English

Dravet Syndrome

Etiologies: It is mainly related to genetic factors, About 75% of patients have SCN1A gene mutations (about 95% are de novo mutations (a small part of them are not really de novo, which may involve gonadal chimerism), and about 5% are inherited (the family members of the carriers may not be affected, or only show genetic epilepsy with febrile seizures plus), germline and somatic mosaicism have been reported). Some are related to gene mutations such as PCDH19, CHD2, SCN1B, SCN2A, SCN8A, SCN9A, HCN1, GABRA1, GABRB2, GABRG2, GABRB3, STXBP1, TBC1D24, KCNA2 (some phenotypes are different from the classic ones) [1-11].

Age of onset: onset of seizures less than 15 months of age (typically around 6 months of age).

Seizure characteristics: Seizures often have fever sensitivity (there may also be non-febrile seizures). Low fever is often easy to induce, including myoclonic seizures, atypical absence seizures or focal seizures (the above seizure types do not necessarily occur, among which hemiclonic seizures are common), status epilepticus is relatively easy to occur, and some patients are also easy to be induced by flash stimulation. In addition, there is little possibility of tonic seizure or epileptic spasm. If these two seizure forms occur, it should be considered whether they have the possibility of other types of epilepsy syndromes [12].

EEG: Interval: most children is typically normal at the beginning, In the later stage (especially after 1 year old), the background activity may slow down, and there may be 4-5Hz paroxysmal theta rhythm in the frontal, central and parietal areas, as well as generalized or focal (often multifocal) epileptic discharges (although seizures are frequent and difficult to control between the ages of 1-2 years, about half of the patients do not have epileptic discharges in the interval). Ictal: EEG often starts from one side of the posterior head during focal seizures, during generalized myoclonic seizures, a generalized spike slow (or multi-spike slow) complex wave burst can be recorded, during sporadic myoclonus, clonus, or focal seizures, some EEGs may only be rhythmic slow waves or sporadic slow waves unrelated to myoclonus [13].

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

Developmental progress: The development can be normal before the onset of the disease, and the development is backward gradually in the later stage (there will be some differences between individuals in the degree of severity).

Treatment:

National Institute for health and Clinical Excellence (NICE) epilepsy guidelines 2022:

First-line treatment: valproate sodium (If sodium valproate alone is unsuccessful as first-line monotherapy for Dravet syndrome, consider triple therapy with stiripentol and clobazam as first-line add-on therapy).

Second-line treatment: If triple therapy is unsuccessful for Dravet syndrome and the child is over 2 years, consider cannabidiol in combination with clobazam as a second-line add-on treatment option in line with NICE's technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Dravet syndrome.

Further treatment options: If the above first-line and second-line treatment schemes are unsuccessful, one of the following treatment can be added (If the first choice is unsuccessful, consider the other add-on options): ketogenic diet, levetiracetam, topiramate.

If all other treatment options for Dravet syndrome are unsuccessful, consider potassium bromide under the guidance of a neurologist with expertise in epilepsy.

Be aware that the following drugs may exacerbate seizures: carbamazepine, gabapentin, lacosamide, lamotrigine, oxcarbazepine, phenobarbital, pregabalin, tiagabine, vigabatrin.

Chinese clinical diagnosis and treatment guidelines epilepsy volume 2015:

First line drugs: valproate, topiramate.

Drugs that can be added: clobazam, stiripentol, levetiracetam, clonazepam.

Be aware that the following drugs may exacerbate seizures: carbamazepine, oxcarbazepine, gabapentin, lamotrigin, phenytoin sodium, pregabalin, tiagabine, vigabatrin.

2022 International League Against Epilepsy (ILAE) diagnostic criteria[14]:

Mandatory: Recurrent focal clonic (hemiclonic), febrile and afebrile seizures (which often alternate sides from seizure to seizure), focal to bilateral tonic-clonic, and/or generalized clonic seizures; age of seizure onset within 1-20 months; Drug-resistant epilepsy, Intellectual disability.

Alerts: No history of prolonged seizures (>10 min); Lack of fever sensitivity as a seizure trigger; Normal EEG background without interictal discharges after age 2 years; age of seizure onset within 1-2 months or 15-20 months; Developmental delay at seizure onset; Focal neurological findings (other than Todd’s paresis); Lack of pathogenic SCN1A or other causal variant; Good efficacy with prophylactic sodium-channel agentsm including carbamazepine, oxcarbazepine, and phenytoin.

Exclusionary: Epileptic spasms, Early infantile SCN1A DEE; MRI showing a causal focal lesion.

 

Reference

  1. Ohmori, I., et al., Significant correlation of the SCN1A mutations and severe myoclonic epilepsy in infancy.Biochem Biophys Res Commun, 2002. 295(1): p. 17-23.
  2. Depienne, C., et al., Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.PLoS Genet, 2009. 5(2): p. e1000381.
  3. Depienne, C., et al., Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.PLoS Genet, 2009. 5(2): p. e1000381.
  4. Ogiwara, I., et al., A homozygous mutation of voltage-gated sodium channel beta(I) gene SCN1B in a patient with Dravet syndrome.Epilepsia, 2012. 53(12): p. e200-3.
  5. Steel, D., et al., Dravet syndrome and its mimics: Beyond SCN1A. Epilepsia, 2017. 58(11): p. 1807-1816.
  6. Singh, N.A., et al., A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.PLoS Genet, 2009. 5(9): p. e1000649.
  7. Mei, D., et al., Dravet syndrome as part of the clinical and genetic spectrum of sodium channel epilepsies and encephalopathies. Epilepsia, 2019. 60 Suppl 3: p. S2-S7.
  8. Carvill, G.L., et al., GABRA1 and STXBP1: novel genetic causes of Dravet syndrome.Neurology, 2014. 82(14): p. 1245-53.
  9. Kang, J.Q. and R.L. Macdonald, Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome. JAMA Neurol, 2016. 73(8): p. 1009-16.
  10. Pavone, P., et al., A novel GABRB3 variant in Dravet syndrome: Case report and literature review. Mol Genet Genomic Med, 2020. 8(11): p. e1461.
  11. Zhang, J., et al., Infantile epilepsy with multifocal myoclonus caused by TBC1D24 mutations. Seizure, 2019. 69: p. 228-234.
  12. Panayiotopoulos.  癫痫综合征及临床治疗.  北京 : 人民卫生出版社, 2012.
  13. 刘晓燕.  临床脑电图学. 第2版.  北京 : 人民卫生出版社, 2017.
  14. Zuberi, S.M., et al., ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia, 2022. 63(6): p. 1349-1397.