Dravet syndrome

C P Panayiotopoulos MD PhD (Dr. Panayiotopoulos of St. Thomas' Hospital has no relevant financial relationships to disclose.)
Jerome Engel Jr MD PhD, editor. (Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.)
Originally released October 18, 1993; last updated March 2, 2018; expires March 2, 2021

This article includes discussion of Dravet syndrome, Dravet s syndrome, epilepsy with polymorphic seizures, severe myoclonic epilepsy in infancy, severe polymorphic epilepsy of infants, severe myoclonic epilepsy of infancy – borderland (SMEB), SME, and SMEI. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Dravet syndrome is an uncommon and severe genetic epilepsy syndrome of infantile onset, mainly caused by SCN1A mutations or deletions. The typical form is characterized by an early onset, in the first year of life, with the occurrence of febrile and afebrile, generalized or unilateral, convulsive seizures in apparently normal infants, later followed by other seizure types (myoclonic and atypical absence seizures, focal seizures, obtundation status epilepticus) persisting into adulthood. Borderline forms may lack 1 of the above features of myoclonic seizures, atypical absences, onset in the first year of life, and others. Developmental delay becomes apparent within the second year of life and is followed by definite neurologic and cognitive impairment, personality disorders of variable intensity, autism, and psychosis. 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 in the first years. There is no underlying brain lesion, and neuroimaging is normal. The long-term prognosis is unfavorable, and early death can occur due to sudden unexplained death in epilepsy (SUDEP) or to status epilepticus.

The genetic etiology of Dravet syndrome has been documented with the finding that 70% to 80% of cases are caused by SCN1A mutations, 90% of which occur de novo. Haploinsufficiency is thought to be the mechanism underlying most cases, and environmental factors probably contribute to the variable phenotype of patients with SCN1A mutations. Experimental studies on animal models gave new insights into the pathogenesis and possible treatments of this severe disease.

Key points

 

• Dravet syndrome is 1 of the most severe epilepsies in infancy.

 

• The onset is always in the first year of life in apparently normal infants.

 

• It is genetically determined due to mutations in SCN1A, the gene encoding the alpha-1 subunit of the Na+ channel, in 70% to 80% of the affected patients.

 

• Mutations are de novo in the majority of patients, but some inherited mutations have been reported (around 5%), leading to the appearance of the disease in siblings.

 

• Treatment is disappointing. Carbamazepine and lamotrigine can aggravate the seizures. Useful antiseizure drugs include valproate, topiramate, carbamazepine, and the newer drug stiripentol. Ketogenic diet is very beneficial for some patients.

 

• Prevention of status epilepticus with regular medication and emergency protocols is important and may influence developmental outcome.

Historical note and terminology

The history of Dravet syndrome has been detailed by Dravet herself (Dravet et al 2011). Dravet syndrome was first described as “severe myoclonic epilepsy in infancy” by Charlotte Dravet in 1978 in a French medical journal from 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 (Dravet 1978). 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 (Dalla Bernardina et al 1982). Subsequently, Dravet, Roger, Bureau, and Dalla Bernardina presented these 42 patients at the XIII International Epilepsy Congress in Kyoto (Dravet et al 1982).

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 (Commission on Classification and Terminology of the International League Against Epilepsy 1989). 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 mutations in the sodium-channel gene SCN1A in all of the 7 studied probands with Dravet syndrome (Claes et al 2001). Since then research has exploded in documenting Dravet syndrome as a channelopathy at the severe end of the spectrum of SCN1A-related disorders (Brunklaus and Zuberi 2014). Thus, the name “Dravet syndrome” is designated to include not only the classic “severe myoclonic epilepsy in infancy” but also other phenotypic variants or borderline forms that may have all the features of the syndrome except one, such as without myoclonic seizures, onset in the second year, or without generalized spike and wave on EEG (Guerrini and Oguni 2011; Stenhouse et al 2013).

In the most recent ILAE proposals, Dravet syndrome is classified as a genetic epilepsy syndrome and an epileptic encephalopathy (Berg et al 2010; Scheffer et al 2017). 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, Lennox Gastaut syndrome and 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 SCN1A mutations, 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 mutations or copy number variants in SCN1A. A small percentage of females with a Dravet syndrome-like phenotype have mutations 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 (Dravet and Guerrini 2011), a supplement to epilepsia (Anonymous 2011), and many relevant chapters in recent epilepsy books (Dravet et al 2012; Dravet and Oguni 2013; Nabbout 2016).

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