Dravet Syndrome – Get to Know It
Dravet syndrome is a severe myoclonic epilepsy occurring in early childhood. It is classified as a rare progressive epileptic encephalopathy, characterized by generalized or lateralized clonic seizures often prolonged and linked to febrile infections. Other forms of seizures later appear, leading to deterioration in psychomotor development and the onset of mental retardation. Early diagnosis and treatment are desirable.
Etiology and Epidemiology
This syndrome was first described in 1978 as severe myoclonic epilepsy in infancy (SMEI) by Charlotte Dravet, and the disease was renamed to Dravet syndrome in 1989.1, 3 It is a developmental and epileptic encephalopathy that begins in early childhood, associated with lifelong occurrence of treatment-resistant seizures and intellectual, behavioral, and gait disturbances.4
In 2001, the genetic basis of DS was discovered to be a de novo mutation of the gene for the α-1 subunit of the sodium channel (SCN1A) on chromosome 2q24.1 It accounts for 70–80% of cases of this disease.2, 3 More rarely, mutations have been identified in other genes in patients with DS: SCN2A, SCN3A, SCN7A, SCN8A, SCN9A, GABARG2, SCN1B, and PCDH19. In 20% of patients, however, the etiology is unknown.1 The incidence is reported to be 1 in 22,000, with boys being more frequently affected at a ratio of 2:1.3
Clinical Manifestations and Prognosis
Clinically, DS manifests in the first year of life (peaking around 5 months of age) in previously normally developing children.2 Recurring prolonged febrile convulsive and hemiconvulsive seizures appear. The epilepsy is pharmacoresistant, with sodium/calcium channel blockers (phenytoin, lamotrigine, carbamazepine, and high doses of phenobarbital) potentially worsening the seizures, while other medications may reduce their occurrence.3
DS further develops with age. Deterioration of psychomotor development appears between the ages of 2 and 6.2 Behavioral disorders and a decline in cognitive functions occur, leading to the development of mental retardation. Neurological findings reveal ataxia, central hypotonia, and positive pyramidal irritative signs.2
In adulthood, the disease manifests as persistent motor and cognitive dysfunction. Other types of seizures (convulsive, myoclonic, absence, focal, and tonic) appear. Motor dysfunctions include ataxia, tremor, dysarthria, and pyramidal and extrapyramidal signs. Cognitive disorders, which are common among patients, include visual-motor integration and visual perception disorders, executive dysfunction, and speech disorders. Patients often have psychiatric disorders such as aggression, agitation, obsession, or pathological hoarding.1
DS is associated with increased mortality; the most common cause of death being sudden unexpected death in epilepsy (SUDEP) and status epilepticus.1 The average age of death for patients is 11 years.2
Diagnosis and Treatment
DS is diagnosed clinically and through genetic testing, which is recommended for developmentally normal children aged 2–15 months with a single prolonged hemiclonic seizure or local/generalized status epilepticus of unknown etiology in connection with vaccination or fever.4
Therapeutic options include antiepileptic drugs, cannabinoids, ketogenic diet, and surgical procedures such as deep brain stimulation (DBS) and vagus nerve stimulation (VNS).1 General treatment principles are applied for each type of seizure based on their clinical predominance.2 For maintenance therapy, valproate, clobazam, stiripentol, and fenfluramine can be considered in the first or second line.4 For instance, fenfluramine can achieve a reduction in seizure occurrence by at least 50% within 3 months in 68% of patients, and complete seizure freedom in 14% of cases according to a German study.5 Given the refractory nature of the seizures to existing antiepileptic drugs, several molecules are in development that may improve the prognosis of patients with DS.
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Sources:
1. Anwar A., Saleem S., Patel U. K. et al. Dravet syndrome: an overview. Cureus 2019; 11 (6): e5006, doi: 10.7759/cureus.5006.
2. Danhofer P., Horák O., Fakusová L. Dravet syndrome: severe myoclonic epilepsy in early childhood. Neurologie pro praxi 2015; 16 (1): 38–42.
3. Danhofer P., Brunová K., Ošlejšková H. Dravet syndrome (severe infantile myoclonic epilepsy): characteristics of the disease in adulthood. Neurologie pro praxi 2017; 18 (2): 113–116.
4. Wirrell E. C., Hood V., Knupp K. G. et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia 2022 Jul; 63 (7): 1761−1777, doi: 10.1111/epi.17274.
5. Strzelczyk A., Pringsheim M., Mayer T. et al. Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: compassionate use program in Germany. Epilepsia 2021; 62 (10): 2518−2527, doi: 10.1111/epi.17034.
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