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content:dravet_syndrome [2020/02/18 14:58] – [Seizure semiology] bijuhameedcontent:dravet_syndrome [2022/04/30 11:53] (current) – changed pubmed syntax administrator@icnapedia.org
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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>{{pubmed>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 =====
   * Incidence probably less than 1 per 40,000   * Incidence probably less than 1 per 40,000
   * Males are more often affected than females, in a ratio of 2:1.   * Males are more often affected than females, in a ratio of 2:1.
-===== History & Clinical Manifestations =====+===== Clinical features =====
   * Dravet syndrome typically occurs in normal infants   * Dravet syndrome typically occurs in normal infants
   * Significant antenatal associations reported in literature include intrauterine growth retardation, prematurity and hypoxic ischemic insults   * Significant antenatal associations reported in literature include intrauterine growth retardation, prematurity and hypoxic ischemic insults
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   * Behaviour becomes more characterised by slowness and perseveration.   * Behaviour becomes more characterised by slowness and perseveration.
 ===== Seizure semiology ===== ===== Seizure semiology =====
-  * the Seizures typically begin before 1 year of age +  * seizures typically begin before 1 year of age 
-  * initially they are prolonged, generalized, or unilateral clonic seizures and are typically triggered by fever+  * __initially they are prolonged, generalized, or unilateral clonic seizures and are typically triggered by fever__
   * the febrile seizures tend to be long (more than 20 min), recur in clusters in the same day and evolve into status epilepticus   * the febrile seizures tend to be long (more than 20 min), recur in clusters in the same day and evolve into status epilepticus
   * sometimes afebrile seizures can also occur initially usually in the context of a vaccination or of an infectious episode, or after a bath but majority of these patients then go on to have febrile seizures   * sometimes afebrile seizures can also occur initially usually in the context of a vaccination or of an infectious episode, or after a bath but majority of these patients then go on to have febrile seizures
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   * About 2 weeks to 2 months ( mean 6 weeks) following the first febrile seizure other febrile seizures occur and later afebrile seizures also appear (mean 5 months).   * About 2 weeks to 2 months ( mean 6 weeks) following the first febrile seizure other febrile seizures occur and later afebrile seizures also appear (mean 5 months).
   * Between 1 and 4 years of age, other seizure types appear, along with a slowing in the psychomotor development attaining a steady state in the disease progress.   * Between 1 and 4 years of age, other seizure types appear, along with a slowing in the psychomotor development attaining a steady state in the disease progress.
-  * once a steady state is achieved then multiple seizure types during the course of the disease +  * __once a steady state is achieved then multiple seizure types during the course of the disease__
- +
   * **Generalized clonic or tonic clonic seizures**   * **Generalized clonic or tonic clonic seizures**
     * usually shorter, with a very brief tonic phase, with few autonomic symptoms, with a transient postictal flattening quickly replaced by diffuse delta waves     * usually shorter, with a very brief tonic phase, with few autonomic symptoms, with a transient postictal flattening quickly replaced by diffuse delta waves
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     * The ways of propagation are very variable from one seizure to another in the same patient and even in the same recording. The relationship between the clinical events and the accompanying EEG is not always clear.     * The ways of propagation are very variable from one seizure to another in the same patient and even in the same recording. The relationship between the clinical events and the accompanying EEG is not always clear.
   * **Myoclonic Seizures**   * **Myoclonic Seizures**
-    * The myoclonic seizures appear between the ages of 1 and 5 years +    * myoclonic seizures appear between the ages of 1 and 5 years 
-    * They are difficult to analyze due to their variability. Sometimes they are barely evident while at times they are massive involving whole muscles. +    * they can be quite variable & sometimes there is an atonic component associated with a head drop 
-    * Sometimes there is an atonic component associated with a head drop. +    * sometimes they are isolated or grouped in brief bursts consisting of two or three jerks 
-    * The myoclonic jerks can be either isolated or grouped in brief burstsconsisting of two or three jerks. +    * they are very frequent, occurring several times a day, sometimes incessantly.
-    * They are very frequent, occurring several times a day, sometimes incessantly.+
     * Interictal segmental myoclonus are often seen sometimes appearing only before a convulsive seizure with no concomitant change in the EEG. They involve either the limbs of the both sides, with a distal predominance, or the facial muscles, independently.     * Interictal segmental myoclonus are often seen sometimes appearing only before a convulsive seizure with no concomitant change in the EEG. They involve either the limbs of the both sides, with a distal predominance, or the facial muscles, independently.
     * They exist at rest, but are increased by voluntary movement.     * They exist at rest, but are increased by voluntary movement.
     * They are more frequent in the period with seizures, particularly in elder children with frequent nocturnal convulsive seizures, after awakening from attacks.     * They are more frequent in the period with seizures, particularly in elder children with frequent nocturnal convulsive seizures, after awakening from attacks.
-    * In hyperactive children the myoclonus could be made evident by asking them to perform a precise activity such as drinking, piling up cubes, or holding a spoon. +    * in hyperactive children the myoclonus could be made evident by asking them to perform a precise activity such as drinking, piling up cubes, or holding a spoon. 
-    * The myoclonic jerks are sometimes observed only on awakening or in the minutes preceding a seizure. +    * the myoclonic jerks are sometimes observed only on awakening or in the minutes preceding a seizure. 
-    * They persist during drowsiness and disappear during slow sleep. +    * they persist during drowsiness and disappear during slow sleep. 
-    * The jerks can be initiated by photic stimulation, variation in light intensity, closure of the eyes, and fixation on patterns. +    * the jerks can be initiated by photic stimulation, variation in light intensity, closure of the eyes, and fixation on patterns. 
-    * They are not typically accompanied by changes in consciousness, except when they occur at very close intervals. +    * they are not typically accompanied by changes in consciousness, except when they occur at very close intervals. 
-    * Video EEG has shown that they are accompanied by generalized or multiple spike-waves, at 3 Hz or more, with higher voltage on the frontocentral areas and on the vertex. Their duration is usually brief (1–3 s), but it can be longer (10 s).  +    * telemetry studies indicate that they are accompanied by generalized or multiple spike-waves, at 3 Hz or more, with higher voltage on the frontocentral areas and on the vertex. Their duration is usually brief (1–3 s), but it can be longer (10 s).  
-    * Electromyography (EMG) can show the postmyoclonic inhibition corresponding to the head drop. +    * electromyography (EMG) can show the postmyoclonic inhibition corresponding to the head drop. 
-    * Sometimes there is successive myoclonic twitching involving mostly head, eyelids, and, at times, arms, resulting in a rhythmic retropulsion of head corresponding to a burst of generalized spike-waves at 3 Hz. When they are sufficiently sustained, they appear to be atypical absence seizures with a myoclonic component. +    * sometimes there is successive myoclonic twitching involving mostly head, eyelids, and, at times, arms, resulting in a rhythmic retropulsion of head corresponding to a burst of generalized spike-waves at 3 Hz. When they are sufficiently sustained, they appear to be atypical absence seizures with a myoclonic component. 
-  * **Atypical Absence Seizures**+  * **Atypical absence seizures**
     * Atypical absence seizures can appear at different ages, either between 1 and 3 years, together with the myoclonic attacks, or later on, from 5 to 12 years.     * Atypical absence seizures can appear at different ages, either between 1 and 3 years, together with the myoclonic attacks, or later on, from 5 to 12 years.
-    * They can be either atypical absence seizures with impaired consciousness only or with a myoclonic component as well. +    * they can be either atypical absence seizures with impaired consciousness only or with a myoclonic component as well. 
-    * Both seizure types correspond to generalized, irregular spike-waves at 2–3.5 Hz +    * both seizure types correspond to generalized, irregular spike-waves at 2–3.5 Hz 
-  * **Obtundation Status** +  * **Obtundation status** 
-    * Characterised by a variable impairment of consciousness often accompanied by fragmentary and segmental, erratic myoclonias, of low amplitude, involving the limbs and the face, sometimes associated with a slight increase of muscular tone. +    * characterised by a variable impairment of consciousness often accompanied by fragmentary and segmental, erratic myoclonias, of low amplitude, involving the limbs and the face, sometimes associated with a slight increase of muscular tone. 
-    * Depending on the level of consciousness patients can or cannot react to stimuli, have simple activities (toy manipulation and eating), interrupted by short episodes of complete loss of contact and staring. Strong sensory stimulations can interrupt but not stop the status. +    * depending on the level of consciousness patients can or cannot react to stimuli, have simple activities (toy manipulation and eating), interrupted by short episodes of complete loss of contact and staring. Strong sensory stimulations can interrupt but not stop the status. 
-    * Convulsive seizures could either initiate, occur during, or terminate these status. These periods could be prolonged for several hours, even several days, maintained by environmental light stimuli, eye closure, and the pattern fixation (dotted lines of the walls, TV screen in two recorded status). +    * convulsive seizures could either initiate, occur during, or terminate these status. These periods could be prolonged for several hours, even several days, maintained by environmental light stimuli, eye closure, and the pattern fixation (dotted lines of the walls, TV screen in two recorded status). 
-    * The EEG is characterized by one diffuse slow-wave dysrrhyhmia, intermixed with rare focal and diffuse spikes, sharp waves, and spike-waves, of higher voltage in the anterior regions and the vertex, without correspondence between the spikes and the myoclonias, except during the myoclonic fits.+    * EEG is characterized by one diffuse slow-wave dysrrhyhmia, intermixed with rare focal and diffuse spikes, sharp waves, and spike-waves, of higher voltage in the anterior regions and the vertex, without correspondence between the spikes and the myoclonias, except during the myoclonic fits.
     * EEG corresponding to a complex partial status with either continuous posterior localized irregular slow waves or spike-waves during unconsciousness with deviations of both eyes to the right or irregular spike-wave complexes over the left hemisphere, predominantly in the occipitotemporal area have also been reported.     * EEG corresponding to a complex partial status with either continuous posterior localized irregular slow waves or spike-waves during unconsciousness with deviations of both eyes to the right or irregular spike-wave complexes over the left hemisphere, predominantly in the occipitotemporal area have also been reported.
-**Focal Seizures** +  * **Focal seizures** 
-    * Focal seizures can appear early, from 4 months to 4 years . They are either Simple partial seizures (SPS) of motor type or more commonly complex partial seizures (CPS), with prominent autonomic symptoms. When the symptomatology is mild, it is difficult to distinguish them from atypical absences without concomitant EEG. The partial seizures could be secondarily generalized. +      * Focal seizures can appear early, from 4 months to 4 years. 
-  * **Tonic Seizures** +      * they are either Simple partial seizures (SPS) of motor type or more commonly complex partial seizures (CPS), with prominent autonomic symptoms. When the symptomatology is mild, it is difficult to distinguish them from atypical absences without concomitant EEG. The partial seizures could be secondarily generalized. 
-    * Tonic seizures are exceptional in Dravet syndrome and are mainly detected by sleep EEG recordings. When present they resemble the axial tonic seizures of the [[Lennox–Gastaut syndrome]] (LGS), sometimes with a myoclonic component but unlike LGS not frequently repeated in the same recording nor the interictal sleep EEG commonly shows rapid rhythms and multiple SWs like in LGS.+  * **Tonic seizures** 
 +    * tonic seizures are exceptional in Dravet syndrome and are mainly detected by sleep EEG recordings. When present they resemble the axial tonic seizures of the [[Lennox–Gastaut syndrome]] (LGS), sometimes with a myoclonic component but unlike LGS not frequently repeated in the same recording nor the interictal sleep EEG commonly shows rapid rhythms and multiple SWs like in LGS.
  
 ===== Neurophysiology ===== ===== Neurophysiology =====
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   * localized findings are usually seated in the central areas, bilaterally, synchronous or asynchronous, and in the vertex, and may spread to the entire hemisphere but can be also recorded in the posterior regions, occipital or temporal.   * localized findings are usually seated in the central areas, bilaterally, synchronous or asynchronous, and in the vertex, and may spread to the entire hemisphere but can be also recorded in the posterior regions, occipital or temporal.
   * The EEGs contain more generalized paroxysms when myoclonic jerks are present. The relationship between the seat of the interictal paroxysms and the ictal discharges are not always clear.   * The EEGs contain more generalized paroxysms when myoclonic jerks are present. The relationship between the seat of the interictal paroxysms and the ictal discharges are not always clear.
-  * The response to **Hyperventilation:** is variable.+  * **Hyperventilation:** variable response
   * **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>{{pubmed>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>{{pubmed>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>{{pubmed>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>{{pubmed>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>{{pubmed>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>{{pubmed>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>{{pubmed>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)].
 ===== Cannabidiol ===== ===== Cannabidiol =====
-  * Clinical trials show that cannabidiol reduces the number of convulsive and non-convulsive seizures when compared with usual care[(:cite:28813226>{{pubmed>28813226}})][(:cite:32040850>{{pubmed>32040850}})].+  * Clinical trials show that cannabidiol reduces the number of convulsive and non-convulsive seizures when compared with usual care[(:cite:28813226>{{pmid>28813226}})][(:cite:32040850>{{pmid>32040850}})].
   * 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[(:cite:miller2019>Miller I, Perry MS, Saneto RP, et al. Cannabidiol (CBD; 10 and 20mg/kg/day) significantly reduces convulsive seizure frequency in children and adolescents with Dravet syndrome (DS): Results of a dose-ranging, multi-center, randomized, double-blind, placebo-controlled trial (GWPCARE2) Presented at: 2019 American Academy of Neurology Annual Meeting. May 4-10, 2019; Philadelphia, PA.)].   * 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[(:cite:miller2019>Miller I, Perry MS, Saneto RP, et al. Cannabidiol (CBD; 10 and 20mg/kg/day) significantly reduces convulsive seizure frequency in children and adolescents with Dravet syndrome (DS): Results of a dose-ranging, multi-center, randomized, double-blind, placebo-controlled trial (GWPCARE2) Presented at: 2019 American Academy of Neurology Annual Meeting. May 4-10, 2019; Philadelphia, PA.)].
-  * 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)[(:cite:30910443>{{pubmed>30910443}})]. +  * 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)[(:cite:30910443>{{pmid>30910443}})]. 
-  * 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[(:cite:30582156>{{pubmed>30582156}})].+  * 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[(:cite:30582156>{{pmid>30582156}})].
 ===== 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 differentialIn an infant less than 1 year, with a family history, the occurrence of long and repeated FS leads one to suspect the diagnosis of SME, mainly when the triggering fever is not high. However, it cannot be confirmed until other seizure types and myoclonic jerks occur, or one records spike-waves resulting from photostimulation. +    * In an infant under 1 year, with a family history, the occurrence of long and repeated FS leads one to suspect the diagnosis of SME, mainly when the triggering fever is not high. 
- +    * 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+) - Characterised by febrile seizures (or FS+) in early childhoodfollowed by occasional tonic, clonic, myoclonic, or absence seizures which respond to medication and remit by late childhood or early adolescence. The proportion of children with GEFS+ whose first seizure occurs in the context of immunization appears to be greater than the proportion of children with febrile seizures unrelated to FS+ and 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: onset by brief, generalized myoclonic attacks, which represent the only ictal manifestation in a child with generalized spike-waves on the EEG without any focal abnormality. Even when FS are also present, they are always simple and infrequent. +    * 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. The EEGs always show diffuse slow spike-waves, grouped in bursts, and specific features during sleep where there is no photosensitivity. +    * increased incidence of first seizure in the context of immunization compared with febrile seizures unrelated to FS+ and GEFS+. 
- +  * [[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 with generalized spike-waves on the EEG without any focal abnormality 
-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. 
- +  [[Lennox-Gastuat Syndrome]] (LGS) 
-[[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, of abnormalities of the fundus, of the peculiar response to IPS in the EEGs, and the negative results of biological investigations eliminate this diagnosis. Moreover, in later childhood and adolescence there is no further deterioration and the patients present rather a picture of a static encephalopathy. +    * 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, grouped in bursts, and specific features during sleep where there is no photosensitivity. 
-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 
- +  Epilepsy with MAE ([[Myoclonic Astatic Epilepsy]]) or [[Doose Syndrome]] 
-Early cryptogenic focal epilepsies. - An early cryptogenic focal epilepsy may have the same onset with FS rapidly progressing to focal seizures. These patients will not present atypical absences and myoclonic jerks in the later course, but the diagnosis may remain uncertain for some months. Besides focal epilepsy is unlikely when the partial motor seizures affect different parts of the body and when the hemiclonic seizures are alternating. +    onset is very similar to that of SME 
- +    * 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 are not seen 
-Several cases have been reported by different authors with a similar picture to that of SMEI, but without appearance of myoclonias, designated as "peripheral" or "borderline" SME (SMEB).The most important problem arises when the onset and the course of SME are atypical. +  [[Progressive Myoclonus Epilepsy]] (PME) 
- +    * 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 in some children, the myoclonias are rare and detectable only by accurate examination and Video EEG recordings. In some others, myoclonic seizures can be observed and recorded only when convulsive seizures are frequent, just before they start. +    * absence of visual disturbances, absence of fundal abnormalities, absence of posterior‐evoked potentials elicited by the [[intermittent photic stimulation]] (IPS) low frequencies, and the negative results of biological investigations eliminate this diagnosis 
- +    * 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 to be: no atypical absences, either few EEG epileptic abnormalities, or only occasional multifocal or diffuse spike-waves during the first stage of the disease, and rare photosensitivity. All the other features are similar, including the bad prognosis and the high rate of early mortality+  Early cryptogenic focal epilepsies 
- +    * 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)[(:cite:seino1978>Seino M, Higashi T. The investigation on a group of secondary generalized epilepsy in childhood with onset in infancy and refractory grand mal. In: Kimura M, ed. Mental and physical disability research group sponsored by Ministry of Health and Welfare. Report of research group of children's health and environment. 1978:79–80)] reported on a group of patients with refractory epilepsy in childhood characterized by predominant generalized tonic clonic seizures and Wada et al. (88) proposed to name it "high-voltage slow-wave–grand-mal syndrome (HVSW-GM)."+  **Severe myoclonic epilepsy, borderline (SMEB)** 
 +    * no atypical absences, either few EEG epileptic abnormalities, or only occasional multifocal or diffuse spike-waves during the first stage of the disease, and rare photosensitivity. 
 +    * similar picture to that of SMEI, but without appearance of myoclonias, designated as "peripheral" or "borderline" SME (SMEB) 
 +      most patients who do not present with myoclonic seizures have an interictal segmental myoclonus affecting motor abilities 
 +      * myoclonias are rare in some children and can be detected only by accurate examination and video telemetry 
 +      * myoclonic seizures are sometimes observed and recorded only when convulsive seizures are frequent, just before they start 
 +    * similar to SME in terms of prognosis and high rate of early mortality 
 +    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 
 +  [[High-voltage slow-wave–grand-mal syndrome]] (HVSW-GM) - Seino and Higashi (1978)[(:cite:seino1978>Seino M, Higashi T. The investigation on a group of secondary generalized epilepsy in childhood with onset in infancy and refractory grand mal. In: Kimura M, ed. Mental and physical disability research group sponsored by Ministry of Health and Welfare. Report of research group of children's health and environment. 1978:79–80)] reported on a group of patients with refractory epilepsy in childhood characterized by predominant generalized tonic clonic seizures and Wada et al. (88) proposed to name it "high-voltage slow-wave–grand-mal syndrome (HVSW-GM)."
  
 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)[(:cite:20194124>{{pubmed>20194124}})] proposed the hypothesis that increasing severity of loss of function mutations of NaV1.1 channels causing increasing impairment of action potential firing in GABAergic inhibitory neurons is responsible for the spectrum of severity of the NaV1.1-associated forms of epilepsy+Catterall et al (2010)[(:cite:20194124>{{pmid>20194124}})] proposed the hypothesis that increasing severity of loss of function mutations of NaV1.1 channels causing increasing impairment of action potential firing in GABAergic inhibitory neurons is responsible for the spectrum of severity of the NaV1.1-associated forms of epilepsy
  
 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. 
  
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