Dravet Syndrome (DS)

Dravet syndrome (DS) is a rare type of severe, intractable childhood epilepsy with an incidence of 1 in 15,700. Dravet syndrome, classified as an epileptic encephalopathy, is characterized by recurrent episodes of prolonged seizures that are difficult to control with antiseizure medications (ASMs). These seizures cause progressive cognitive impairment, behavioral problems, developmental delay, and forms of motor dysfunction, such as ataxia and gait disturbances.^1,2

Pathophysiology of DS

Approximately 80% of patients with DS have a mutation in the SCN1A gene, which encodes the voltage-gated sodium channel protein Na_V1.1.^1,2 In approximately 90% of cases, these mutations are acquired following conception (de novo); the remaining 10% are inherited, largely in an autosomal-dominant pattern.^3,4

An absence or dysfunction of the protein subunits involved in the regulation of sodium channels within neurons interferes with sodium currents and action potentials required by neurons to communicate, particularly GABAergic interneurons that inhibit neuronal excitation. The lack of neuronal inhibition results in increased neuronal hyperexcitability and promotes recurrent seizure activity in individuals with DS.^1,2 

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Pathophysiology of Prolonged, Refractory Seizures

Because the seizures are refractory to treatment with ASMs, recurrent episodes of prolonged convulsive seizures (status epilepticus) are characteristic of DS.⁵

Recurrent, refractory, and prolonged seizures in children with DS cause brain damage through a series of metabolic and excitotoxic events that accompany convulsive status epilepticus. Frequently damaged areas of the brain include the CA1 and CA3 zones of the hippocampus, amygdala, thalamus, cerebellum, and cerebral neocortex.⁵ 

Swelling observed on magnetic resonance imaging (MRI) during or following an episode of status epilepticus suggests the possibilities of vasogenic, cytotoxic edema and disruption of the blood-brain barrier, which in turn contribute to neuronal damage in these areas of the brain.⁵ 

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Associated Cognitive Impairment and Behavioral Problems

Comorbidities commonly observed in individuals with DS develop as a consequence of neuronal damage in specific regions of the brain.^6-9 These include emotional dysregulation, sleep disturbances, problems with learning and memory, and dysautonomia; the latter contributes to temperature dysregulation and decreased sweating, which in turn can trigger additional seizures as a consequence of hyperthermia.^9,10

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Temporal correlations have been made between a high frequency of convulsive seizures (>5 per month) and severe cognitive impairment and behavioral problems.⁵ One study reported that cognitive outcomes in a cohort of 26 patients with DS did not correlate with age at seizure onset, type of genetic mutation, convulsive status, or types of seizures. However, when individual cognitive profiles were compared across the group, cognitive outcomes were worse in children with an early appearance of absence seizures and myoclonus than in those without these seizure types.^5,11

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Pathophysiology of Developmental Delay

Initially, children with DS develop normally, but frequent, intractable seizures contribute to developmental delay or regression. Even when the seizures are fairly well controlled with a combination of ASMs, children with DS exhibit progressive neurodevelopmental deterioration.¹²

Language delay may occur in children with DS; multiple contributing factors include physical difficulty coordinating the lips and tongue to form words, cognitive impairment, motor planning difficulties, and poor postural control.¹³

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Pathophysiology of Motor Dysfunction

Forms of motor dysfunction affect approximately 50% to 60% of patients with DS, including ataxia, crouched gait, and progressive gait disturbances; these are in part related to skeletal malalignments, worsening foot deformities, and small muscular contractures around the hip and knee.¹⁴

Impairment of sodium currents and action potential firing in GABAergic inhibitory Purkinje neurons within the cerebellum may contribute to the development of ataxia.^2,5 

Crouched gait is frequent among patients with DS and worsens progressively with age. A specific pathogenesis has yet to be identified.^14,15

Read more about DS signs and symptoms

References

1. What is Dravet syndrome? Dravet Syndrome Foundation. Accessed March 22, 2023.
2. Oakley JC, Kalume F, Catterall WA. Dravet syndrome: insights into pathophysiology and therapy from a mouse model of Dravet syndrome. Epilepsia. 2011;52(Suppl 2):59-61. doi:10.1111/j.1528-1167.2011.03004.x
3. Genetics of Dravet syndrome. Dravet Syndrome Foundation. Accessed March 22, 2023.
4. Dravet syndrome. GARD. Accessed March 22, 2023.
5. Guerrini R, Falchi M. Dravet syndrome and SCN1A gene mutation related-epilepsies: cognitive impairment and its determinants. Dev Med Child Neurol. 2011;53(s2):11-15. doi:10.1111/j.1469-8749.2011.03966.x
6. Amygdala. Britannica. Accessed March 22, 2023.
7. Hippocampus. Britannica. Accessed March 22, 2023.
8. Thalamus. Cleveland Clinic. Accessed March 22, 2023.
9. Comorbidities. Dravet Syndrome UK. Accessed March 22, 2023.
10. Dysautonomia. Dravet Syndrome UK. Accessed March 22, 2023.
11. Ragona F, Granata T, Dalla Bernardina B, et al. Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients. Epilepsia. 2011;52(2):386-392. doi:10.1111/j.1528-1167.2010.02925.x
12. Dravet syndrome. Child Neurology Foundation. Accessed March 22, 2023.
13. Turner SJ, Brown A, Arpone M, Anderson V, Morgan AT, Scheffer IE. Dysarthria and broader motor speech deficits in Dravet syndrome. Neurology. 2017;88(8):743-749. doi:10.1212/WNL.0000000000003635
14. Rodda JM, Scheffer IE, McMahon JM, Berkovic SF, Graham HK. Progressive gait deterioration in adolescents with Dravet syndrome. Arch Neurol. 2012;69(7):873-878. doi:10.1001/archneurol.2011.3275
15. Selvarajah A, Gorodetsky C, Marques P, et al. Progressive worsening of gait and motor abnormalities in older adults with Dravet syndrome. Neurology. 2022;98(22):e2204-e2210. doi:10.1212/WNL.0000000000200341

Reviewed by Kyle Habet, MD, on 3/28/2023.

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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.