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  • Updated 11.24.2020
  • Released 10.18.1993
  • Expires For CME 11.24.2023

Dravet syndrome

Introduction

Overview

Dravet syndrome is a severe developmental and epileptic encephalopathy caused by pathogenic variants in the neuronal sodium-channel α1-subunit gene (SCN1A) and is the most common monogenic cause of epilepsy. Dravet syndrome is characterized by an early onset in the first year of life (3 to 15 months), with the occurrence of febrile and afebrile, hemiclonic or generalized, and convulsive seizures in apparently normal infants; Dravet syndrome is later followed by other seizure types (myoclonic and atypical absence seizures, focal seizures, and obtundation status epilepticus) persisting into adulthood. Borderline forms have historically been described lacking one of the above features of myoclonic seizures, atypical absences, or onset in the first year of life; however, they are now considered part of the Dravet syndrome spectrum. Developmental slowing becomes apparent within the second year of life and is followed by the emergence of significant intellectual disability and associated comorbidities including behavioral difficulties and features of autism spectrum disorder. The EEGs show both generalized and multifocal abnormalities, without a specific pattern, but initial interictal EEGs may be normal. Pharmacoresistance is one of the main features, and episodes of status epilepticus are frequent. Treatment options are currently expanding, which include the emergence of new gene-specific, disease-modifying therapies.

Dravet syndrome is a genetic disorder with 80% to 90% of cases being caused by pathogenic SCN1A variants, 90% of which occur de novo. Haploinsufficiency resulting in varying degrees of loss of protein function is thought to be the mechanism underlying most cases, with modifying factors including the genetic and environmental background contributing to the variable phenotype of patients with pathogenic SCN1A mutations.

Experimental studies on animal models continue to provide new insights into the pathogenesis and possible treatments of this severe sodium ion channelopathy. There is no underlying brain lesion, and neuroimaging is normal. The long-term prognosis is unfavorable and includes significant mortality due to sudden unexpected death in epilepsy (SUDEP) or status epilepticus.

Key points

• Dravet syndrome is one of the most severe epilepsies in infancy, leading to a developmental and epileptic encephalopathy, with significant long-term neurocognitive and motor comorbidities.

• The onset is between 3 to 15 months of age with recurrent and often prolonged febrile and afebrile seizures in apparently normal infants.

• It is caused by pathogenic variants; the neuronal sodium-channel α1-subunit gene (SCNA1) is in 80% to 90% of affected individuals.

• Pathogenic variants are de novo in most cases, but some inherited variants have been reported in a minority of patients.

• The epilepsy often remains treatment resistant despite evidence-based treatments, including sodium valproate, clobazam, and stiripentol, as well as the use of cannabidiol and fenfluramine. Topiramate, bromide, and the ketogenic diet are alternative options.

• Use of sodium channel blockers such as carbamazepine or lamotrigine is contraindicated as they may worsen seizures and developmental outcome.

• Prevention of status epilepticus with regular medication and emergency protocols is important to reduced mortality.

• Gene-specific, disease-modifying therapies are currently being developed and offer promising new treatment options.

Historical note and terminology

The history of Dravet syndrome has been detailed by Charlotte Dravet herself (41). Dravet syndrome was first described as “severe myoclonic epilepsy in infancy” by Charlotte Dravet in 1978 in a French medical journal from the Centre Saint-Paul, Marseille. She reported several very severe cases of epilepsy beginning early in life which, despite certain similarities, could not be categorized as Lennox-Gastaut syndrome for several reasons, especially their stereotyped mode of early onset, the frequent myoclonic seizures, and the absence of axial tonic seizures (40). Dalla Bernardina, who worked simultaneously in Verona, Italy and the Centre Saint-Paul, also observed the same electroclinical features in 20 of his Italian patients (30). Subsequently, Dravet, Roger, Bureau, and Dalla Bernardina presented these 42 patients at the XIII International Epilepsy Congress in Kyoto (47).

In 1989, the revised classification of the International League Against Epilepsy placed this syndrome under “epilepsies and syndromes undetermined as to whether they are focal or generalized,” as the syndrome shows both generalized and localized seizure types and EEG paroxysms (27). It was defined as follows:

"Severe myoclonic epilepsy in infancy is a recently defined syndrome. The characteristics include a family history of epilepsy or febrile convulsions, normal development before onset, seizures beginning during the first year of life in the form of generalised or unilateral febrile clonic seizures, secondary appearance of myoclonic jerks, and often partial seizures. EEGs show generalised spike-waves and polyspike-waves, early photosensitivity, and focal abnormalities. Psychomotor development is retarded from the second year of life on, and ataxia, pyramidal signs, and interictal myoclonus appear. This type of epilepsy is very resistant to all forms of treatment."

A landmark discovery was made in 2001 by Claes and colleagues who found the genetic etiology of Dravet syndrome with de novo pathogenic variants in the sodium-channel gene SCN1A in all of the 7 studied probands with Dravet syndrome (25). Since then research has expanded in documenting Dravet syndrome as a channelopathy at the severe end of the spectrum of SCN1A-related disorders (14; 76). Thus, the name “Dravet syndrome” is designated to include not only the classic “severe myoclonic epilepsy of infancy” but a spectrum comprising other phenotypic variants or borderline forms, including those without myoclonic seizures, onset in the second year, or without generalized spike and wave on EEG (53; 101; 76).

In the most recent ILAE proposals, Dravet syndrome is classified as a genetic epilepsy syndrome and a developmental and epileptic encephalopathy (07; 95). The complete description from the ILAE epilepsy manual is detailed below (Commission on Classification and Terminology of the International League Against Epilepsy 2014):

Dravet syndome. Dravet syndrome (previously known as severe myoclonic epilepsy of infancy, SMEI) typically presents in the first year of life in a normal child with prolonged, febrile and afebrile, focal (usually hemiclonic), or generalized convulsive seizures. Other seizure types including myoclonic and atypical absence seizures appear between the age of 1 and 4 years. Seizures are usually intractable, and from the second year of life children demonstrate cognitive and behavior impairments. The clinical diagnosis is supported by the presence of abnormalities in the sodium channel gene SCN1A (found in 75% of cases).

Note. The term Dravet syndrome is now also used to encompass atypical or borderline cases, previously known as severe myoclonic epilepsy of infancy - borderland (SMEB).

Note. Dravet syndrome may be considered an “epileptic encephalopathy.” This term denotes the concept that the epileptic activity itself might directly contribute additional cognitive and behavioral impairments over those expected from the underlying etiology alone, and that suppression of epileptic activity might minimize this additional impairment.

Clinical context. This syndrome is characterized by onset of seizures typically around 6 months of age. Most have had seizure onset less than 15 months of age; however, a small minority of cases have onset in the second year of life. Both sexes are affected. Antecedent, birth, and neonatal history is normal. The first seizure is associated with a fever in about 60% of cases. Not all patients start with febrile convulsions. Immunization may be a nonspecific trigger to the first seizure leading to an earlier age of seizure onset, but cases with onset with a vaccine proximate seizure have the same outcome as other children with Dravet syndrome. Sensitivity of seizures to fever may persist throughout life. Head size and neurologic examination are usually normal initially; over time ataxia and pyramidal signs may develop. Development is typically normal in the first year of life, with plateauing or regression in later years.

Caution. Antiseizure medications that have sodium channel blocking properties may aggravate seizures in this syndrome.

Caution. Tonic seizures and epileptic spasms are not expected; if present, consider other epilepsy syndromes.

Mandatory seizures. Focal and generalized seizure types occur in this syndrome. A clonic-tonic-clonic sequence to the convulsive seizures may occur. Hemiclonic seizures may involve different sides of the body in different seizures.

Patients may have atypical absence seizures, myoclonic seizures, atonic seizures, or nonconvulsive status epilepticus.

One quarter of patients have seizures induced by visual stimuli.

EEG background. The background EEG activity is typically normal in the first year of life. Postictal slowing may be seen initially, and diffuse slowing may appear over time.

Interictal EEG. By the second to fifth year of age, generalized spike-and-wave and multifocal discharges are seen.

Activation. Photic and pattern stimulation precipitate generalized spike-and-wave, with or without associated clinical events (atypical absence seizures and/or myoclonic seizures). Photosensitivity can be present in infancy and is seen at all ages. EEG abnormality is enhanced by sleep deprivation and by sleep.

Ictal EEG. The ictal EEG varies according to the type of seizure.

Caution. The presence of diffuse electrodecremental patterns or paroxysmal fast activity are not seen: then Lennox Gastaut syndrome should be considered.

Imaging. Neuroimaging is usually normal at onset. Abnormalities may be found later in life in 10% of cases, including generalized atrophy or hippocampal sclerosis.

Genetics.

Pattern of inheritance. In Dravet syndrome patients with pathogenic SCN1A variants, 95% are de novo and 5% are inherited. Carrier relatives are either unaffected or mildly affected with genetic epilepsy with febrile seizures plus phenotypes. Germline and somatic mosaicism have been reported.

Known genes. Approximately 75% of patients with Dravet syndrome have pathogenic variants or copy number variants in SCN1A. A small percentage of females with a Dravet syndrome-like phenotype have pathogenic variants in the PCDH19 gene. These females usually have clusters of seizures with fever as opposed to the prolonged status epilepticus with fever that occurs in SCN1A-related Dravet syndrome.

Family history of seizures/epilepsy. A family history of epilepsy and/or febrile seizures is present in 30% to 50% of patients. In some children with Dravet syndrome, the family history is consistent with genetic epilepsy with febrile seizures plus.

Differential diagnosis.

• Febrile seizures plus, genetic epilepsy with febrile seizures plus
• Epilepsy with myoclonic-atonic seizures
• Lennox-Gastaut syndrome

Dravet syndrome has been detailed in a book (41), a supplement to epilepsia (02), and many relevant chapters in epilepsy books (44; 46; 79). The Epilepsia Supplement 3 of 2019 is devoted to “Dravet syndrome and other sodium channel related encephalopathies.”

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