Neurol. 2017;68:18-34.e3. doi:10.1016/j.pediatrneurol.2017.01.025
3. Wirrell EC, Hood V, Knupp KG, et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia. 2022;63(7):1761-1777. doi:10.1111/epi.17274
4. Zuberi SM, Wirrell E, Yozawitz E, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63(6):1349-1397. doi:10.1111/epi.17239
5. Cardenal-Muñoz E, Auvin S, Villanueva V, et al. Guidance on Dravet syndrome from infant to adult care: road map for treatment planning in Europe. Epilepsia Open. 2022;7(1):11-26. doi:10.1002/epi4.12569
6. Lee J, Lee C, Park WY, Lee J. Genetic diagnosis of Dravet syndrome using next generation sequencing-based epilepsy gene panel testing. Ann Clin Lab Sci. 2020;50(5):625-637.
7. Joshi C, Wirrell E. Dravet syndrome. Epilepsy Foundation. August 24, 2020. Accessed March 23, 2023.
8. What is a SAP? Seizure Action Plans. Accessed March 23, 2023.

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

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Erum Naqvi, PhD

Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.