The second stage (18mo to 5y) is characterized by the onset of various seizure types, the beginning of cognitive slowing and the appearance of gait disturbance. The syndrome becomes evident and the diagnosis cannot be missed at this stage. Fever sensitivity remains frequent; in addition, exercise and external heat can be the major trigger factors. Pattern sensitivity can also occur at this stage. Various seizure types appear between 18 months and 4–5 years: atypical absences, focal seizures, brief myoclonic seizures or myoclonic non-convulsive status described as “obtundation status” (status with consciousness impairment of variable intensity) (Yakoub et al. 1992; Dravet et al. 2005a).

At this stage, neurological signs are observed in some of the patients: gait delay and gait disturbances in almost 60% of patients resembling ataxia but with no signs of cerebellar involvement, such as nystagmus or dysmetria, and moderate pyramidal signs.

The third stage is reported in the literature as ‘stabilization stage’. This stabilization is not synonymous with improvement but with the chronicity of the ongoing symptoms. Seizures remain pharmacoresistant, and although they tend to decrease in some patients, they can remain active in many others, and only a few patients became seizure free despite polytherapies. Nocturnal seizures might become predominant with a decrease in convulsive diurnal seizures (Dravet et al. 2005b). Fever sensitivity persists at this stage.

More than 800 mutations have been associated with Dravet syndrome, randomly distributed across the SCN1A protein. Most mutations are de novo, and approximately 5%–10% are inherited from an unaffected parent (Depienne et al. 2009; Ragona et al. 2010; Marini et al. 2011; Caraballo et al. 2013).

The cognitive and behavioural outcome

Fig. 12.1 The course of Dravet syndrome in three stages with the clinical and cognitive states at each stage.

Some variability has been reported with the onset of the stagnation of acquisitions later up to the fourth year (Guzzetta 2011; Nabbout et al. 2013).

Nonetheless, a few patients corresponding to the diagnostic criteria for Dravet syndrome had preserved intellectual abilities over 6 years of life. Buoni et al. (2006) reported a 13-year-old boy with a normal IQ (125 at the Wechsler Intelligence Scale for Children-Revised). He presented a de novo frameshift mutation in the exon 14 causing a premature termination (c.2528delG). The authors attributed the normal cognitive development to the reduction in the frequency of seizures. Chieffo et al. (2011a), in a longitudinal clinical and neuropsychological evaluation of 12 patients with Dravet syndrome, reported 1 patient presenting a borderline IQ score at 6 years, who reached again the normal range in the last evaluation at 9 years. This was the only patient who was seizure free in their small series.

Patients with Dravet syndrome often present characteristic neuropsychiatric comorbidities, in particular hyperactivity, attention deficit, opposing and provocative behaviours, anxiety-like behaviours, impaired social interactions, restricted interests and poor danger awareness (Giovanardi-Rossi et al. 1991; Yakoub 1992; Wang et al. 1996; Caraballo and Fejerman 2006; Wolff et al. 2006; Genton et al. 2011; Brunklaus et al. 2012; Li et al. 2011; Nabbout et al. 2013; Villeneuve et al. 2014).

Wolff et al. (2006), in their prospective study, have clinically observed hyperactivity, poor relational capacities and gestural stereotypies in 18 of 20 patients.

Through the Achenbach and Conners scales, Nabbout et al. (2013) have observed attention deficit and hyperactivity, reaching the highest pathological scores (Conners test hyperactivity score >70) between 2 and 5 years.

In adulthood, these behavioural disorders tend to change, in particular with an improvement in attention deficit and hyperactivity replaced by extreme slowness and perseveration in movement, thinking and verbal expression (Scheffer and Dravet 2014).

Patients with Dravet syndrome might present some traits within the spectrum of autism spectrum disorders but without the involvement of the three main domains: stereotypical behaviours, social interactions and verbal and non-verbal communication. Li et al. (2011) have evaluated 37 Dravet syndrome patients with the DSM-IV, criteria, the Autism Behaviour Checklist and the Childhood Autism Rating Scale. Patients were aged from 2 to 6 years, and 9 of 37 patients had a diagnosis of autism, and most of the remaining showed some traits without fulfilling the criteria for autism. The mostly affected domains were verbal communication, narrow interests and emotional reciprocity (Li et al. 2011). There was no difference in the clinical characteristics of epilepsy between patients with and without autism. In another series of 21 patients aged 6 to 10 years assessed by the Vineland Adaptive Behaviour Scale, communication was significantly more affected than socialisation (Villeneuve et al. 2014). The authors also suggested that patients can present some autistic traits, but they do not fulfil all the criteria of autism.

Cognitive profiles in Dravet syndrome

In an attempt to better define the cognitive profile, three main domains of intellectual abilities have been reported as compromised: (1) executive functions, (2) the output of the language more than its comprehension and (3) visual functions.