Dravet Syndrome diagnosis

Dravet syndrome is a clinical disorder often caused by a genetic mutation of the SCN1A gene. However, its diagnosis is based on clinical criteria.

Signs and symptoms

Typical form

The clinical description of Dravet syndrome includes (Dravet et al. 1978; Dravet et al. 2011):

Examination of patients with Dravet syndrome during the first year of life (onset phase) reveal no pathological signs. However, analysis of the semiology and of the seizure course may bring Dravet syndrome to mind. EEG recordings and neuroimaging, as well as CT scans and MRIs, usually remain normal.

By the age of two, typical forms present a worsening phase characterised by the appearance of other types of seizure(myoclonic jerks, atypical absences, obtundation status or focal seizures), lack of coordination (ataxia), developmental delay and low muscle tone (hypotonia).

After the age of five (stabilization phase) motor functions and gait may worsen over time leading to decreased mobility and even crouch gait.

For more information, please refer to the course section.

Incomplete forms

Patients with Dravet Syndrome do not all present 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 (Guerrini et al. 2011).

Other atypical features can also be observed.

Regarding seizures at onset, these patients may experience usually clonic afebrile or focal seizures but located in just one limb or on the face.

Compared to typical Dravet syndrome, they will have scarcer febrile 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 do not have the same prognosis.

All patients with Dravet Syndrome, typical or incomplete forms, have their own history, phenotype and expression of the disease.

Medical exams

Medical examination includes:

  • Clinical examination
  • Electroencephalogram (EEG) recording
  • Neuroimaging (MRI and CT scan)
  • Developmental and cognitive assessment
When to perform an EEG ?

EEG is unnecessary for a child over one year of age with no neurological history, if the febrile (>38.5°C) seizure is simple, short-lasting and generalised with no postictal deficit.

EEG must be performed for a child aged less than one year, with neurological history, having a long-lasting (>5 minutes), complex (complicated), unilateral, febrile (<38.5°C) seizure, with a postictal deficit.

Neuroimaging

In most cases, at onset, patients with Dravet syndrome have normal CT and MRI scans.

During the course of the disease, neuroimaging may vary. MRI may show cerebral or cerebellar atrophy, or hippocampal sclerosis but data issued from the literature is discordant regarding the frequency of these abnormalities (Dravet et al. 2011).

Differential diagnosis

There are many types of epilepsy sharing some features with Dravet syndrome. In this section, you can learn more about the differences between Dravet syndrome and the most frequent types of epilepsy.

The table below provides a quick summary of the key characteristics of some of the main epileptic syndromes in comparison with Dravet syndrome.

Summary of the key characteristics of some other pathologies in comparison with Dravet syndrome, from Catherine Chiron (2018)

Febrile seizures
Focal epilepsy
Doose Syndrome
Lennox-Gastaut Syndrome
PCDH19

FEBRILE SEIZURES

A febrile seizure is a convulsion that occurs in young children and is triggered by fever/a spike in body temperature (>38°C). The fever may accompany common childhood illnesses such as a cold, the flu, or an ear infection. It occurs mostly in normal developing children, aged between 6 months and 5 years, without a history of neurological symptoms. Febrile seizures are classified as simple or complex:
– Simple febrile seizures: the most common, they last from a few seconds to 15 minutes and do not recur within a 24-hour period. They are not specific to one part of the body.
– Complex febrile seizures: they last longer than 15 minutes and occur multiple times within a 24-hour period. They are confined to one side of the body.

The vast majority of febrile seizures are short and do not cause any long-term damage (cognition). Most of the children will not present epileptic seizures again.

Patients with febrile seizures may carry a mutation within the SCN1A gene, since it is possible that they suffer from inherited GEFS+.
Should the first seizure appear in a low fever context (<38.5°C), be long-lasting, unilateral, or with signs of lateralisation, Dravet syndrome may be considered. Prescription of emergency anti-epileptic treatment is an option to prevent prolonged seizure (Dravet and Guerrini, 2011).

FOCAL EPILEPSY

Focal epilepsy is a neurological condition characterized by seizures arising from one specific part (lobe) of the brain. It often occurs in infants with a perinatal history, but this is not always the case. Focal epilepsies may occur in normal infants without previous pathological history and with repeated febrile seizures as in Dravet syndrome, making early diagnosis difficult. At onset, no 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 MRI may also be normal at onset (Dravet and Guerrini, 2011).

Later, the appearance of focal seizures without myoclonus or atypical absences may confirm 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 (Dravet and Guerrini, 2011).

Focal abnormalities will always be localised in the same region with EEG recordings (Sarisjulis et al. 2000). The presence of alternating, hemiclonic seizures is a strong indicator in favour of the diagnosis of Dravet syndrome (Sarisjulis et al. 2000).
SCN1A mutation was found only in some very rare cases of patients suffering from focal epilepsy (Okumura et al. 2007).
Carbamazepine is recommended in the treatment of focal epilepsy (Chen et al. 2020), whereas it is known to worsen seizures and should be avoided in patients with Dravet syndrome (Guerrini et al. 1996; Cross et al. 2019).

DOOSE SYNDROME

Doose syndrome, also known as Myoclonic Astatic Epilepsy (MAE), is an epilepsy syndrome of early childhood, usually appearing between ages 1 and 5 and featuring generalised tonic clonic seizures (GTCS). Unlike Dravet syndrome, generalised tonic-clonic seizures are not triggered by fever (Guerrini et al. 2005).

Doose syndrome is characterized by drop attacks (myoclonic-atonic seizures) leading to abrupt falls. It causes an immediate loss of muscle tone and strength. All or most of the muscles in the body may go limp, including the legs and arms (Dravet and Guerrini, 2011).

In both syndromes, patients experience an overall cognitive decline while the MRI remains normal.

Regarding EEGs, patients with Doose syndrome have constant generalised spike-waves, often in long bursts without focal or multifocal abnormalities (Dravet and Guerrini, 2011).

Patients with Doose syndrome do not carry an SCN1A mutation. Doose syndrome is idiopathic, meaning the cause is not yet known (Dravet and Guerrini, 2011).

Seizures in Doose syndrome are often resistant to medication but it can be improved by lamotrigine. Lamotrigine is generally not recommended in Dravet syndrome. After a period of severe and pharmacoresistant seizures, many patients may become seizure-free but their cognitive outcome often remains unfavourable.

LENNOX-GASTAUT SYNDROME

Lennox-Gastaut syndrome is a severe form of epilepsy that typically appears in children between the ages of 2 and 6 years. 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). Genetic analysis remains negative and no mutation is found in the SCN1A gene. Typical features of the syndrome can appear after another type of epilepsy such as West syndrome, which is never observed in Dravet syndrome (Dravet and Guerrini, 2011).

The most common types of seizures associated with Lennox-Gastaut syndrome are tonic and atonic seizures (drop attacks, sometimes limited to a head drop) and atypical absences. Additional types of seizures can affect patients with Lennox-Gastaut syndrome, including myoclonic seizures, tonic-clonic seizures and partial seizures. Unlike Dravet syndrome, no fever sensitivity is observed in this syndrome (Dravet and Guerrini, 2011).

In Lennox-Gastaut syndrome there are specific EEG patterns. One, interictal diffuse slow spike-waves, occurs when awake. The other, bursts of diffuse fast rhythms of high amplitude, occurs during sleep (Dravet and Guerrini, 2011).

Adult patients with Dravet syndrome and adults with Lennox-Gastaut syndrome should be differentiated by carefully looking at their medical history to look for signs of 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 does not preclude the diagnosis of Dravet syndrome.

PCDH19

PCDH19 epilepsy is a rare epilepsy syndrome with early onset seizures, cognitive and sensory delays, and behavioural problems. It is caused by a mutation of the PCDH19 gene found on the X chromosome (Dravet and Guerrini, 2011).

PCDH19 mutation may appear de novo (new to the patient) or may be inherited (please refer to the the genetic causes part for definition of de novo and heredity).

Males who can carry the PCDH19 gene mutation on their only X chromosome are typically not affected. In contrast, 90% of women who have the PCDH19 gene mutation on one of their two X chromosomes have symptoms (Depienne et al. 2009).

Seizures usually start between 3 months and 3 years of age, usually during an episode of fever. Seizures may become less frequent later in childhood and adolescence. They include generalised tonic-clonic, tonic, clonic, complex partial, atypical absence, myoclonic, and atonic seizures (Dravet and Guerrini, 2011).