Emma Losito and Rima Nabbout
Dravet syndrome is classified in the group of epileptic encephalopathies (Berg et al. 2010), where the epileptic activity itself contributes to the final cognitive and behavioural impairment (Nabbout and Dulac 2003). Up to 80% of patients with Dravet syndrome present a genetic basis (Depienne et al. 2009; Marini et al. 2011). However, as for many of genetic epileptic encephalopathies, the impact of seizures, EEG abnormalities, treatments and genetic mutations on the global outcome is not clear.
Dravet syndrome was first described by Charlotte Dravet in 1978 under the terminology of severe myoclonic epilepsy in infancy (Dravet 1978). It was recognized as an epileptic syndrome in 1989 by the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) (1989). Typical Dravet syndrome is characterised by ‘febrile and afebrile 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. Seizures are resistant to antiepileptic drugs (AEDs). Developmental delay becomes apparent within the second year of life and is followed by definite cognitive impairment and personality disorders’ (Commission on Classification and Terminology of the International League Against Epilepsy 1989).
The course of the epilepsy in Dravet syndrome can be divided into three stages (Bureau and Dalla Bernardina 2011; Dravet and Guerrini 2011). The first or “febrile stage” is characterized by the occurrence of the first seizure at the age of less than 1 year and mainly between the ages 3 and 9 months in a previously normal infant. The first seizure is usually febrile (70% of patients), convulsive and related to fever due to febrile illness or vaccination. Typically, the seizure is clonic with a focal onset and invading one side of the body (hemiclonic). It can generalize secondarily. The seizure usually lasts for longer than15 minutes, and can evolve into status epilepticus if not treated. Neurological examination is normal and might reveal transient unilateral motor deficit on the same side of the hemiclonic seizure. EEG and MRI are normal at this stage. This first seizure is often considered as a complicated febrile seizure (in opposition to simple febrile seizures because of the focal onset and the long duration) and the diagnosis of Dravet syndrome is rarely suspected. Shortly after, often within a few weeks, other seizures occur despite the initiation of therapy with AEDs. Seizures can be febrile or not, brief or long lasting. At this stage, the diagnosis should be highly suspected especially in case of alternating hemiclonic seizures. This sequence is highly pathognomonic and should not be wrongly considered as complicated febrile seizures.
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
The cognitive outcome in patients with Dravet syndrome is usually considered poor (Giovanardi-Rossi et al. 1991; Yakoub et al. 1992; Wang et al. 1996; Caraballo and Fejerman 2006) (Table 12.1). Few papers described the time course of psychomotor and cognitive development (Fig 12.1) (Cassé-Perrot et al. 2001; Wolff et al. 2006; Ragona et al. 2010; 2011; Nabbout et al. 2013).
The development is reported as normal before the onset of seizures and during the first months after seizures (Dravet et al. 2002; 2005a; 2005b). In one paper focusing on the early developmental profile, Chieffo et al. (2011b) suggested, on a small series of five patients, that some slight abnormalities might be present when patients are tested during the first months after onset. Five patients, with a diagnosis of Dravet syndrome, were longitudinally followed up from the clinical onset (follow-up between 24mo and 42mo) and underwent a full assessment, including global development, visual functions and behaviour. Four of them showed an early impairment of visual functions, preceding the cognitive decline, appearing between 6 and 30 months.
A progressive stagnation of acquisitions is observed from the age of 18 months to 2 years until the instauration of an intellectual disability, generally reported after the age of 4 years followed by a stabilisation after the age of 6–7 years. The decline in the developmental quotient is constant although variable in different studies (Wolff et al. 2006; Ragona et al. 2011; Nabbout et al. 2013). This delay is often heterogeneous and might affect differently the specific skills (Wolff et al. 2006; Nabbout et al. 2013).This decline results from the stagnation of the psychomotor development and is not due to a regression as in neurodegenerative diseases (Ragona et al. 2011; Nabbout et al. 2013).
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.
Nabbout et al. (2013) reported 4 patients with normal IQ aged more than 5 years in a large series of 67 patients. They all presented SCN1A mutation, three received the tritherapy (Valproate, stiripentol, Clobazam) and two were almost seizure free.
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.
In a prospective and retrospective study, Nabbout et al. (2013) have reported 67 patients with typical Dravet syndrome and described their cognitive development using the Brunet-Lezine scale (Joose 1997). They have observed that developmental quotient DQ/IQ decreased with age (in all except for four patients), from a normal score before 2 years to below the normal score after 4 years. Comparing the four tested domains in this scale (hand–eye coordination, language, posture and sociability), they observed that hand–eye coordination sub-scores (oculomotor abilities) were significantly lower than the three others. Villeneuve et al. (2014) have evaluated the IQ (Wechsler Intelligence Scale) and adaptive scores (Vineland Adaptive Behavioural Scale) in 21 patients aged 6 to 10 years. They have observed a significant deficit in executive functions (verbal planning, auditory and working memory, visuomotor abilities, visuospatial organisation and fine motor skills), and they have related it to a possible ‘dysexecutive syndrome’.