content:dravet_syndrome

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 [{{ :content:charlotte_dravet.jpg?150|Charlotte Dravet (Born 14 July 1936)}}] [{{ :content:charlotte_dravet.jpg?150|Charlotte Dravet (Born 14 July 1936)}}]
-Severe myoclonic epilepsy in infancy (SME) was described by Charlotte Dravet in 1978. In the Revised ILAE classification of epilepsies, the SMEI is named "Dravet syndrome" because of the lack of myoclonic seizures in many patients and is considered under Electroclinical syndromes[(:cite:20196795>{{pmid>20196795}})]. Dravet syndrome is characterized by febrile and afebrile generalized and unilateral clonic or tonic clonic seizures that occur in the first year of life in an otherwise normal infant and are later associated with myoclonus, atypical absences, and partial seizures. All seizure types are resistant to antiepileptic drugs with developmental delay becomes apparent within the second year of life and is followed by definite cognitive impairment and personality disorders.+Severe myoclonic epilepsy in infancy (SME) was described by Charlotte Dravet in 1978. In the Revised ILAE classification of epilepsies, the SMEI is named "Dravet syndrome" because of the lack of myoclonic seizures in many patients and is considered under Electroclinical syndromes[(:cite:20196795>{{pmid>long:20196795}})]. Dravet syndrome is characterized by febrile and afebrile generalized and unilateral clonic or tonic clonic seizures that occur in the first year of life in an otherwise normal infant and are later associated with myoclonus, atypical absences, and partial seizures. All seizure types are resistant to antiepileptic drugs with developmental delay becomes apparent within the second year of life and is followed by definite cognitive impairment and personality disorders.
  
 ===== Epidemiology ===== ===== Epidemiology =====
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   * **Eye closure:** The eye closure may facilitate the occurrence of localized and generalized abnormalities.   * **Eye closure:** The eye closure may facilitate the occurrence of localized and generalized abnormalities.
   * **Sleep:** Sleep is usually well structured with physiological patterns and cyclic organization, except when several seizures occur during the night. The paroxysmal, generalized as well as localized, activities are enhanced or appear.   * **Sleep:** Sleep is usually well structured with physiological patterns and cyclic organization, except when several seizures occur during the night. The paroxysmal, generalized as well as localized, activities are enhanced or appear.
-  * **Photosensitivity:** Photosensitivity on EEG is variable. Seizures have been reported to become very frequent under bright conditions, while they were remarkably reduced in the dark. Early photosensitivity is noted with generalized spike-waves following intermittent photic stimulation (IPS). There is a discrepancy between photosensitivity in the EEG lab and day to day life clinical photosensitivity.Patients with SME seem to have a paroxysmal response different from that observed in patients with idiopathic generalized epilepsy, dependent on the quantity of light rather than wavelength[(:cite:10496248>{{pmid>10496248}})]. The constant light sensitivity might correspond to the strongest end of the photosensitive spectrum in SME patients representing the most resistant type in SME.+  * **Photosensitivity:** Photosensitivity on EEG is variable. Seizures have been reported to become very frequent under bright conditions, while they were remarkably reduced in the dark. Early photosensitivity is noted with generalized spike-waves following intermittent photic stimulation (IPS). There is a discrepancy between photosensitivity in the EEG lab and day to day life clinical photosensitivity.Patients with SME seem to have a paroxysmal response different from that observed in patients with idiopathic generalized epilepsy, dependent on the quantity of light rather than wavelength[(:cite:10496248>{{pmid>long:10496248}})]. The constant light sensitivity might correspond to the strongest end of the photosensitive spectrum in SME patients representing the most resistant type in SME.
   * **Fever Sensitivity:**    * **Fever Sensitivity:** 
     * Epileptic seizures in SME are very sensitive to body temperature elevation itself, regardless of etiology, either due to infection, hot baths, or even physical exercise. In the Japanese population, frequent seizures triggered by fever and Japanese style hot-water immersion have been reported. The convulsive seizures are often prolonged and develop into status during such episodes.     * Epileptic seizures in SME are very sensitive to body temperature elevation itself, regardless of etiology, either due to infection, hot baths, or even physical exercise. In the Japanese population, frequent seizures triggered by fever and Japanese style hot-water immersion have been reported. The convulsive seizures are often prolonged and develop into status during such episodes.
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 ===== Genetics ===== ===== Genetics =====
   * Between 70% and 80% of patients carry sodium channel α1 subunit gene ([[https://www.omim.org/entry/182389|SCN1A]]) abnormalities   * Between 70% and 80% of patients carry sodium channel α1 subunit gene ([[https://www.omim.org/entry/182389|SCN1A]]) abnormalities
-  * truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset[(:cite:21463275>{{pmid>21463275}})].+  * truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset[(:cite:21463275>{{pmid>long:21463275}})].
   * remaining SCN1A mutations comprise [[splice_site_mutation|splice-site]] and [[https://www.genome.gov/genetics-glossary/Missense-Mutation|missense mutations]], most of which fall into the pore-forming region of the sodium channel   * remaining SCN1A mutations comprise [[splice_site_mutation|splice-site]] and [[https://www.genome.gov/genetics-glossary/Missense-Mutation|missense mutations]], most of which fall into the pore-forming region of the sodium channel
   * mutations are randomly distributed across the SCN1A protein   * mutations are randomly distributed across the SCN1A protein
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   * A majority of cases have a family history of epilepsy or febrile seizures (FS).   * A majority of cases have a family history of epilepsy or febrile seizures (FS).
 ===== Pathophysiology ===== ===== Pathophysiology =====
-  * The voltage-gated sodium channel is responsible for the initiation of action potentials and, therefore, is involved in neuronal excitability[(:cite:16921370>)][(:cite:18804930>{{pmid>18804930}})].+  * The voltage-gated sodium channel is responsible for the initiation of action potentials and, therefore, is involved in neuronal excitability[(:cite:16921370>)][(:cite:18804930>{{pmid>long:18804930}})].
   * The α subunit has 4 homologous domains, with 6 transmembrane segments each, that form the voltage sensor and ion-conducting pore[(:cite:16921370>)].   * The α subunit has 4 homologous domains, with 6 transmembrane segments each, that form the voltage sensor and ion-conducting pore[(:cite:16921370>)].
   * Mutations cause either a gain or a loss of function[(:cite:18804930>)].   * Mutations cause either a gain or a loss of function[(:cite:18804930>)].
-  * A mouse model of DS showed selective loss of sodium current in the hippocampal γ-aminobutyric acid(GABA)–mediated inhibitory interneurons. Failure of inhibition leading to excitation is hence a potential pathogenetic mechanism in this mutation causing DS[(:cite:16921370>{{pmid>16921370}})].+  * A mouse model of DS showed selective loss of sodium current in the hippocampal γ-aminobutyric acid(GABA)–mediated inhibitory interneurons. Failure of inhibition leading to excitation is hence a potential pathogenetic mechanism in this mutation causing DS[(:cite:16921370>{{pmid>long:16921370}})].
  
 ===== Outcome ===== ===== Outcome =====
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 Stiripentol -The use of Stiripentol, in association with VPA and CLB was shown to be efficacious on convulsive seizures. Stiripentol is mainly beneficial on the status in the first stage of the disease. This therapy is accepted today as the gold standard for this syndrome.  Stiripentol -The use of Stiripentol, in association with VPA and CLB was shown to be efficacious on convulsive seizures. Stiripentol is mainly beneficial on the status in the first stage of the disease. This therapy is accepted today as the gold standard for this syndrome. 
  
-A ketogenic diet may be helpful in some cases and has recently shown to be beneficial in children receiving a combination of Stiripentol, VPA and CLB[(:cite:21569025>{{pmid>21569025}})].+A ketogenic diet may be helpful in some cases and has recently shown to be beneficial in children receiving a combination of Stiripentol, VPA and CLB[(:cite:21569025>{{pmid>long:21569025}})].
  
 It is very important to aggressively treat the status episodes and prophylaxis of infections and hyperthermia. Rectal diazepam can prevent the evolution into status in the case prolonged or repeated convulsive seizures. IV Benzodiazepines are best for status particularly Clonazepam (CZP), Midazolam along with Chloral hydrate or barbiturates. It is very important to aggressively treat the status episodes and prophylaxis of infections and hyperthermia. Rectal diazepam can prevent the evolution into status in the case prolonged or repeated convulsive seizures. IV Benzodiazepines are best for status particularly Clonazepam (CZP), Midazolam along with Chloral hydrate or barbiturates.
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 ===== Epilepsy surgery ===== ===== Epilepsy surgery =====
-Andrade et al (2010)[(:cite:19919661>{{pmid>19919661}})] reported two adults aged 19&34 with Dravet syndrome who were treated with thalamic deep brain stimulation (DBS) , where the 19yr old showed marked improvement over a 10yr follow up, while the other did not.Small case series have also reported that palliative epilepsy surgery including Vagal Nerve Stimulation (VNS) and corpus callosotomy (CC) can be effective at reducing seizure frequency in Dravet syndrome[(:cite:27465677>{{pmid>long:27465677}})].+Andrade et al (2010)[(:cite:19919661>{{pmid>long:19919661}})] reported two adults aged 19&34 with Dravet syndrome who were treated with thalamic deep brain stimulation (DBS) , where the 19yr old showed marked improvement over a 10yr follow up, while the other did not.Small case series have also reported that palliative epilepsy surgery including Vagal Nerve Stimulation (VNS) and corpus callosotomy (CC) can be effective at reducing seizure frequency in Dravet syndrome[(:cite:27465677>{{pmid>long:27465677}})].
  
 The presumed topography of the epileptogenic areas involves preferentially the mesial frontal lobe, the central area, sometimes the parietal and, even, the occipital lobes. Few interictal foci are localized in the temporal area. Surprisingly a hippocampal sclerosis has not been shown in the MRI of these patients who had prolonged and repeated severe FS[(:ref:todo)]. The presumed topography of the epileptogenic areas involves preferentially the mesial frontal lobe, the central area, sometimes the parietal and, even, the occipital lobes. Few interictal foci are localized in the temporal area. Surprisingly a hippocampal sclerosis has not been shown in the MRI of these patients who had prolonged and repeated severe FS[(:ref:todo)].
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