Dravet Syndrome (DS)

Dravet syndrome (DS) is a rare type of intractable epilepsy that first manifests in infancy. Progression and increasing morbidity have a significant effect on individuals throughout life.¹

In 1978, Charlotte Dravet first referred to DS as severe myoclonic epilepsy of infancy (SMEI); the disease was renamed Dravet syndrome in 1989. In 2001, the genetic basis of DS was found to be a mutation in the SCN1A gene, which codes for the alpha 1 subunit of voltage-gated sodium channel protein and is located on chromosome 2q24.² DS affects approximately 1 in 15,700 Americans, or 0.0064% of the population.³

Etiology of DS

Mutations in SCN1A are noted in up to 85% of children with DS. Most DS mutations lead to loss-of-function and haploinsufficiency of SCN1A.⁴ Additional genes that have been linked to a DS phenotype are PCDH19, GABRA1, STXBP1, CHD2, SCN1B, SCN2A, and rarely KCNA2, HCN1, and GABRG2.²  

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Clinical Presentation of DS

DS typically manifests during the first year of life in an apparently healthy infant as a generalized tonic-clonic or hemiclonic seizure with a prolonged duration of more than 5 minutes. Status epilepticus, in which a seizure lasts longer than 5 minutes and occasionally longer than 30 minutes, occurs frequently, particularly in the early years, and requires urgent medical attention. Before the age of 5 years, additional types of seizures, such as myoclonic, atypical absence, and complex partial seizures, occur.³

Developmental delay is noticed as the child ages. Most children show signs of hypotonia by the time they are 1 year old. Ataxia is noted when the child begins to walk. Dysautonomia, characterized by variation in heat or sweating, and pyramidal signs have a different frequency and variation.²

Autism, attention-deficit/hyperactivity disorder (ADHD), aggression, irritability, relationship issues, and opposition are the most prevalent behavioral disturbances in DS. Behavioral changes are also related to cognitive and motor disability. Social interactions and adaptive behavior are adversely affected by behavioral problems and cognitive deficits.² 

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Diagnosis of DS

Over 80% of individuals with DS have an SCN1A mutation, but the presence or absence of a mutation alone does not confirm or rule out a diagnosis of DS. SCN1A mutations can cause a variety of conditions, including migraines, childhood epilepsy, and more serious, lifelong epilepsy syndromes. DS is at the severe end of the spectrum of mutant SCN1A-related disorders. Rarely, DS can be caused by mutations in genes other than SCN1A.¹

According to the 2017 consensus of North American neurologists with experience in DS, the presentation of DS is distinctive and characterized by the onset of seizures (as previously described) between the ages of 1 month and 18 months, although usually by 12 months. Hyperthermia due to illness, exertion, warm baths, or vaccination is a trigger for seizures in most patients.³

At disease onset, the child’s development is normal, as are the findings on neurological examination. Electroencephalographic (EEG) findings are also nonspecific at disease onset. The results of imaging studies, such as magnetic resonance imaging (MRI), also appear normal.³ 

In older children and adults, seizures are persistent but may or may not be prolonged. With time, status epilepticus becomes less frequent and may not be noticeable by early adulthood. As the patient gets older, hyperthermia may no longer be a seizure trigger. By 18 months to 60 months of age, intellectual impairment is apparent. Crouched gait, hypotonia, lack of balance, and poor dexterity are noted. The EEG findings can show generalized or multifocal interictal discharges along with diffuse background slowing. MRI results may be normal, as before, or reveal hippocampal sclerosis and/or mild generalized atrophy.³ 

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Treatment of DS

An early diagnosis is essential for guiding appropriate treatment and reducing progressive dysfunction. In order to manage the various complications of DS, a multidisciplinary team of caretakers is required.⁵

Common antiseizure medications (ASMs) used to treat DS include Epidiolex® (cannabidiol), Onfi® (clobazam), Diacomit® (stiripentol), Topamax® (topiramate), and Depakote® (valproate).⁵ The seizures in DS are difficult to control but can be reduced by administration of anticonvulsant medication. Some ASMs, such as Trileptal® (oxcarbazepine), Tegretol® (carbamazepine), Dilantin® (phenytoin), and Lamictal® (lamotrigine), should not be used regularly because they can worsen seizures. A ketogenic diet, which is high in fats and low in carbohydrates, is also beneficial for patients with DS.⁶ 

For patients who do not respond to ASMs and/or a ketogenic diet, surgical therapies such as deep brain stimulation and vagus nerve stimulation may also be used.² 

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Prognosis of DS

Patients with DS experience a higher mortality rate than the general population of individuals with epilepsy. By adulthood, estimated mortality rates vary from 15% to 20%. The leading cause of death is sudden unexpected death in epilepsy (SUDEP), which typically occurs during sleep. Status epilepticus and its complications are the second most frequent cause of death.³ 

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References

1. What is Dravet syndrome? Dravet Syndrome Foundation. Accessed March 26, 2023.
2. Anwar A, Saleem S, Patel UK, Arumaithurai K, Malik P. Dravet syndrome: an overview. Cureus. 2019;11(6):e5006. doi:10.7759/cureus.5006
3. Dravet syndrome. NORD – National Organization for Rare Disorders. Updated July 24, 2020.  Accessed March 26, 2023.
4. Wu YW, Sullivan J, McDaniel SS, et al. Incidence of Dravet syndrome in a US population. Pediatrics. 2015;136(5):e1310-e1315. doi:10.1542/peds.2015-1807
5. Joshi C, Wirrell E. Dravet syndrome. Epilepsy Foundation. August 24, 2020. Accessed March 26, 2023.
6. Dravet syndrome. NIH |National Institute of Neurological Disorders and Stroke. Reviewed January 23, 2023. Accessed March 26, 2023.

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

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.