Dravet syndrome is a rare progressive epileptic encephalopathy that is overwhelmingly due to genetic factors. In recent years, significant progress has been made regarding the genetic mechanisms and diagnosis of Dravet syndrome.
I. Epidemiological data
The onset of Dravet syndrome is always within 1 year of age, with a peak in the first 5 months of life. The male to female ratio is about 2:1, and about 500 cases of Dravet syndrome have been reported. The prevalence of Dravet syndrome accounts for 6% of epilepsy cases with onset before the age of 3 years, and the incidence is about 1/30,000.
Clinical presentation
Dravet syndrome is characterized by four sequential signs of seizures.
1. early-onset febrile clonic convulsions in infants.
2, myoclonic seizures.
3, atypical aphasic seizures.
4. complex focal seizures.
In addition, the typical tetralogy of febrile clonic seizures, myoclonic seizures, ataxic seizures, and complex focal seizures is common in more than half of the cases of convulsive, myoclonic, and ataxic status epilepticus. The rest of the cases may lack one of these features. Myoclonic seizures were once thought to be the typical form of seizures in this syndrome and can precede febrile convulsions.
Most refractory seizures occur all at once, and progressive neuropsychiatric decline characterizes Dravet syndrome.
The syndrome evolves in 3 stages.
Stage 1 (early): relatively mild clinical symptoms, manifested by febrile convulsions and febrile convulsive epilepsy continuum.
Stage 2 (middle stage): severe clinical symptoms, manifesting as multiple forms of intractable seizures.
Stage III (late): clinical symptoms are quiescent and seizures improve but are accompanied by severe psychomotor sequelae.
(I) Stage I with predominantly febrile convulsions
In the first stage (early), the clinical symptoms are relatively mild, and the seizures mostly appear with fever and manifest as unilateral or generalized, transient or sustained clonic seizures.
All patients present with convulsive seizures within 1 year of age (peak onset at 5 months of age), typically starting with febrile convulsions. The seizures consist of unilateral and, less commonly, bilateral clonic convulsions, mixed with some tonic components. Seizures are generally long in duration (more than 10 minutes) and often (in about a quarter of cases) progress to convulsive status epilepticus.
Seizures in three-quarters of children are often precipitated by a fever of about 38°C, a mild infection, vaccination, or a hot bath. The remaining one-third of cases present without febrile convulsions. Isolated myoclonic seizures and, more rarely, focal seizures may precede febrile convulsions. frequent seizures for 6-8 weeks, after which febrile convulsion-free seizures may also occur.
This stage lasts from 2 weeks to 6 months before progressing to the second stage.
(ii) Severe second stage
In the second (middle) stage, clinical symptoms are severe, with multiple seizure forms and severe neurocognitive decline. Multiple forms of seizures, such as febrile or non-febrile seizures, myoclonic seizures, atypical aphasic seizures, and complex focal seizures, often evolving into status epilepticus, are present daily.
1. Convulsive seizures (febrile or ataxic)
The seizures in this phase are similar to the first phase, but they are more frequent and last longer.
2. Clonic seizures
Often appear between 1 and 4 years of age, on average 1-2 years from onset. Some cases may appear earlier, sometimes even before febrile convulsions, with cluster myoclonic seizures. Myoclonic episodes occur as phasic or generalized, phasic myoclonus involving the facial muscles and extremities (distal predominant), and generalized myoclonus involving mainly the trunk muscles, resulting in flexion or extension of the trunk muscles, often leading to falls. Frequent myoclonic seizures are characteristic of this syndrome, and myoclonic seizures can be characterized by clustered outbursts but no significant impairment of consciousness when they are sustained. However, some children have myoclonic seizures that occur only a few hours or days before a convulsive episode. Myoclonus is often intense, but it can also be mild, unnoticeable, or only detectable by clinical examination or video EEG. One fifth of children present with mild segmental myoclonic seizures.
3. Atypical akathisia seizures
40-93% of children have atypical aphasic seizures of short duration (5-6 seconds) with moderate impairment of consciousness, often accompanied by myoclonic jerking and nodding of the upper limbs.
4. Complex focal seizures
Nearly half of the children present with focal seizures, which take various forms, such as atonic seizures, or with a deflection component, autonomic symptoms (pallor and perioral cyanosis), and automatism. Focal seizures may occasionally progress to GTCS.
5. Persistent status epilepticus
Myoclonic, atypical disorientation, complex partial seizures and convulsive epileptic status epilepticus are common and can occur alone or in combination. The various epileptic continuations can last for hours or days and can be triggered by light stimulation, closed eyes, or graphic patterns.
Atypical aphasic seizures with reduced responsiveness are often accompanied by gait instability, salivation, marked ataxia, and wandering mild myoclonus, sometimes with increased muscle tone. Typically, complex focal epileptic states are less common than pure focal epileptic states. Wandering mild myoclonic seizures with paroxysmal GSWD EEG changes can last for hours or days.
6. Cognitive and neurological decline
All children show varying cognitive deficits, usually more severe, usually appearing between 2 and 6 years of age (with a peak around 1 year of age), and relatively stable thereafter. This is followed by progressive neurological deficits such as ataxia, pyramidal fasciculus symptoms, and also paroxysmal motor deficits.
(iii) Stage 3 (waning phase)
In the third (late) stage, the clinical symptoms are quiescent and the seizures may improve, but severe neuropsychological dysfunction persists. Symptoms usually cease to progress by 11-12 years of age, which marks the third stage of the disease, a period in which seizures improve but do not completely disappear.
1. Convulsive seizures are the type of seizures that last the longest. During this stage seizures become less severe and less frequent, occurring mainly in the early morning hours. Fever can still induce convulsive seizures, which manifest as generalized tonic-clonic or clonic-tonic-clonic seizures, with seizure onset and often with a focal component during or at the end of the seizure. Seizures that occur during the day may present as tonic convulsions limited to a phase of the face or limbs, followed by decreased muscle tone and sleep. Febrile convulsive states may persist into adolescence.
2. Complex focal seizures with autonomic symptoms and hypotonia tend to disappear, but may also persist.
3. Myoclonic seizures, phasic myoclonus, and atypical aphasic seizure persistence tend to decrease or disappear and may be exacerbated by fever.
Cognitive and neurological deficits and signs can persist and no longer worsen.
I. Triggers of Dravet syndrome seizures
Febrile illness, elevated body temperature, and high ambient temperature (hot baths) are common triggers, especially at the beginning of the onset, and can also persist into adolescence (febrile convulsions additionally). Elevated body temperature is the precipitating factor, independent of the cause of the elevated body temperature. GSWD, myoclonic seizures and aphasic seizures can be triggered by light and graphic stimuli, movement and eye closure, and in a quarter of cases they can be triggered by light stimulation, by wiggling the finger in front of the eyes or by graphic stimulation.
Dravet syndrome
Dravet syndrome is mainly caused by genetic factors, but the mechanism of inheritance is unknown. About half of the children have a family history of multiple epilepsy syndromes (including idiopathic generalized epilepsy) and a history of febrile convulsions.
Children with Dravet syndrome have a high rate of mutations in the SCN1A gene (35%-100%) and may have a combination of other mutations, the mechanism of which is unclear.
Diagnosis of Dravet syndrome
Dravet syndrome is not recognized as a metabolic abnormality and mitochondrial disease is rare, but other causes of progressive infantile myoclonic epileptic encephalopathy need to be excluded.
(i) Genetic analysis
Genetic analysis is not specific and the presence of a severe SCN1A gene defect is strong evidence for the diagnosis of Dravet syndrome, the diagnosis of which must be clinically dependent.
(ii) Brain imaging
CT and MRI of the brain are normal or show mild atrophy of the brain or cerebellum.
(iii) Electroencephalographic EEG
Progressive changes from normal to severe abnormalities, similar to the clinical progression.
1. Interictal EEG
The earliest, interictal EEG is mostly normal. About 20% of children have spike-wave or multi-spike slow-wave paroxysmal responses.
Two-thirds of the children have significant EEG abnormalities within 1 year. Sleepiness and sleep are the main contributing factors to paroxysmal EEG abnormalities.
2. EEG in the seizure phase
The EEG during seizures varies depending on the form of the seizure. Myoclonic seizures are often, but not always, accompanied by full-blown multiple spikes and slow waves.