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content:dravet_syndrome [2020/02/23 19:51] – [Neurophysiology] icna | content:dravet_syndrome [2022/04/30 11:53] (current) – changed pubmed syntax administrator@icnapedia.org | ||
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- | Severe myoclonic epilepsy in infancy (SME) was described by Charlotte Dravet in 1978. In the Revised ILAE classification of epilepsies, the SMEI is named " | + | Severe myoclonic epilepsy in infancy (SME) was described by Charlotte Dravet in 1978. In the Revised ILAE classification of epilepsies, the SMEI is named " |
===== 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, | * **Sleep:** Sleep is usually well structured with physiological patterns and cyclic organization, | ||
- | * **Photosensitivity: | + | * **Photosensitivity: |
* **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:// | * Between 70% and 80% of patients carry sodium channel α1 subunit gene ([[https:// | ||
- | * truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset[(: | + | * truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset[(: |
* remaining SCN1A mutations comprise [[splice_site_mutation|splice-site]] and [[https:// | * remaining SCN1A mutations comprise [[splice_site_mutation|splice-site]] and [[https:// | ||
* 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[(: | + | * The voltage-gated sodium channel is responsible for the initiation of action potentials and, therefore, is involved in neuronal excitability[(: |
* The α subunit has 4 homologous domains, with 6 transmembrane segments each, that form the voltage sensor and ion-conducting pore[(: | * The α subunit has 4 homologous domains, with 6 transmembrane segments each, that form the voltage sensor and ion-conducting pore[(: | ||
* Mutations cause either a gain or a loss of function[(: | * Mutations cause either a gain or a loss of function[(: | ||
- | * 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[(: | + | * 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[(: |
===== Outcome ===== | ===== Outcome ===== | ||
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Stiripentol -The use of Stiripentol, | Stiripentol -The use of Stiripentol, | ||
- | A ketogenic diet may be helpful in some cases and has recently shown to be beneficial in children receiving a combination of Stiripentol, | + | A ketogenic diet may be helpful in some cases and has recently shown to be beneficial in children receiving a combination of Stiripentol, |
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)[(: | + | Andrade et al (2010)[(: |
+ | |||
+ | 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[(: | ||
===== Cannabidiol ===== | ===== Cannabidiol ===== | ||
- | * Clinical trials show that cannabidiol reduces the number of convulsive and non-convulsive seizures when compared with usual care[(: | + | * Clinical trials show that cannabidiol reduces the number of convulsive and non-convulsive seizures when compared with usual care[(: |
* Cannabidiol (CBD) has been shown to cut seizure occurrence by almost 50% in patients with Dravet syndrome in doses of 10 mg/kg per day and 20 mg/kg per day, based on the results of a phase 3 study[(: | * Cannabidiol (CBD) has been shown to cut seizure occurrence by almost 50% in patients with Dravet syndrome in doses of 10 mg/kg per day and 20 mg/kg per day, based on the results of a phase 3 study[(: | ||
- | * In a separate study in Dravet syndrome, the median frequency of convulsive seizures per month declined by -6.5 from 12.4 at baseline for patients treated with cannabidiol. In the placebo group, seizures declined by just 0.8 from baseline. There were 43% of patients achieving a 50% reduction with cannabidiol compared with 27% with placebo (OR, 2.00; P = .08)[(: | + | * In a separate study in Dravet syndrome, the median frequency of convulsive seizures per month declined by -6.5 from 12.4 at baseline for patients treated with cannabidiol. In the placebo group, seizures declined by just 0.8 from baseline. There were 43% of patients achieving a 50% reduction with cannabidiol compared with 27% with placebo (OR, 2.00; P = .08)[(: |
- | * Interim interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5 showed that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS[(: | + | * Interim interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5 showed that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS[(: |
===== Differential Diagnoses ===== | ===== Differential Diagnoses ===== | ||
- | There are several differential diagnoses in Dravet syndrome | + | * [[Febrile Seizures]] (FS) |
- | + | * At the very onset FS is the main differential | |
- | Febrile Seizures (FS) – At the very onset FS is the main differential. In an infant | + | * In an infant |
- | + | * However, it cannot be confirmed until other seizure types and myoclonic jerks occur, or one records spike-waves resulting from photostimulation. | |
- | Generalized epilepsy with febrile seizures plus (GEFS+) | + | * [[Generalized epilepsy with febrile seizures plus]] (GEFS+) |
- | + | * febrile seizures (or FS+) in early childhood | |
- | Benign myoclonic epilepsy (BME) - The diagnostic of BME is based on two major features: | + | * followed by occasional tonic, clonic, myoclonic, or absence seizures |
- | + | * respond to medication and remit by late childhood or early adolescence. | |
- | [[Lennox Gastuat Syndrome]] (LGS) - The early LGS is completely different. The occurrence of repeated FS in the first year virtually eliminates this diagnosis. LGS starts later, in a more variable way, and often in children with preexisting brain lesions. It essentially consists of atypical absences, drop attacks, and axial tonic seizures (which are exceptional in SME), even if they are associated with myoclonias in the myoclonic variant. | + | * increased incidence |
- | + | * [[Benign myoclonic epilepsy]] (BME) | |
- | Epilepsy with MAE ([[Myoclonic Astatic Epilepsy]]) or [[Doose Syndrome]]– SME might be difficult to differentiate from MAE, a classification category in which children first seen with early-onset generalized convulsive seizures triggered by fever are also included.. | + | * onset by brief, generalized myoclonic attacks, which represent the only ictal manifestation in a child |
- | + | * associated | |
- | Although the onset is very similar to that of SME, the course is different, with myoclonic-astatic seizures becoming a major feature, and the absence of any focal clinical or EEG manifestation. Patients with SME do not have recurrent drop attacks. | + | * FS when present are always simple and infrequent. |
- | + | | |
- | [[Progressive Myoclonus Epilepsy]] (PME) -The course of SME in its second stage could resemble a progressive metabolic disease mainly the neuronal ceroid lipofuscinoses. The absence of visual disturbances, | + | * atypical absences, drop attacks, and axial tonic seizures (which are exceptional in SME), even if they are associated with myoclonias in the myoclonic variant. |
- | + | * EEGs always show diffuse slow spike-waves, | |
- | A [[mitochondrial encephalomyopathy with ragged red fibers]] (MERRF) should be eliminated in the most severe cases by CSF lactate and by muscle biopsies. | + | * Lennox‐Gastaut syndrome is virtually excluded by a history of febrile clonic seizures in the first year of life |
- | + | | |
- | Early cryptogenic focal epilepsies. - An early cryptogenic focal epilepsy | + | |
- | + | * but course is different, with myoclonic-astatic seizures becoming a major feature, and the absence of any focal clinical or EEG manifestation | |
- | **Severe myoclonic epilepsy, borderline (SMEB)** | + | * recurrent drop attacks |
- | Several cases have been reported by different authors with a similar picture to that of SMEI, but without appearance of myoclonias, designated as " | + | |
- | + | * SME in second stage could resemble a progressive metabolic disease mainly the neuronal ceroid lipofuscinoses | |
- | However often most of the patients who do not present with myoclonic seizures have an interictal segmental myoclonus, which disturbs their motor abilities. Besides | + | * absence of visual disturbances, |
- | + | * in later childhood and adolescence there is no further deterioration and the patients present rather a picture of a static encephalopathy. | |
- | The main characteristics of the SMEB are considered | + | |
- | + | * may have the same onset with FS rapidly progressing to focal seizures | |
- | More than 70% of patients with SMEB carry SCN1A mutations that are spread throughout the gene with a mixture of mutations including truncating, missense, and splice-site changes | + | * will not present atypical absences and myoclonic jerks in the later course, but the diagnosis may remain uncertain for some months |
- | + | * focal epilepsy is unlikely when the partial motor seizures affect different parts of the body and when the hemiclonic seizures are alternating. | |
- | [[High-voltage slow-wave–grand-mal syndrome]] (HVSW-GM) - Seino and Higashi (1978)[(: | + | |
+ | * no atypical absences, either few EEG epileptic abnormalities, | ||
+ | * similar picture to that of SMEI, but without appearance of myoclonias, designated as " | ||
+ | | ||
+ | * myoclonias are rare in some children and can be detected | ||
+ | * myoclonic seizures | ||
+ | * similar | ||
+ | | ||
+ | | ||
The criteria for this syndrome are generalized and/or unilateral clonic or tonic clonic seizures in normal infants, occurring in the first year; almost no other type of seizures occur throughout the course; | The criteria for this syndrome are generalized and/or unilateral clonic or tonic clonic seizures in normal infants, occurring in the first year; almost no other type of seizures occur throughout the course; | ||
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| SCN2B | GEFS+ | | | SCN2B | GEFS+ | | ||
- | Catterall et al (2010)[(: | + | Catterall et al (2010)[(: |
Mild impairment of NaV1.1 channel function causes febrile seizures; moderate to severe impairment of NaV1.1 function by missense mutations and/or altered mRNA processing causes the range of phenotypes observed in GEFS+ epilepsy; and very severe to complete loss of function causes SMEI. | Mild impairment of NaV1.1 channel function causes febrile seizures; moderate to severe impairment of NaV1.1 function by missense mutations and/or altered mRNA processing causes the range of phenotypes observed in GEFS+ epilepsy; and very severe to complete loss of function causes SMEI. | ||
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There is a wide variation among the phenotypes in these conditions and is possibly due to the strong influence of the genetic background. | There is a wide variation among the phenotypes in these conditions and is possibly due to the strong influence of the genetic background. | ||
- | ===== Classification | + | ===== References |
- | Dravet syndrome is classified under Electroclinical syndromes in the Revised ILAE Classification and Terminology (2010). In the majority of cases, no etiology has been found. A mitochondrial cytopathy has been reported in rare cases. | + | ~~REFNOTES~~ |
- | 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. | ||