Diagnosis

Dravet syndrome is a clinical disorder caused by a genetic alteration, usually in the SCN1A gene. However, its diagnosis is mainly based on clinical criteria and may be made even when genetic analysis does not reveal any alteration, as is observed in around 20% of cases.

1/ Dravet syndrome diagnosis

Dravet Syndrome was first described in 1978 as « Severe Myoclonic Epilepsy in Infancy » (SMEI) by Dr Charlotte DRAVET and has been recognized throughout the world since then; and much published on.

  • According to the 1989 ILAE (International League Against Epilepsy) classification, typical Dravet syndrome is characterised by “
    febrileWith fever
    and
    afebrileWithout fever
    generalised 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 seizures types are resistant to anti-epileptic drugs (
    AEDsAntiEpileptic Drugs
    ). Developmental delay becomes apparent within the second year of life and is followed by definitive cognitive impairment and personal disorder”.
  • Because not all of these clinical signs (myoclonic seizures) were found to be present in every patient and since the syndrome persisted into adulthood, the terms ”myoclonic” and “infancy” were no longer appropriate. Therefore, in 2001, the International League Against Epilepsy changed the epilepsy syndrome name from “SMEI” to “Dravet syndrome”.
  • The exact frequency in the general population is unknown and, according to the literature, greatly varies. A 1990 estimation given by a US study gave a frequency of 1/40,000 births. This frequency was probably underestimated because the disease was not always well diagnosed. The incidence is more likely to be between 1/20,000 and 1/30,000 as published in 1992 by a French study.

Dravet syndrome seems to equally affect boys and girls and no geographic region has a particularly high or low number of cases.

A/ TYPICAL FORM

  • The clinical picture of Dravet syndrome patients is typically as follows: onset during the first year of life (generally between 4 and 8 months) following a
    febrileWith fever
    triggered seizure, usually a typical clonic generalised or unilateral long-lasting seizure (>15 minutes), sometimes even turning into
    status epilepticusSeizures lasting for more than 30 minutes
    . This first febrile seizure may coincide with a vaccination.
  • In the following weeks or months, other febrile seizures occur as well as
    afebrileWithout fever
    seizures. Over the following years, throughout the course of this syndrome other seizure types appear such as myoclonic jerks, atypical absences, obtundation status or focal seizures.
  • Despite early medication, the seizures remain, characterising it as highly pharmacoresistant.
  • During the onset period,
    EEGElectroencephalography
    recordings and neuroimaging as well as CT scans and
    MRIsMagnetic Resonnance Imaging
    usually remain normal.
  • Dravet syndrome can be defined as an encephalopathy since deterioration or stagnation of
    cognitive functions Any mental process that involves symbolic operations such as : perception, memory, creation of imagery, and thinking.
    is generally observed. Indeed from around the age of two a slowdown in development (language and motor skills) is common, as well as neurological manifestations (gait disturbance, ataxia and pyramidal signs) and some behavioural changes (lack of attention, hyperactivity and poor communication).
  • These patients are also characterised by a low epileptic threshold to external as well as internal stimuli. Stimuli may be a variation in body temperature (fever, hot bath, hot environment, physical exercise). They might also be visual (light, patterns) or just emotions. Along with these manifestations, an EEG may show generalised spike-waves and polyspike waves, focal/multifocal abnormalities.
  • Despite physical and psychological decline as well as EEG activities, no etiological factors have been identified after investigations and neuroimaging generally remains normal.
  • Since 2001, this epilepsy has also been classed as a channelopathy. It had long been suspected because of the frequent family epileptic history of Dravet children, and of the absence of etiological factors, but it was only with the discovery of mutation on the SCN1A gene that this hypothesis was confirmed.
  • Dravet syndrome is therefore an epileptic encephalopathy, usually related to a channelopathy.

B/ Incomplete forms

  • Dravet syndrome patients do not all present with the complete clinical picture. Regardless of seizure type, they all share other characteristics. Such forms used to be called severe myoclonic epilepsy borderline (SMEB) or, more appropriately, mild or incomplete forms of Dravet syndrome.
  • Other atypical features can also be observed.
  • Regarding seizures at onset, these patients may experience usually clonic
    afebrileWithout fever
    or focal seizures but located in one limb or on the face.
  • Compared to typical Dravet syndrome, they will have scarcer
    febrileWith fever
    seizures in the weeks or months following the first episode.
  • Patients who do not present myoclonic seizures but rather tonic or tonic clonic seizures were classified by Japanese authors as “High Voltage slow-wave Grand Mal syndrome”.
  • All these atypical forms have the same prognosis, genetic background and therefore fully belong to the Dravet syndrome classification.

2/ Medical exams

  • Medical examination includes:
  • Clinical examination
  • EEGElectroencephalography
    recording
  • Neuroimaging
  • Developmental and cognitive assessment

A/ Clinical signs

Clinical signs will vary as the syndrome evolves. A close examination during the three main evolution phases will allow you to notice some of the characteristic signs of Dravet syndrome.

1- Onset phase

Examination of a Dravet syndrome patient during the onset phase will reveal no pathological signs. However analysis of the semiology and of the seizure course may bring Dravet syndrome to mind.

Japanese authors tested and proposed a predictive Dravet syndrome risk factor test, to be used in children under one year of age, to help early diagnosis.

It is a two-phase test (described here below):

First phase calculation

If the calculated clinical risk score is ≥6 then genetic testing should be considered.

Second Phase: Calculation of genetic score

Overall results:

If the total calculated risk score is ≥7 then a diagnosis of Dravet syndrome should be strongly suspected.

This test was also used in Italy, confirming its utility.

2- Worsening phase

Examination of Dravet syndrome patient during the worsening phase shows hypotonia, ataxia, segmental interictal myoclonic jerks, and coordination impairment.

3- Stabilisation phase

Examination of Dravet syndrome patient during the stabilisation phase shows that motor problems may worsen, even leading to crouch gait.

 

B/ EEG recording

  • Clinical examination should be helped by
    EEGElectroencephalography
    recording. You may have at your disposal a standard EEGi, a polygraphic recording, video EEG or even ambulatory EEG monitoring.
  • If you use standard EEG, including during sleep, the exam must last at least 40 to 60 minutes. EEG during sleep is absolutely necessary for children up to the age of five. This EEG must be performed during a spontaneous sleeping period.
  • If you use the polygraphic exam you have to put the electrodes in contact with different surfaces of the body, mainly on the two deltoid muscles (
    EMGElectromyography
    ), and to record the
    ECGElectrocardiography
    .
  • If you use video EEG, you may either go for a 2 hour exam in the lab or a 24 hour bedside exam. When using such method the presence of a parent is necessary during the recording time.

When to perform an EEG?

  • For a child over one year with no neurological history, if the
    febrileWith fever
    (>38.5°C) seizure is simple, short-lasting, generalised with no postictal deficit, then the EEGi is unnecessary.
  • For a child aged less than one year, with neurological history, having a long-lasting (>5minutes), complex (complicated), unilateral, febrile (<38.5°C) seizure, with a postictal deficit, then the EEG must be performed.

1- EEG during the onset phase

  • In the vast majority of Dravet syndrome patients, the interictal
    EEGElectroencephalography
    shows normal background activity according to the patient’s age during wakefulness and the sleep period. Sometimes a rhythmic theta activity 4-5Hz may be present on centro-parietal areas and
    vertexThe uppermost surface of the head
    . If the EEG is performed immediately after a long-lasting seizure, a diffuse or asymmetrical slowing is observed.

Recording in a 9-months-old patient :

Normal symmetrical background activity when drowsy.
Normal symmetrical background activity when drowsy.

2- EEG during the worsening phase

  • Interictal
    ECGElectrocardiography
    during the wakefulness period will show a slowing down of background activity, being more pronounced if seizures are frequent. The EEG will still show rhythmical theta activity on central areas.

Recording in an awake 3-year-old patient :

Slowing of background activity, with 4Hz theta rhythms mostly on central areas.
Slowing of background activity, with 4Hz theta rhythms mostly on central areas.

Generalised, focal and multifocal abnormalities, spikes, spike-waves, multiple spike-waves, symmetrical or not, will be more frequent on central areas as well as in temporal and occipital ones.

Recording in an awake 4-year-old patient :

Slowing of background activity and rare bilateral central spikes.
Slowing of background activity and rare bilateral central spikes.

Recording in an awake 5-year-old patient :

Burst of generalised spike-waves associated with independent multifocal spikes over the frontal-central and parieto-occipital areas.
Burst of generalised spike-waves associated with independent multifocal spikes over the frontal-central and parieto-occipital areas.

Interictal EEG during the sleep period shows normal age-linked sleep patterns or the same pathological findings as in the wakefulness period. Therefore both generalised and focal spikes, and spike-waves are enhanced or appear if the seizures are more frequent.

Recording in an asleep 4-year-old patient :

Bilateral spikes, polyspikes and rare spike-waves on both central areas.
Bilateral spikes, polyspikes and rare spike-waves on both central areas.

Regarding ictal EEG, they depend on the type of seizure.

Recording in a 4-year-old patient :

Bilateral tonic-clonic seizure, EMG on the 2 deltoid muscles showing both tonic and clonic movements.
Bilateral tonic-clonic seizure, EMG on the 2 deltoid muscles showing both tonic and clonic movements.

Recording in a 6-year-old patient during a myoclonic status :

Diffuse spike-waves more marked on central areas. Clonic jerks recorded on both EMG derivations on deltoid muscles.
Diffuse spike-waves more marked on central areas. Clonic jerks recorded on both EMG derivations on deltoid muscles.

3- EEG during the stabilisation phase

  • The
    ECGElectrocardiography
    evolution is patient-dependent. Background activity will fluctuate depending on the number and duration of seizures. A particularly strong increase of theta activity in the central regions and
    vertexThe uppermost surface of the head
    , elicited by eye closure, is often observed.

A special feature during sleep is sometimes observed with focal abnormalities.

Recording in an asleep 10-year-old patient

Rare sleep spindles and subcontinuous biphasic spikes on both central regions, symmetrical or not.
Rare sleep spindles and subcontinuous biphasic spikes on both central regions, symmetrical or not.

Recording in a 12-year-old patient during a focal seizure

Focal seizure starting on the left temporal region, moving to the whole left side and to the right frontal region.
Focal seizure starting on the left temporal region, moving to the whole left side and to the right frontal region.

c/ Cognitive and behavioural assessment tests

In order to detect the first signs of abnormality, these tests should be assessed from the onset and even when development is apparently normal. These tests must be standardised and adapted to the age and cognitive level of the patient.

For example: Griffiths scale, Brunet-Lézine, Bailey, Wechsler Preschool and Primary Scale of Intelligence (WPPSI), Wechsler Intelligence Scale for Children Revised (WISC-R).

 

 

Some questionnaires may also be used, this time for parents, such as the Vineland Adaptive Behaviour Scales (VABS) and the Child Behaviour Check List (CBCL).

Testing should be repeated in order to adapt to education, pedagogic and rehabilitative methods as well as pharmacological treatments. But the frequency of the tests must be adjusted according to the patient’s age and the course of the disease.

d/ Neuroimaging

  • In most cases, at onset, Dravet syndrome patients have a normal CT scan and
    MRIMagnetic Resonnance Imaging
    .
  • During the course of the disease, neuroimaging may vary. MRI may show cerebral or cerebellar atrophy, or hippocampal sclerosis. Data issued from the literature are discordant regarding the frequency of these abnormalities.

3/ Differential diagnosis

  • There are a large number of epilepsy types, but in this section we will only discuss differences between Dravet syndrome and the most frequent ones.
  • The table below is a quick summary of the key characteristics of some of the main epileptic syndromes in comparison with Dravet syndrome.

A/ At onset

At onset it is difficult to diagnose Dravet Syndrome. Not all clinical signs are present and therefore other types of epilepsies may be considered.

1- Febrile seizures

  • febrileWith fever
    seizures occur mostly in otherwise normal developing children, aged between 9 months and 5 years. Toddlers are the most commonly affected. Brief seizures are induced by a high and rapid rise in body temperature. The vast majority of these patients will not present with epileptic seizures later on and their cognitive outcome will be normal.
  • Patients with febrile seizures may carry a mutation of the SCN1A gene, since it is possible that he suffers from an inherited
    GEFS+Genetic (Generalised) Epilepsy with Febrile Seizures more
    .
  • Should the first seizure appear in a low temperature context (<38.5°C), be long-lasting, unilateral, or with signs of lateralisation, Dravet syndrome may be considered. Prescription of an emergency antiepileptic treatment is an option for future seizures.

2- Focal epilepsy

  • Focal epilepsies often occur in infants with a perinatal history but not consistently. Other focal epilepsies may occur in normal infants without previous pathological history and with repeated
    febrileWith fever
    seizures as in Dravet syndrome, making early diagnosis difficult. During this period, no real difference may be observed regarding psychomotor development, since it may remain normal or subnormal in both Dravet syndrome and focal epilepsies. In focal epilepsies, the
    MRIMagnetic Resonnance Imaging
    may also be normal at the onset.
  • Later on the appearance of focal seizures, without myoclonus or atypical absences, may confirm a focal epilepsy. MRI should be repeated because it will be abnormal if the epilepsy is related to a structural abnormality that would have been difficult to detect in the first year of life.
  • On the
    EEGElectroencephalography
    , focal abnormalities will constantly be localised in the same region.

Recording in a 2-year-old patient suffering from a symptomatic focal epilepsy

Interictal EEG with a right posterior focus of spikes and spike-waves.
Interictal EEG with a right posterior focus of spikes and spike-waves.

The presence of alternating, usually clonic, seizures is a strong argument in favour of the diagnosis of Dravet Syndrome.

SCN1A mutation was found only in some very rare cases of patients suffering from focal epilepsy.

Carbamazepine is recommended in the treatment of focal epilepsy whereas it has been demonstrated that it worsens Dravet syndrome patients’ condition. Should you have doubts, avoid its use.

B/During evolution

In comparison with the onset age, it is easier to establish a firm diagnosis during the evolution.

 

1- Doose syndrome

  • Doose syndrome generally occurs in children aged two to four years and rarely before the age of one. Unlike for Dravet syndrome, the trigger for generalised tonic clonic seizures is not fever related.
  • Myoclonic-atonic seizures leading to abrupt falls (drop attacks) are the hallmark of Doose syndrome.
  • In both syndromes patients will experience a global cognitive decline and the
    MRIMagnetic Resonnance Imaging
    remains normal.
  • Regarding
    EEGsElectroencephalography
    , Doose syndrome patients have constant generalised spike-waves, often in long bursts without focal or multifocal abnormalities.

Recording in an asleep 4-year-old patient

Myoclonic jerks (recorded on the deltoid surface EMG) synchronous of the generalised spike-waves.
Myoclonic jerks (recorded on the deltoid surface EMG) synchronous of the generalised spike-waves.

Recording in an awake 5-year-old patient experiencing a myoclonic-atonic seizure

Falling of the body, burst of spike-waves synchronous of the myoclonic event.
Falling of the body, burst of spike-waves synchronous of the myoclonic event.

Patients with Doose syndrome do not carry an SCN1A mutation. No causative mutation is known for this syndrome.

After a period of severe and pharmacoresistant seizures, many patients may become seizure-free but their cognitive outcome often remains unfavourable.

2- LENNOX-GASTAUT SYNDROME

  • Lennox-Gastaut syndrome appears between the age of two and six years and rarely before the age of one. It is frequently caused by various lesional aetiologies (brain malformation, perinatal asphyxia, severe head injury, and central nervous system infection, inherited degenerative or metabolic condition). In cases without known aetiology, genetic analysis remains negative and no mutation is found in the SCN1A gene. Typical features of the syndrome can appear after another epilepsy type such as West syndrome, which is never observed in Dravet syndrome.
  • Lennox-Gastaut syndrome seizures are mostly atypical absences and tonic seizures occurring while awake as well as asleep. No fever sensitivity is observed in this syndrome.
  • Other seizures types can be present, such as atonic seizures (drop attacks, sometimes limited to a head drop), myoclonic seizures and focal seizures.
  • In Lennox-Gastaut syndrome there are specific
    EEGElectroencephalography
    patterns. One when awake: being interictal diffuse slow spike-waves. The other during sleep: bursts of diffuse fast rhythms of high amplitude.

Recording in an asleep 15-year-old patient

Sleep, tonic seizure with a bilateral fast activity preceding the tonic event recorded on both deltoid surface EMG.
Sleep, tonic seizure with a bilateral fast activity preceding the tonic event recorded on both deltoid surface EMG.

Recording in an awake 20-year-old patient

Tonic seizure with elevation of the 2 arms at the time of a fast activity on the tracing, followed by frontal spike-waves.
Tonic seizure with elevation of the 2 arms at the time of a fast activity on the tracing, followed by frontal spike-waves.

Adult Dravet syndrome and adult Lennox-Gastaut syndrome should be differentiated by a careful medical history so as to recognize the early typical history. Careful semiological analysis of the seizures and a prolonged video-EEG during wakefulness and sleep periods allowing interictal analysis and seizure capture may help.

Finally, genetic analysis is also necessary, knowing that the absence of the SCN1A mutation or deletion does not preclude the diagnosis of Dravet syndrome.