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.
Dravet syndrome is an uncommon and severe genetic epilepsy syndrome of infantile onset, frequently 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, clonic seizures in apparently normal infants, later followed by other seizure types (myoclonic and atypical absence seizures, focal seizures, obtundation status epilepticus) persisting into adulthood. The borderline form is characterized by the lack of myoclonic and atypical absence seizures. The seizures are usually accompanied by a slowing of psychomotor development and cognitive impairment as well as behavioral disturbances. 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. Other genes involved in Dravet syndrome include SCN1B and GABRG2. PCDH19 and SCN2A mutations, and deletions involving the chromosome 2q SCN cluster, have been reported in Dravet syndrome–like syndromes (borderline forms). Experimental studies on mice models were performed and gave new insights into the pathogenesis of this malignant epilepsy.
• Dravet syndrome is 1 of the most severe epilepsies in infancy and the antiepileptic drugs are not able to control the seizures permanently.
• 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
Severe myoclonic epilepsy in infancy was described by Dravet in 1978 from Centre Saint-Paul, Marseille, who reported in a French journal 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 onset 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."
Many children have been reported to have symptoms similar to Dravet syndrome but without myoclonias (Ogino et al 1989; Kanazawa 1992; Yakoub et al 1992). This has also been mentioned by Dravet (Dravet et al 1992; Dravet et al 2005; Dravet et al 2012). These patients may have different EEG features but they share the same course and outcome as the patients with myoclonias, and they can be included in the same syndrome. This seems to be supported by the genetic studies in which the same SCN1A gene mutation was discovered in patients with and without myoclonias (Fukuma et al 2004). Thus, it has been proposed to change its name, first to “epilepsy with polymorphic seizures” and then to “Dravet syndrome.” In the ILAE Task Force proposal (Engel 2001), Dravet syndrome is considered an “epileptic encephalopathy,” defined as a condition in which the epileptiform abnormalities themselves are believed to contribute to the progressive disturbance in cerebral function. However, it is not proved that the cognitive decline observed in the first stages of the disease is only the consequence of the epilepsy (Catarino et al 2011; Ragona et al 2011; Brunklaus and Zuberi 2014).
In the most recent ILAE proposal Dravet syndrome is classified as an epileptic syndrome with onset in the infantile period of age (Berg et al 2010). The complete description from the ILAE epilepsy manual (Commission on Classification and Terminology of the International League Against Epilepsy 2014) can be accessed at www.epilepsydiagnosis.org.
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