Dravet Syndrome (DS)

Dravet syndrome (DS) is a rare, severe form of epilepsy that typically begins within the first year of life and is lifelong. DS is an epileptic encephalopathy characterized by recurrent, prolonged seizures that are usually resistant to treatment with antiseizure medications. The refractory nature of the seizures leads to developmental delay or regression, cognitive impairment, motor deficits, and behavioral challenges. Discovering the etiology of a patient’s disease is often part of the diagnostic process of DS.¹ 

Genetic Etiology of DS

Approximately 80% of patients with DS carry mutations in the SCN1A gene, which codes for alpha subunit 1 voltage-gated sodium channel protein (Na_V1.1).^1-4 Complete loss-of-function mutations in Na_V1.1 result in the development of DS.⁴

Researchers have identified more than 500 mutations in the SCN1A gene that are associated with DS. Most of the mutations are sequencing mutations (70% of cases of DS) that comprise truncating, missense, and splice-site mutations.²  

Most SCN1A mutations occur de novo, whereas 5% to 10% are inherited from a parent in an autosomal-dominant pattern.^2,5

Although SCN1A mutations account for most cases of DS, variations in other genes, including SCN1B, SCN2A, GABRA1, GABRG2, and PCDH19, have also been found to contribute to its development.⁵

Read more about DS genetics 

Pathogenesis of DS

Voltage-gated sodium channels (VGSCs) initiate action potentials in brain neurons and contribute to neuronal excitability. In DS, dysfunctional alpha 1 subunits in the VGSC complex impair the sodium currents, thereby interfering with action potential firing within hippocampal GABAergic inhibitory neurons. The lack of adequate neuronal inhibition results in the hyperexcitability of neurons in the brain and increased seizure activity in DS.⁴

Sodium currents and action potential firing are also impaired in GABAergic Purkinje neurons within the cerebellum, which may be an underlying cause of ataxia and unsteady gait in patients with DS.⁴

Read more about DS signs and symptoms

Possible Seizure Triggers in DS

Elevated Body Temperature

The initial seizure of a child with DS is typically accompanied by fever (febrile seizure). Subsequent seizures may occur with or without fevers. Some seizures may be triggered by increases in body temperature due to a warm bath, physical exertion, or a high ambient temperature.⁶

The underlying mechanisms by which fevers trigger seizure activity in DS are not well understood, but theories have been proposed. Fevers usually occur when an infection triggers the release of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin 1-beta (IL-1β), and other chemical mediators. Research suggests that an increase in cytokine activity may contribute to an increase in brain excitability.⁷

However, some seizures in DS occur in the absence of fevers. In a study conducted in mice with DS due to SCN1A and GABRG2 gene mutations, even brief periods of temperature elevation resulted in temperature dysregulation in the brain, which increased brain excitability and triggered seizure onset. The seizures were characterized by myoclonic jerks and spike-wave discharges on electroencephalography.⁷ 

In this same study, other factors influencing seizure onset include duration of heating and peak core body temperature. Age was also a factor: Younger mice exhibited more myoclonic jerks following hyperthermia than did older mice.⁷ Similarly, in humans with DS, seizure activity may decrease or even disappear in adulthood.⁸ 

Read more about DS risk factors

Vaccination

Vaccinations may trigger vaccine-proximate febrile seizures in individuals with a genetic predisposition to DS, such as an SCN1A mutation. Following the administration of inactivated vaccines for infectious diseases, such as diphtheria, tetanus, pertussis, and influenza, the onset of fever is usually within 48 hours; the onset of fever is within 5 to 14 days following the administration of live-attenuated vaccines for infectious diseases such as measles, mumps, rubella, and varicella.⁹

The vaccines trigger a reactogenic immune response, contributing to elevated body temperature and the release of inflammatory mediators, both of which may increase neuronal excitability and provoke seizures in patients with DS.^7,10

Read more about DS pathophysiology

References

1. Dravet syndrome. Epilepsy Foundation. Accessed March 20, 2023.
2. Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia. 2011;52(s2):24-29. doi:10.1111/j.1528-1167.2011.02997.x
3. SCN1A-related epilepsies. Epilepsy Foundation. Accessed March 20, 2023.
4. Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol. 2010;588(Pt 11):1849-1859. doi:10.1113/jphysiol.2010.187484
5. Dravet syndrome. GARD. Accessed March 20, 2023.
6. Dravet syndrome. Children’s Hospital of Philadelphia. Accessed March 20, 2023.
7. Warner TA, Liu Z, Macdonald RL, Kang JQ. Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice. Epilepsy Res. 2017;134:1-8. doi:10.1016/j.eplepsyres.2017.04.020
8. Selvarajah A, Zulfiqar-Ali Q, Marques P, Rong M, Andrade DM. A systematic review of adults with Dravet syndrome. Seizure. 2021;87:39-45. doi:10.1016/j.seizure.2021.02.025
9. Deng L, Wood N, Danchin M. Seizures following vaccination in children. Aust J Gen Pract. 2020;49(10). doi: 10.31128/AJGP-02-20-5236  
10. Hervé C, Laupèze B, Giudice GD, Didierlaurent AM, Da Silva FT. The how’s and what’s of vaccine reactogenicity. NPJ Vaccines. 2019;4:39. doi:10.1038/s41541-019-0132-6

Reviewed by Kyle Habet, MD, on 3/21/2023.

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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.