Dravet syndrome

Classification according to ICD-10
G40.4	Other generalized epilepsies and epileptic syndromes Early myoclonic encephalopathy (symptomatic)
ICD-10 online (WHO version 2019)

The Dravet syndrome ( severe myoclonic epilepsy in early childhood , Early infantile epileptic encephalopathy ) is a rare genetically induced encephalopathy with intractable myoclonic epilepsy in infancy.

root cause

In 70–80% of cases, Dravet syndrome is caused by a loss of function mutation in the SCN1A gene . This gene codes for the alpha-1 unit of the voltage-dependent sodium channel . This ion channel is mainly expressed on inhibitory interneurons , which leads to a reduced inhibition of the pyramidal cells in the cerebral cortex, which leads to a hyperexcitatory and epileptogenic state. Mutations in this gene almost always occur randomly ( spontaneous mutation ), so they cannot be detected in the parents.

Variants of the genes GABRA1, GABRB3, GABRG2, SCN2A, SCN1B and STXBP1 come into consideration as further possible causes.

Boys are affected significantly more often than girls.

Symptoms

The syndrome usually occurs in normally developed children around six months of age, with a sudden seizure, often with a high fever. The seizures are often refractory and psychomotor and intellectual development usually slows down in the second year of life, sometimes there is also a loss of previously acquired developmental steps. Other symptoms and disorders such as attention deficit and hyperactivity disorder (ADHD), ataxia (in more than 50%), impaired language development or pyramidal orbit signs can also occur. Due to the persistent seizures, there is also an increased risk of mortality , the SUDEP risk is up to 20%.

The children's seizure readiness may be a. increased by infections (with and without fever), warmth, bathing water temperatures above approx. 35 ° C, overexertion (trigger likely increase in body temperature), photosensitivity (e.g. light reflections) and lack of sleep.

After the first myoclonic seizure, other types of seizures can occur, in addition to generalized clonic and tonic-clonic seizures (often unilateral) and myoclonic seizures (with spike-wave patterns ) as well as irregular myoclonic (without spike-wave patterns), (complex) focal ones Seizures, atypical absences, gaze cramps, weak convulsions and falls. There is often a tendency towards status epilepticus .

Treatment and development prognosis

The spectrum within Dravet syndrome is very wide. The course is individual. The child's development is usually normal until the onset of the disease. Thereafter, psychomotor and intellectual development slows down in most cases, this is particularly noticeable in language development. The prognosis for cognitive development and seizure frequency is very different. There are Dravet children who respond very well to well to one of the possible drug combinations and thus show a rather atypical Dravet syndrome with no or only mild cognitive impairment. Freedom from seizures is achieved only very rarely, in the majority of cases the course is rather unfavorable with moderate or severe intellectual disabilities. It is believed that not only epileptic activity but also other previously unknown factors and genetic mutation play a role in the mental development of the children concerned.

Valproate can be used for drug treatment . Stiripentol and clobazam have proven to be useful as additional agents. Topiramate and levetiracetam are available as alternatives. Lamotrigine and carbamazepine , like other sodium channel blockers, are not indicated and almost always lead to an increase in seizures. A ketogenic diet can help relieve symptoms.

In a multicenter, double-blind, placebo- controlled, randomized clinical study with 120 children who suffered from Dravet's syndrome and had therapy-resistant seizures, a response to the administration of cannabidiol was shown. While 5% of the children on cannabidiol remained seizure-free, none of the children in the placebo group did. The median number of seizures per month decreased from 12.4 to 5.9 (placebo: from 14.9 to 14.1) and in 43% of the children (versus 27% in the placebo group) the seizure rate decreased by at least 50%. However, with 16% (compared to 5%) there were more undesirable effects, especially tiredness up to somnolence , loss of appetite and diarrhea, as well as increased interactions with other anti-epileptic drugs. The intake therefore had to be stopped prematurely in eight children (compared to one child in the placebo group).

history

The syndrome got its name from the French psychiatrist and epileptologist Charlotte Dravet (born July 14, 1936), who first described the syndrome named after her from a scientific point of view in 1978 and differentiated it from other epilepsy syndromes. By 1992 she and her colleagues had published 172 case studies.

Web links

• non-profit association Dravet Syndrome eV
• Dravet Syndrome Association Switzerland (non-profit association)

Individual evidence

1. ^ DS Auerbach, J. Jones et al. a .: Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome. In: PloS one. Volume 8, number 10, 2013, p. E77843, ISSN  1932-6203 . doi: 10.1371 / journal.pone.0077843 . PMID 24155976 . PMC 3796479 (free full text).
2. ↑ ^{a b} Le SV, Le PHT, Le TKV, Kieu Huynh TT, Hang Do TT: A mutation in GABRB3 associated with Dravet syndrome . In: Am. J. Med. Genet. A . 2017. doi : 10.1002 / ajmg.a.38282 . PMID 28544625 .
3. ↑ X. Xu, Y. Zhang et al. a .: Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. In: Brain & development. [electronic publication before printing] October 2013, ISSN  1872-7131 . doi: 10.1016 / j.braindev.2013.10.004 . PMID 24168886 .
4. ↑ A. Suls, JA Jaehn and a .: De Novo Loss-of-Function Mutations in CHD2 Cause a Fever-Sensitive Myoclonic Epileptic Encephalopathy Sharing Features with Dravet Syndrome. In: American Journal of Human Genetics . Volume 93, Number 5, November 2013, pp. 967-975, ISSN  1537-6605 . doi: 10.1016 / j.ajhg.2013.09.017 . PMID 24207121 .
5. ↑ Chiron C: Current therapeutic procedures in Dravet syndrome . In: Dev Med Child Neurol . 53 Suppl 2, 2011, pp. 16-8. doi : 10.1111 / j.1469-8749.2011.03967.x . PMID 21504427 .
6. ↑ Orrin Devinsky, J. Helen Cross, Linda Laux, Eric Marsh, Ian Miller, Rima Nabbout, Ingrid E. Scheffer, Elizabeth A. Thiele, Stephen Wright: Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome In: New England Journal of Medicine Volume 376, Issue 21 of May 25, 2017, pp. 2011-2020, doi: 10.1056 / NEJMoa1611618
7. ↑ Dravet C .: Les Epilepsies graves de l'enfant. In: Vie Med . tape 8 , 1978, p. 543-548 .

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