Severe myoclonic epilepsy in infancy (SME) was described by Charlotte Dravet in 1978. In the Revised ILAE classification of epilepsies, the SMEI named "Dravet syndrome" because of the lack of myoclonic seizures in many patients and is considered under Electroclinical syndromes.
- History & Clinical Manifestations
- Seizure semiology
- At disease onset
- EEG at disease onset
- Steady State
- Neurophysiology of the myoclonus
- Differential Diagnoses
Severe myoclonic epilepsy in infancy (SME) was described by Charlotte Dravet in 1978. In the Revised ILAE classification of epilepsies, the SMEI has been named "Dravet syndrome" because of the lack of myoclonic seizures in many patients and is considered under Electroclinical syndromes (Berg AT et al., 2010). 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.
- Incidence probably less than 1 per 40,000
- Males are more often affected than females, in a ratio of 2:1.
History & Clinical Manifestations
- Dravet syndrome typically occurs in normal infants.
- Significant antenatal associations reported in literature include intrauterine growth retardation, prematurity and hypoxic ischemic insults, .
- Children start walking at a normal age but later develop ataxia and upper motor neuron signs.
- Language also starts at the normal age, but it progresses very slowly, and children often do not attain sentence constructing ability.
- The motor and cognitive delay becomes progressively evident from the second year onwards
- After the age of 2 years, children exhibit difficult behaviour with hyperactivity and severe learning difficulties.
- Developmental delay affects all domains with the motor, linguistic, and visual abilities being affected the most.
- Behavior is often marked by hyperactivity, psychotic type of relationships and, sometimes, autistic traits.
- Neuropsychologic and cognitive deficits are related to the severity of the epilepsy including the duration and frequency of convulsive seizures during the first 2 years of life.
- Neurologic deficits do not generally worsen after the age of 4 years.
- Ataxia and UMN signs tend to disappear but poor coordination remains with often a slight action myoclonus or a tremor.
- Neuropsychologic deficits also improve through adolescence with improvement in the hyperactivity
- Behaviour becomes more characterised by slowness and perseveration.
At disease onset
The Seizures typically begin before 1 year of age. 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.
Uncommonly 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.
Isolated episodes of focal myoclonic jerking are sometimes noted weeks or days before the appearance of the first afebrile seizure and remain isolated or in the hours preceding the first febrile convulsive seizure. Very rarely complex partial seizures or focal seizures are also seen.
About 2 weeks to 2 months ( mean 6 weeks) after 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.
EEG at disease onset
EEGs are usually normal at disease onset. Sometimes a diffuse or unilateral slowing of the background if they are recorded after a prolonged seizure. Early photosensitivity is noted with generalized spike-waves elicited by the intermittent photic stimulation (IPS). Rhythmic theta activities at 4–5 Hz can also be present in the centroparietal areas and the vertex
Multiple seizure types during the course of the disease
- 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. In some seizures, the initial tonic phase is almost immediately mixed with the clonic jerks, giving a vibratory aspect
- Unilateral seizures –Short duration, associated with contralateral tone changes, ictal EEG anomalies more limited to one hemisphere. They can begin with diffuse spike-waves. EEG shows postictal asymmetric signs and, often there is a postictal transitory hemiparesis. These seizures can be either on one side or on the other side in the same patient. This pattern of alternating unilateral seizures is one of the main characteristics of this syndrome. True hemiclonic seizures are rare.
A left hemiclonic seizure recorded in a 2-year 6-month-old boy during a status
- "Falsely Generalized" seizures – Clinical description often from parents correspond to a GTC seizure but close observation shows that it is not a primarily generalized seizure and differs from patient to patient. Video telemetry may reveal bilateral, asymmetric, tonic contraction, leading to variable postures during the seizure (extension of one limb, flexion of another). The onset can be an opening of the eyes preceding the motor phenomena, with or without deviation of the eyes, the head, and the mouth. The patients seeming to be unconscious not reacting to stimuli.
- Clonic jerks may start in the face or immediately involve the limbs. They are asynchronous, with an asymmetric frequency (vibratory in one side, slower in the other). They may stop on one side and persist on the other, even on a single segment lasting from 30 s to 2 min.
- Autonomic symptoms are often mild with cyanosis, apnea, hypersalivation, and respiratory obstruction only occur following very prolonged attacks.
- The EEG abnormaplities are bilateral and asymmetric either from the very onset or becoming so during the seizures. The abnormalities are characterised by slow spike or a spike-wave, sometimes followed by a brief attenuation, followed by rapid activities and slow waves. The postictal EEG shows either a diffuse flattening or a diffuse slowing. Sometimes the end of the seizure is not easy to recognize and the child continues to sleep.
Most of the convulsive seizures in DS are not actually generalized. They probably correspond to focal seizures generated by several foci that successively fire, as shown by the "falsely generalized" and the "unstable" seizures. The epileptic process seems to implicate several cortical areas, either successively or alternatively, and variable from one ictal event to another one. Thus, it could be multifocal epilepsy with an extremely rapid, sometimes simultaneous, burning of the different foci, because of a very low convulsive threshold.
The clinical manifestations are near that of the "falsely generalized" seizures with asymmetric and asynchronous tonic and clonic movements, sometimes predominant on one side or shifting from one side to the other. However, the EEG discharge involves irregularly different parts of the brain. It can start in one localized area of one hemisphere, then spread either to the entire hemisphere, either asymmetrically to the two hemispheres, or to another area of the same hemisphere or of the opposite hemisphere, then return to the first involved hemisphere. The end of the discharge can occur either in this hemisphere or contralaterally
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 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. Sometimes there is an atonic component associated with a head drop. The myoclonic jerks can be either isolated or grouped in brief bursts, consisting of two or three jerks. 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. 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. 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. 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. 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). Myoclonic 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.
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. 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
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. 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 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 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.
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.
The EEGs often change with the progression of the condition with the occurrence of generalized, focal, and multifocal abnormalities. Characteristically specific features are absent. The background activity is slow when the convulsive seizures are numerous. Out of these periods it can be either normal or slow and disorganized.
Sometimes a rhythmical theta activity is recorded in the central and vertex areas.
The paroxysmal abnormalities are also variable and can be absent. When present, they consist of spikes, single and multiple spike-waves, generalized, symmetric or asymmetric, isolated or in brief bursts, and of localized sharp waves, slow waves, and spikes. The 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.
Hyperventilation: The response to hyperventilation is variable.
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.
EEG photosensitivity has been observed variably in patients. Sseizures have been reported to become very frequent under bright conditions, while they were remarkably reduced in the dark. A strong response to IPS was also observed. 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. The constant light sensitivity might correspond to the strongest end of the photosensitive spectrum in SME patients representing the most resistant type in SME
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. There is no evidence however to link SME with increased susceptibility to infections.
Even though the fever sensitivity is most prominent during infancy and the hyperthermia and infections continue to remain as potential triggers and febrile status epilepticus can still occur during adolescence.
Neurophysiology of the myoclonus
Segmentary interictal myoclonus: In segmentary interictal myoclonus, time-locked EEG potentials are not detectable and C-reflex and enlarged somatosensory evoked potentials are absent. These small jerks either are not produced in the cortex or result from discharges involving such a small number of neurons that their electrical activity is undetectable.
Generalized ictal myoclonic jerks: The generalized ictal myoclonic jerks are always preceded by clear-cut spike-wave discharges. Available evidence suggests that they originate from the spread of focal cortical myoclonic activity. However, the leading hemisphere shifts from one discharge to the next, according to the muscle used as trigger, with an interside latency consistent with transcallosal spread. Thus, there is some evidence that myoclonus in SME can originate, like the other seizures, from multiple cortical areas.
Neuroimaging do not normally show any abnormalities particularly malformations. However, CT scan and MRI can show signs of slight or moderate, diffuse, cerebral atrophy, cerebellar atrophy, sometimes increased white matter signal (T2 weight). In some cases, neuroimaging may be normal at the onset with the cerebral atrophy appearing during the course of epilepsy.
Interictal SPECT could be normal or show areas of hypoperfusion localised in one or both hemispheres. The areas of hypoperfusion not necessarily in concordance with the prevalence of EEG paroxysms. PET studies have also been either normal or showing hypometabolism with no consistent correlation between the focal ictal symptoms.
Between 70% and 80% of patients carry sodium channel α1 subunit gene (SCN1A) abnormalities, and truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset.(Marinj C et al., 2011)
The remaining SCN1A mutations comprise splice-site and missense mutations, most of which fall into the pore-forming region of the sodium channel. Mutations are randomly distributed across the SCN1A protein. Most mutations are de novo, but familial SCN1A mutations also occur.
Somatic mosaic mutations have also been reported in some patients and might explain the phenotypical variability seen in some familial cases. SCN1A exons deletions or chromosomal rearrangements involving SCN1A and contiguous genes are also detectable in about 2–3% of patients. A small percentage of female patients with a DS-like phenotype might carry PCDH19 mutations. Rare mutations have been identified in the GABARG2 and SCN1B genes. The etiology of about 20% of DS patients remains unknown, and additional genes are likely to be implicated.
A majority of cases have a family history of epilepsy or febrile seizures (FS).
Long-Term Outcome is unfavourable with persistent seizures and severe cognitive impairments. The mortality rate is very high. It is important to carefully treat the prolonged convulsive seizures during the early years of life.
The stagnant or delayed development during the first 6 years subsequently evolves positively although in a dysharmonic way and patients might be able to receive and benefit from specialized educational input in later years.
- Extremely resistant to any kind of treatment during the first years
- The partial seizures, myoclonic seizures, and atypical absences tend to disappear later while the convulsive seizures persist. They preferentially occur during the night and can be repeated during the same night, particularly in the case of fever, and then again preceded by myoclonias.
Phenobarbital (PB), valproate (VPA), Phenytoin and benzodiazepines (clonazepam (CZP), Nitrazepam, Clobazam (CLB)) may decrease the frequency and the duration of convulsive seizures.
VPA, benzodiazepines, ethosuximide, high doses of piracetam, can improve the myoclonic syndrome. Zonisamide (ZNS) when started early has been reported to prevent the appearance of myoclonias
Clorazepate, methsuximide, acetazolamide, allopurinol, and sulthiame have also been used with partial results.
Bromide (Brk) has been found to be beneficial particularly for the treatment of refractory grand-mal epilepsy in SME with excellent short term outcomes. In Japan BrK is often used first in conjunction with VPA or CZP, ZNS, clorazepate, and ketogenic diet is introduced if drug therapy is not sufficient.
Corticosteroids can be useful in cases of repeated status, but do not have any long term benefits. Immunotherapy has also been reported to be of some benefit.
Lamotrigine (LTG) worsens the condition and is contraindicated
Carbamazepine is also believed to worsen the condition. The use of CBZ has been suggested in the early phase of the epilepsy as a test to confirm the diagnostic of SME when it is suspected.
Vigabatrin also has been found to be beneficial on convulsive and partial seizures in our older patients, when the myoclonic syndrome was attenuated.
Topiramate has been shown to achieve excellent control of the convulsive and partial seizures in children and adults.
Rufinamide, with a pharmacologic mechanism similar to carbamazepine and phenytoin may also exacerbate seizures
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 (Nabbout R et al., 2011).
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.
In the case of prolonged or repeated convulsive seizures, the use of rectal diazepam can prevent the evolution into status. In case of status, the best drugs are the intravenous benzodiazepines, particularly the CZP and the midazolam associated with chloral hydrate or barbiturates.
The photo and pattern sensitivities associated with self-stimulation are extremely drug resistant and can produce long-lasting obtundation and myoclonic status in patients with Dravet syndrome. Wearing sunglasses is usually not enough.
Since monocular light stimulation fails to provoke epileptic discharges, complete inhibition of the self-stimulation can be obtained by using glasses masking one eye has been tried but tolerance is poor. Optical filters tinted with a particular color (the procion turquoise blue = MGL), have been used in Japan to inhibit flickering hand movements and forced eye closure, but again children tolerate this poorly.
Specially adapted blue-tinted contact lenses that had transmission spectra similar to that of MGL have also been used with some benefit. After a period of adjustments, the flicker hand movements have been shown to disappear completely and the self-stimulation by hand flicker movement did not return even after the contact lenses were removed later. The forced eye closure self-stimulation however has not yet been successfully inhibited.
Andrade et al (2010) 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.
There are several differential diagnoses in Dravet syndrome
Febrile Seizures (FS) – At the very onset FS is the main differential. In 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.
Generalized epilepsy with febrile seizures plus (GEFS+) - Characterised by febrile seizures (or FS+) in early childhood, followed 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+.
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.
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.
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..
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.
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.
A mitochondrial encephalomyopathy with ragged red fibers (MERRF) should be eliminated in the most severe cases by CSF lactate and by muscle biopsies.
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.
Severe myoclonic epilepsy, borderline (SMEB)
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.
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.
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.
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) 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;
EEG is normal at the initial stage, and then shows rather poor epileptiform discharges, such as generalized spike-waves or polyspike-waves without focal abnormalities.
There is inefficiency of treatment. Psychomotor development is normal in the first stage and then slows down. Thus, the initial stage is very near that of SME. These conditions are thought to be all part of one infantile refractory grand mal syndrome with the same physiopathological basis and poor prognosis.
The SCN1A gene mutation has also been demonstrated in patients with borderline SME and in patients with only refractory grand-mal seizures. However, as already underlined, these findings remain heterogeneous and not easy to explain and they are not sufficient to put all the cases together in the same syndrome.
The early diagnosis of SME thus remains a challenge. To summarise the diagnosis is probable when the first seizure occurs between 2 and 9 months, in a neurologically normal baby, when the first two seizures are clonic, generalized or alternating, when they are afebrile or triggered by a moderately high temperature, and when the development is normal during the first year.
Relationship between DS and GEFS+
Recent advances in the molecular genetic studies, suggest that DS may be due to a channelopathy related to the GEFS+ syndrome, a condition which also exhibitis fever sensitivity.
DS shares the same gene with GEFS+, wich was described by Scheffer and Berkovic in 1997 in a large Australian family with epilepsy. GEFS+ is an autosomal-dominant disorder in which the seizures start early and persist beyond 6 years of age. In the affected family coexist members with FS, FS+ and various types of afebrile seizures, such as GTCS, absence, atonic, myoclonic and also partial seizures. .
The afebrile seizures usually begin in childhood a continuum with febrile seizures being characteristic, occurring often after a variable seizure-free period. The prognosis is relatively benign without severe neurologic impairment. Affected members can exhibit more severe epileptic syndromes such as myoclonic astatic epilepsy (MAE), LG, and rarely DS.
GEFS+ is a heterogeneous genetic syndrome caused by more genes. The first gene is SCN1B located on 19q 13.1 encoding the beta 1 subunit of the neuronal voltage- gated sodium channel. A second gene map in the region 2q21-q33 on SCN1A as in DS and finally a third SCN2A gene is located on 2q21-q23 encoding the alfa 2 subunit of the voltage-gated sodium channel. Some patients have also expressed an abnormality in another gene of the gamma aminobutyric acid receptor (GABA A) on chromosome 5q34
Currently DS, the less severe borderline forms (SMEB) and GEFS+, are considered as a continuum of the same condition
|Sodium channel Gene for DS and GEFS+|
BFNIS (benign familial neonatal infantile seizures)
Catterall et al (2010) 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.
There is a wide variation among the phenotypes in these conditions and is possibly due to the strong influence of the genetic background.
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.
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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Nabbout R, Copioli C, Chipaux M, Chemaly N, Desguerre I, Dulac O et al. (2011) Ketogenic diet also benefits Dravet syndrome patients receiving stiripentol: a prospective pilot study. Epilepsia 52 (7):e54-7. DOI: 10.1111/j.1528-1167.2011.03107.x PMID: 21569025.
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