Hostname: page-component-758b78586c-qzq9q Total loading time: 0 Render date: 2023-11-27T20:29:03.207Z Has data issue: false Feature Flags: { "corePageComponentGetUserInfoFromSharedSession": true, "coreDisableEcommerce": false, "useRatesEcommerce": true } hasContentIssue false

Dravet Syndrome: Diagnosis and Long-Term Course

Published online by Cambridge University Press:  06 June 2016

Mary B. Connolly*
Department of Paediatrics, British Columbia’s Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada
Correspondence to: Mary Connolly, Clinical Professor of Paediatrics (Neurology), Head, Division of Paediatric Neurology, and Director of the Epilepsy Program, British Columbia’s Children’s Hospital, 4480 Oak Street, Vancouver, British Columbia V6H 3V4, Canada. Email:
Rights & Permissions [Opens in a new window]


Dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality. The typical presentation is characterized by hemiclonic or generalized clonic seizures triggered by fever during the first year of life, followed by myoclonic, absence, focal and generalized tonic-clonic seizures. Non-convulsive status epilepticus and epileptic encephalopathy are common. Development is normal in the first year of life, but most individuals eventually suffer from intellectual impairment. Dravet syndrome is associated with mutations in the sodium channel alpha1 subunit gene (SCN1A) in 70-80% of individuals. SCN1A mutation results in inhibition of the GABAergic inhibitory interneurons, leading to excessive neuronal excitation. The “interneuron hypothesis” is the current most accepted pathophysiological mechanism of Dravet syndrome. The mortality rate is increased significantly in Dravet syndrome. Ataxia, a characteristic crouched gait and Parkinson’s symptoms may develop in some individuals. It is likely that Dravet syndrome is underdiagnosed in adults with treatment-resistant epilepsy. Early diagnosis is important to avoid anti-seizure medications that exacerbate seizures.

Copyright © The Canadian Journal of Neurological Sciences Inc. 2016 


Dravet syndrome (previously known as “severe myoclonic epilepsy of infancy”) was first described by Dr. Charlotte Dravet in 1978.Reference Dravet 1 It is an early-onset treatment-resistant epilepsy syndrome that typically presents during the first year of life. The incidence of Dravet syndrome is estimated at 1 per 22,000-40,000 based on studies in the United Kingdom and Denmark,Reference Brunklaus, Ellis, Reavey, Forbes and Zuberi 2 , Reference Bayat, Hjalgrim and Moller 3 and it affects males twice as often as females. It typically causes an epileptic encephalopathy. In 2001, Claes and colleaguesReference Claes, Del-Favero, Ceulemanns, Lagae, Van Broeckhoven and De Jonghe 4 discovered mutations in the sodium channel alpha1 subunit gene SCN1A in seven individuals with Dravet syndrome. SCN1A mutations, usually de novo, are found in 70 to 80% of patients with Dravet syndrome. It is now appreciated that the electroclinical features of Dravet syndrome are broader than the original description and that the myoclonic seizures or generalized spike and wave are not present in all patients. Focal seizures that may evolve to generalized convulsive seizures are the dominant seizure type in some individuals and are associated with multifocal EEG abnormalities. With the wider application of new genomic technologies in the diagnosis of epilepsy of unknown cause, it is recognized that other genetic abnormalities (PCDH19, GABRG2, SCN1B and SCN2A) may cause a similar phenotype as Dravet syndrome.

Clinical Presentation and Evolution of Epilepsy in Dravet Syndrome

Seizure onset is typically in the first year of life, with prolonged, febrile and afebrile hemiclonic or generalized clonic seizures in previously healthy children. They may be associated with vaccinations or hyperthermia, including a warm bath. Over the subsequent months, affected individuals experience recurrent febrile and afebrile seizures that often affect alternate sides of the body. Between one and four years of age, other seizure types develop, including myoclonic and atypical absences, focal seizures and generalized tonic-clonic seizures. Focal seizures, with or without impairment of awareness, may be associated with such prominent autonomic features as pallor, cyanosis and drooling, and may evolve into a focal motor or bilateral convulsive seizure. Tonic seizures are reported to be uncommon in Dravet syndrome. In some individuals, myoclonic seizures do not develop and other seizure types, particularly focal or multifocal seizures, are the predominant seizure types.

In a retrospective surveyReference Xu, Zhang, Sun, Liu, Yang and Xiong 5 of 138 children with Dravet syndrome with SCN1A mutations from China, seizure onset was before the age of 7 months in 77%. 72% of the children in that study had febrile seizures with a duration longer than 15 minutes, and 67% had two or more febrile seizures within a 24-hour period. Seizures were hemiclonic with fever in 80%.Reference Xu, Zhang, Sun, Liu, Yang and Xiong 5 In a study of 96 children who had febrile seizures prior to one year of age, 46 of whom had Dravet syndrome and 50 of whom did not, the factors that correlated significantly with Dravet syndrome were onset of febrile seizures under the age of 7 months, 5 or more seizures, duration of seizures longer than 10 minutes, hemiconvulsions, focal seizures, myoclonic seizures and hot-water-induced seizures.Reference Hattori, Ouchida, Ono, Miyake, Maniwa and Mimaki 6 Reflex seizures are frequent, and the most common trigger is hyperthermia (fever, immersion in hot water, intense physical exercise or high ambient temperature).

Status epilepticus occurs commonly in Dravet syndrome, both the convulsive and non-convulsive types. Non-convulsive status epilepticus is also described in the literature as “obtundation status epilepticus.” Obtundation status epilepticus is characterized by altered awareness, autonomic symptoms and subtle myoclonus that commonly involves the fingers and orobuccal muscles, and it may last for many hours or days.Reference Bureau and Dalla Bernardina 7 Status epilepticus may be life threatening, and the symptoms and signs of non-convulsive status epilepticus may be subtle and difficult to appreciate. Thus, it is of utmost importance to educate parents and caregivers about the early symptoms and signs of non-convulsive status epilepticus. It is also very important to put an individualized emergency (rescue) management plan in place for each individual so as to facilitate early intervention to prevent prolonged status epilepticus and its associated complications.

With respect to the evolution of epilepsy over time, seizures tend to become less frequent and severe in adolescence and adulthood. Fever sensitivity persists but has less impact. Myoclonic, atypical absence and focal seizures with altered awareness are less common in adulthood.Reference Genton, Velizarova and Dravet 8 The most common seizure type in adulthood is generalized tonic-clonic, which may be focal in onset and occurs mainly during sleep. Patients may also experience bilateral or asymmetrical posturing, which may be followed by tonic vibratory or clonic movements. However, there are few studies that describe in detail the electroclinical features of the seizure types in Dravet syndrome during adolescence or adulthood. Ictal recordings of five adults revealed subclinical focal seizures in three, focal seizures that evolved into bilateral convulsive seizures (secondarily generalized tonic-clonic seizures) in three, obtundation status in one and tonic events in another patient.Reference Genton, Velizarova and Dravet 8 In a long-term studyReference Caraballo and Fejerman 9 of 53 children aged 4 to 14 years who were followed for from 3 to 14 years, seizure frequency was weekly in 74%, monthly in 13% and daily in 13%. The most common treatments employed in this study were valproic acid, clobazam and a ketogenic diet.

Takayama and colleaguesReference Takayama, Fujiwara, Shigematsu, Imai, Takahashi and Yamakawa 10 described 64 patients followed at one epilepsy center in Japan. The median age at last follow-up was 30 years (range=19-45), and only 1 of 44 individuals with typical Dravet syndrome was in remission, in contrast with 4 of 20 individuals with atypical Dravet syndrome. In this study, atypical Dravet syndrome was characterized by absence of myoclonic and atypical absence seizures.

EEG Evolution in Dravet Syndrome

The EEG is typically normal during the first year of life. Subsequently, the EEG background may be normal or slow. Sleep architecture is typically preserved. Generalized spike and wave, polyspike wave and multifocal spikes are common.

Few studies have carefully documented the evolution of EEG findings over time in Dravet syndrome. Speechio and colleaguesReference Specchio, Balestri, Trivisano, Japaridze, Striano and Carotenuto 11 described EEG findings in 22 children with Dravet syndrome over the first five years following diagnosis. In all these children, the EEG background was normal, but background slowing was seen in 27% after six months. Epileptiform discharges were present in 27% at seizure onset and in 64% by 5 years follow-up. Multifocal epileptiform discharges were observed in 57%, focal epileptiform discharges in 29%, and 14% had generalized epileptiform discharges. A photoparoxysmal response was seen in 9% at seizure onset and in 41% by the end of the study. In a study of 16 children, Korff et al.Reference Korff, Laux, Kelley, Goldstein, Koh and Nordli 12 reported that the EEG was abnormal in 81%. However, at the time of seizure onset, the EEG was abnormal in only 25% of the children. The most common epileptiform pattern consisted of generalized spike wave discharges.Reference Korff, Laux, Kelley, Goldstein, Koh and Nordli 12

In a study of 23 patients in whom seizures were recorded during video-EEG monitoring, Kim and colleaguesReference Kim, Nordli, Berg, Koh and Laux 13 divided patients into three groups: 0-5 years (n=7), 6-10 years (n=11) and 11 years and older (n=5). Slowing of the EEG background was more common in older patients and a photoparoxysmal response in younger children. Epileptiform discharges were found in most patients, and the most common pattern was multifocal epileptiform discharges.

Nabbout et al.Reference Nabbout, Desguerre, Sabbagh, Depienne, Plouin and Dulac 14 also described five adolescents with Dravet syndrome who had bifrontal spike and slow wave and generalized fast polyspikes in sleep, features similar to Lennox–Gastaut syndrome. In another study of EEG evolution in 24 patients with Dravet syndrome, Genton et al.Reference Genton, Velizarova and Dravet 8 described normal EEG background in 8 and slow and disorganized background in 11. Epileptiform activity was multifocal in 11, focal in 7 and generalized in 6. Photosensitivity and pattern sensitivity tended to disappear by 20 years of age.

There is still an opportunity to add to the literature on the evolution of the electroclinical features of Dravet syndrome with SCN1A mutations over time, and additional ictal EEG data would be very informative.

Family History of Epilepsy/Febrile Seizures

The first report of SCN1A mutations in epilepsy was in the syndrome of genetic epilepsy with febrile seizures plus.Reference Escayg, MacDonald, Meisler, Baulac, Huberfeld and An-Gourfinkel 15 A family history of epilepsy or febrile seizures has been observed in 15-35% of individuals with Dravet syndrome, and the most common phenotype seen in affected relatives is genetic epilepsy with febrile seizures plus.Reference Singh, Andermann, Whitehouse, Harvey, Keene and Seni 16 Dravet syndrome has been reported in monozygotic twins and rarely in zygotic twins. There are also rare reports of two or more affected children in the same family. Somatic or germline mosaic mutations may explain an unaffected or mildly affected parent, and in one studyReference Depienne, Trouillard, Saint-Martin, Gourfinkel-An, Bouteiller and Carpentier 17 mosaicism was found in 7% of families with Dravet syndrome. The observation of a positive family history of febrile seizures and epilepsy in individuals with Dravet syndrome and de novo mutations in SCN1A suggest that the mode of inheritance is polygenic and that other modifier genes such as SCN9A contribute to the phenotype.

Genetic Testing in Dravet Syndrome

The first mutations in the SCN1A gene in seven individuals with Dravet syndrome were discovered by Claes and colleaguesReference Claes, Del-Favero, Ceulemanns, Lagae, Van Broeckhoven and De Jonghe 4 in 2001. It is now recognized that SCN1A mutations are seen in 75-80% of individuals with Dravet syndrome. More than 500 mutations have been reported in individuals with Dravet syndrome. Mutations are truncating in 40-50%, missense in 40% and splice site in the remainder. Whole-gene deletions are observed in 2-3%, and gene duplications are rare. Most gene mutations are de novo, but familial mutations occur in 5-10% and are usually missense.Reference Claes, Del-Favero, Ceulemanns, Lagae, Van Broeckhoven and De Jonghe 4 , Reference Nabbout, Gennaro, Dalla Bernardina, Dulac, Madia and Bertini 18 , Reference Wallace, Hodgson, Grinton, Gardiner, Robinson and Rodriguez-Casero 19

Truncating, nonsense and frameshift mutations and gene deletions correlate with the classical Dravet syndrome phenotype with an earlier age at onset.Reference Marini, Mei, Temudo, Ferrari, Buti and Dravet 20 , Reference Marini, Scheffer, Nabbout, Suls, De Jonghe and Zara 21 Missense mutations that affect the pore-forming region are associated with a more severe phenotype. Individuals who test negative for SCN1A sequence-based mutations may have SCN1A exon deletions or chromosomal rearrangements involving SCN1A and contiguous genes, which may be detected using multiplex ligation-dependent probe amplification (MPLA) and comparative genome hybridization (CGH). The Genetics Commission of the International League Against Epilepsy (ILAE) has recently published guidelines for SCN1A testing in clinical practice.Reference Hirose, Scheffer, Marini, De Jonghe, Andermann and Goldman 22 Their recommendations are summarized in Table 1.

Table 1 Predominant seizure types in Dravet syndrome

The phenotype of SCN1A mutations may be heterogeneous even within the same family, and it is likely that modifying genes are important in determining the severity of epilepsy and possibly comorbidities.Reference Brunklaus, Ellis, Reavey, Forbes and Zuberi 2 In animal models, SCN8A may restore a normal seizure threshold in the presence of SCN1A mutations.Reference Martin, Tang, Ta and Escayg 23 The compensatory up-regulation of SCN3A may mitigate the effects of Nav1.1 deficiency. Variants in CACNA1A genes may also modify the phenotype in Dravet syndrome. In a studyReference Ohmori, Ouchida, Kobayashi, Jitsumori, Mori and Michiue 24 of 48 patients with Dravet syndrome and SCN1A mutations, CACNA1A variants were observed in 20 subjects. In individuals with CACNA1A variants, absence seizures, earlier age at seizure onset and more frequent prolonged seizures before the age of one year were more common than in Individuals without CACNA1A variants.Reference Ohmori, Ouchida, Kobayashi, Jitsumori, Mori and Michiue 24 SCN9A mutations have also been observed in some individuals with SCN1A mutations and may be associated with a more severe clinical phenotype.Reference Mulley, Hodgson, McMahon, Iona, Bellows and Mullen 25 , Reference Singh, Pappasa, Dahle, Claes, Pruess and De Jonghe 26

In children where SCN1A mutations are not found, several other genes have been reported, including CHD2, GABRA1, GABARG2, STXBP1, SCN1B, SCN2A and PCDH19.Reference Suls, Jaehn, Kecskés, Weber, Weckhuysen and Craiu 27 - Reference Depienne, Bouteiller, Keren, Cheuret, Poirier and Trouillard 29 However, the electroclinical phenotypes associated with these other gene abnormalities are often somewhat atypical for Dravet syndrome. With the wider application of next-generation sequencing in the evaluation of epilepsy of unknown cause, it is likely that the electroclinical features associated with gene mutations other than SCN1A will be better described.

Pathophysiology of Dravet Syndrome

Several pathophysiological mechanisms have been reported in Dravet syndrome, and the most accepted is the “interneuron hypothesis,” where SCN1A mutations result in inhibition of the GABAergic inhibitory interneurons, resulting in excessive excitation. This mechanism is supported by a mouse model.Reference Cheah, Yu, Westenbroek, Kalume, Oakley and Potter 30 Nav1.1 was preferentially expressed in the axon initial segments of the parvoalbumin-positive interneurons, the main type affected in Dravet syndrome.Reference Yamakawa 31 Studies using models involving human-derived induced pluripotent stem cell neurons suggest that both GABAergic inhibitory neurons and glutamatergic excitatory neurons in the forebrain of patients with Dravet syndrome are hyperexcitable with increased sodium current density, overall resulting in network hyperexcitability.Reference Liu, Lopez-Santiago, Yuan, Jones, Zhang and O’Malley 32 SCN1A haploinsufficiency may result in a compensatory increase in the sodium current via expression of other sodium channels.Reference Chopra and Isom 33

Neuroimaging in Dravet Syndrome

Structural brain imaging using MRI is usually normal in Dravet syndrome, but imaging abnormalities are described in some patients. In a reviewReference Barba, Parrini, Coras, Galuppi, Craiu and Kluger 34 of 120 patients in Italy with Dravet syndrome, malformations of cortical development were detected in 4. In another study,Reference Gaily, Anttonen, Valanne, Liukkonen, Träskelin and Polvi 35 of 18 children with Dravet syndrome who had MR imaging after 3 years of age, 7 had hippocampal sclerosis or loss of grey–white definition in the temporal lobe. In a studyReference Pérez, García-Pentón, Canales-Rodríguez, Lerma-Usabiaga, Iturria-Medina and Román 36 comparing nine patients with Dravet syndrome and SCN1A mutations and nine controls without seizures, globally reduced grey and white matter volumes were seen in individuals with Dravet syndrome.

Neurodevelopment in Dravet Syndrome

Neurodevelopment and formal neurological examination are typically normal at the time of seizure onset. However, there is slowing of the rate of the developmental progress along with variable decline in the developmental quotient over time.Reference Dravet, Bureau, Dalla Bernardina and Guerrini 37 Ataxia and pyramidal signs were present in 59 and 22% of subjects, respectively.Reference Dravet, Bureau, Dalla Bernardina and Guerrini 37 Attention, visual/motor integration, visual perception and executive function are impaired, whereas language may be less involved in some patients.Reference Chieffo, Ricci, Baranello, Martinelli, Veredice and Lettori 38 , Reference Chieffo, Battaglia, Lettori, Del Re, Brogna and Dravet 39

In a studyReference Villeneuve, Laguitton, Viellard, Lépine, Chabrol and Dravet 40 of 21 children aged 6 to 10 years with Dravet syndrome, seen at a single institution and assessed using the WISC and Vineland Adaptive Behaviour scales, no child had a normal IQ after the age of 6 years. Only 5 of the 21 children had a verbal or non-verbal IQ score greater than 60. The children had attention problems, impulsivity, perseverative responses and deficits in planning. Socialization skills assessed using the Vineland scale were significantly better than communication skills. No correlation was observed between age at seizure onset, status epilepticus, number of seizures, myoclonic or absence seizures with IQ. Nabbout and colleaguesReference Nabbout, Chemaly, Chipaux, Barcia, Bouis and Dubouch 41 reported cognitive findings in 67 children with Dravet syndrome, 52 of whom were tested only once and 15 underwent repeat testing. IQ was typically normal before the age of 2 years (mean of 80) but low after age 3 years (mean=48, range=30-69). However, there was no evidence of regression. Attention and hyperactivity were common. No significant correlation was seen between IQ and age at first seizure, number of episodes of status epilepticus, or myoclonic and focal seizures. However, IQ was lower in those with SCN1A mutations. Thus, it was the conclusion of the authors that the encephalopathy was not a pure consequence of epilepsy but that the SCN1A mutation played an additional direct role.

Genton and colleaguesReference Genton, Velizarova and Dravet 8 reported 24 patients with Dravet syndrome followed to 20-50 years of age. Only three individuals lived independently, and the remainder had moderate to severe delay. Ataxia was seen in nine, dysarthria in eight and tremor in seven. In another report of 31 patients, only 1 lived independently, 7 had no language and 9 spoke only a few words.Reference Akiyama, Kobayashi, Yoshinaga and Ohtsuka 42 Catarino et al.Reference Catarino, Liu, Liagkouras, Gibbons, Labrum and Ellis 43 described the long-term follow-up in 22 adults followed to a median of 39 years. Most had intellectual disability, 16 lived in residential care and 6 at home with support. Takayama and colleaguesReference Takayama, Fujiwara, Shigematsu, Imai, Takahashi and Yamakawa 10 reported on long-term outcome in 64 patients followed to a median of 30 years. All had intellectual disability, which was severe in 75%, moderate in 20% and mild in 5%. Only two individuals lived independently.

In Dravet syndrome, there is widespread dysfunction of Nav1.1. Maturation of sodium channels in humans and mice shows that Nav1.1 expression is very low in neonates, and other alpha subunits Nav1.2 and 1.3 compensate. Normally, with increasing age, Nav1.3 declines and Nav1.1 increases. In Dravet syndrome, Nav1.1 fails to increase normally, resulting in widespread dysfunction of Nav1.1. This may explain why seizures do not start until later on, during the first year of life. Furthermore, mouse modelsReference Han, Tai, Westenbroek, Yu, Cheah and Potter 44 of Dravet syndrome demonstrate hyperactivity, stereotypic behaviour and cognitive deficits due to reduced expression of GABAergic interneurons in the forebrain. In a studyReference Bender, Natola, Ndong, Holmes, Scott and Lenck-Santini 45 of mice where SCN1A was selectively reduced but the animals did not develop seizures, cognitive function was affected, providing further evidence that Nav1.1 dysfunction plays a role independent of seizures on cognitive decline.

Comorbidities in Dravet Syndrome

A crouch gait has been described in many reports on Dravet syndrome. In one studyReference Rodda, Scheffer, McMahon, Berkovic and Graham 46 utilizing formal gait analysis in patients with Dravet syndrome who ranged in age from 2 to 34 years, crouch gait was seen in 8 of 9 children aged 13 years and older, in 50% of children aged 6-12 years and in no child younger than 6 years. Fasano and colleagues,Reference Fasano, Borlot, Lang and Andrade 47 in a study of 12 adults with Dravet syndrome, described features of Parkinsonism with bradykinesia, asymmetric rigidity and cogwheeling in 11 (91%). Two patients were treated successfully with levodopa, resulting in significant improvement in their Parkinsonian symptoms. Osteopenia and increased risk of fractures are common in individuals with treatment-resistant epilepsy, particularly when enzyme-inducing drugs are used or there is reduced mobility, but this has not been studied in Dravet syndrome.

Despite sleep concerns being a common complaint in individuals with Dravet syndrome, the literature on this topic is limited. A small, retrospective studyReference Dhamija, Erickson, St Louis, Wirrell and Kotagal 48 of polysomnogram findings in six children with Dravet syndrome referred for sleep assessment found no abnormalities in sleep macroarchitecture despite parental concerns.

SUDEP and Mortality

Mortality is increased significantly in Dravet syndrome, and death may occur at any age but is more frequent during childhood. Death may be due to status epilepticus, SUDEP or accidental death, and it may also be related to seizures associated with drowning or injury. Mortality rates have varied in reported studies from 3.1 to 20.8%, with deaths due to sudden, unexpected death of someone with epilepsy (SUDEP), status epilepticus and accidents (especially drowning) being the most common. In a reportReference Skluzacek, Watts, Parsy, Wical and Camfield 49 based on data from a patient support group, it was estimated that individuals with Dravet syndrome have a risk of SUDEP approximately 15-fold higher than those with other childhood epilepsies.

Studies in Dravet mice modelsReference Kalume, Westenbroek, Cheah, Yu, Oakley and Scheuer 50 suggest that SUDEP is due to increased parasympathetic activity after a generalized tonic-clonic seizure, resulting in lethal bradycardia and electrical ventricular dysfunction. As this finding was seen in mice with the SCN1A mutations selectively targeted to affect the brain, but not if the SCN1A mutations were selectively targeted to affect the heart only, it was proposed that SUDEP is due to a brain effect on the heart after a seizure. Cheah and colleaguesReference Cheah, Westenbroek, Roden, Kalume, Oakley and Jansen 51 proposed that the natural decline in Nav1.3 channel expression with the failure of increase in Nav1.1 channel expression leads to disinhibition of neuronal circuits, treatment-resistant epilepsy and premature death. In a studyReference Auerbach, Jones, Clawson, Offord, Lenk and Ogiwara 52 of mice with an SCN1A mutation, Auerbach observed a twofold increase in sodium current density in ventricular myocytes, resulting in increased excitability, prolongation of action potential duration, which results in QT prolongation, abnormal rhythms and spontaneous deaths in some mice. Thus, it is possible that altered electrical cardiac function may increase the risk of SUDEP, but these animal data have not been confirmed in humans.


Dravet syndrome remains one of the most severe epilepsy syndromes of early childhood and is characterized by very high morbidity and mortality. It impacts physical and cognitive function, mental health, bone health and sleep. Anxiety about the risk of death and SUDEP is very high in parents and caregivers. Early diagnosis of Dravet syndrome is important to avoid anti-seizure medications that exacerbate seizures, but there is a major need for new therapies to improve seizure control and long-term outcomes.

Transition from paediatric to adult services is very challenging, and there is a great need to improve this process.Reference Ceulemans 53 , Reference Kuchenbuch, Chemaly, Chiron, Dulac and Nabbout 54 It is also likely that Dravet syndrome is underdiagnosed in adults with treatment-resistant epilepsy. It is therefore important to educate colleagues who are caring for adults about this epilepsy syndrome.


Mary Connolly has the following disclosures: Novartis, site principal investigator, research support; Novartis, speaker, honorarium; UCB, speaker, honorarium. All funds go to the Epilepsy Research and Development Fund (no personal benefit).


1. Dravet, C. Les epilepsies graves de l’enfant. Vie Med. 1978;8:543-548.Google Scholar
2. Brunklaus, A, Ellis, R, Reavey, E, Forbes, GH, Zuberi, SM. Prognostic, clinical and demographic features in SCN1A mutation–positive Dravet syndrome. Brain. 2012;135:2329-2336.Google Scholar
3. Bayat, A, Hjalgrim, H, Moller, RS. The incidence of SCN1A-related Dravet syndrome in Denmark is 1:22,000: a population-based study from 2004 to 2009. Epilepsia. 2015;56:36-39.Google Scholar
4. Claes, L, Del-Favero, J, Ceulemanns, B, Lagae, L, Van Broeckhoven, C, De Jonghe, P. De novo mutations in sodium channel SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68:1327-1332.Google Scholar
5. Xu, X, Zhang, Y, Sun, H, Liu, X, Yang, X, Xiong, H, et al. Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. Brain Dev. 2014;36:676-681.Google Scholar
6. Hattori, J, Ouchida, M, Ono, J, Miyake, S, Maniwa, S, Mimaki, N, et al. A screening test for the prediction of Dravet syndrome before one year of age. Epilepsia. 2008;49:626-633.Google Scholar
7. Bureau, M, Dalla Bernardina, B. Electroencephalographic characteristics of Dravet syndrome. Epilepsia. 2011;52(Suppl 2):13-23.Google Scholar
8. Genton, P, Velizarova, R, Dravet, C. Dravet syndrome: the long-term outcome. Epilepsia. 2011;52(Suppl 2):44-49.Google Scholar
9. Caraballo, RH, Fejerman, N. Dravet syndrome: a study of 53 patients. Epilepsy Res. 2006;70(Suppl 1):S231-S238.Google Scholar
10. Takayama, R, Fujiwara, T, Shigematsu, H, Imai, K, Takahashi, Y, Yamakawa, K, et al. Long-term course of Dravet syndrome: a study from an epilepsy center in Japan. Epilepsia. 2014;55:528-538.Google Scholar
11. Specchio, N, Balestri, M, Trivisano, M, Japaridze, N, Striano, P, Carotenuto, A, et al. Electroencephalographic features in Dravet syndrome: five-year follow-up study in 22 patients. J Child Neurol. 2012;27:439-444.Google Scholar
12. Korff, C, Laux, L, Kelley, K, Goldstein, J, Koh, S, Nordli, D Jr. Dravet syndrome (severe myoclonic epilepsy in infancy): a retrospective study of 16 patients. J Child Neurol. 2007;22:185-194.Google Scholar
13. Kim, SH, Nordli, DR Jr, Berg, AT, Koh, S, Laux, L. Ictal ontogeny in Dravet syndrome. Clin Neurophysiol. 2015;126:446-455.Google Scholar
14. Nabbout, R, Desguerre, I, Sabbagh, S, Depienne, C, Plouin, P, Dulac, O, et al. An unexpected EEG course in Dravet syndrome. Epilepsy Res. 2008;81:90-95.Google Scholar
15. Escayg, A, MacDonald, BT, Meisler, MH, Baulac, S, Huberfeld, G, An-Gourfinkel, I, et al. Mutations of SCN1A encoding a neuronal sodium channel in two families with GEFS+2. Nat Genet. 2000;24:343-345.Google Scholar
16. Singh, R, Andermann, E, Whitehouse, WP, Harvey, AS, Keene, DL, Seni, MH, et al. Severe myoclonic epilepsy of infancy: extended spectrum of GEFS+? Epilepsia. 2001;42(7):837-844.Google Scholar
17. Depienne, C, Trouillard, O, Saint-Martin, C, Gourfinkel-An, I, Bouteiller, D, Carpentier, W, et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J Med Genet. 2009;46:183-191.Google Scholar
18. Nabbout, R, Gennaro, E, Dalla Bernardina, B, Dulac, O, Madia, F, Bertini, E, et al. Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology. 2003;60:1961-1967.Google Scholar
19. Wallace, RH, Hodgson, BL, Grinton, BE, Gardiner, RM, Robinson, R, Rodriguez-Casero, V, et al. Sodium channel alpha1-subunit in severe myoclonic epilepsy of infancy and infantile spasms. Neurology. 2003;61:765-769.Google Scholar
20. Marini, C, Mei, D, Temudo, T, Ferrari, AR, Buti, D, Dravet, C, et al. Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities. Epilepsia. 2007;48:1678-1685.Google Scholar
21. Marini, C, Scheffer, IE, Nabbout, R, Suls, A, De Jonghe, P, Zara, F, et al. The genetics of Dravet syndrome. Epilepsia. 2011;52(Suppl 2):24-29.Google Scholar
22. Hirose, S, Scheffer, IE, Marini, C, De Jonghe, P, Andermann, E, Goldman, AM, et al. SCN1A testing for epilepsy: application in clinical practice. Epilepsia. 2013;54:946-952.Google Scholar
23. Martin, MS, Tang, B, Ta, N, Escayg, A. Characterization of 5′ untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncoding sequences. Genomics. 2007;90:225-235.Google Scholar
24. Ohmori, I, Ouchida, M, Kobayashi, K, Jitsumori, Y, Mori, A, Michiue, H, et al. CACNA1A variants may modify the epileptic phenotype of Dravet syndrome. Neurobiol Dis. 2013;50:209-217.Google Scholar
25. Mulley, JC, Hodgson, B, McMahon, JM, Iona, X, Bellows, S, Mullen, SA, et al. Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome. Epilepsia. 2013;54:122-126.Google Scholar
26. Singh, NA, Pappasa, C, Dahle, EJ, Claes, LR, Pruess, TH, De Jonghe, P, et al. A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet. 2009;5(9):e1000649.Google Scholar
27. Suls, A, Jaehn, JA, Kecskés, A, Weber, Y, Weckhuysen, S, Craiu, DC, et al. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet. 2013;93:967-975.Google Scholar
28. Carvill, GL, Weckhuysen, S, McMahon, JM, Hartmann, C, Møller, RS, Hjalgrim, H, et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology. 2014;82:1245-1253.Google Scholar
29. Depienne, C, Bouteiller, D, Keren, B, Cheuret, E, Poirier, K, Trouillard, O, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet. 2009;5(2):e1000381.Google Scholar
30. Cheah, CS, Yu, FH, Westenbroek, RE, Kalume, FK, Oakley, JC, Potter, GB, et al. Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A. 2012;109:14646-14651.Google Scholar
31. Yamakawa, K. Molecular and cellular basis: insights from experimental models of Dravet syndrome. Epilepsia. 2011;52(Suppl 2):70-71.Google Scholar
32. Liu, Y, Lopez-Santiago, LF, Yuan, Y, Jones, JM, Zhang, H, O’Malley, HA, et al. Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann Neurol. 2013;74:128-139.Google Scholar
33. Chopra, R, Isom, LL. Untangling the Dravet syndrome seizure network: the changing face of a rare genetic epilepsy. Epilepsy Curr. 2014;14:86-89.Google Scholar
34. Barba, C, Parrini, E, Coras, R, Galuppi, A, Craiu, D, Kluger, G, et al. Co-occurring malformations of cortical development and SCN1A gene mutations. Epilepsia. 2014;55:1009-1019.Google Scholar
35. Gaily, E, Anttonen, AK, Valanne, L, Liukkonen, E, Träskelin, AL, Polvi, A, et al. Dravet syndrome: new potential genetic modifiers, imaging abnormalities, and ictal findings. Epilepsia. 2013;54:1577-1585.Google Scholar
36. Pérez, A, García-Pentón, L, Canales-Rodríguez, EJ, Lerma-Usabiaga, G, Iturria-Medina, Y, Román, FJ, et al. Brain morphometry of Dravet syndrome. Epilepsy Res. 2014;108:1326-1334.Google Scholar
37. Dravet, C, Bureau, M, Dalla Bernardina, B, Guerrini, R. Severe myoclonic epilepsy in infancy (Dravet syndrome) 30 years later. Epilepsia. 2011;52(Suppl 2):1-2.Google Scholar
38. Chieffo, D, Ricci, D, Baranello, G, Martinelli, D, Veredice, C, Lettori, D, et al. Early development in Dravet syndrome: visual function impairment precedes cognitive decline. Epilepsy Res. 2011;93:73-79.Google Scholar
39. Chieffo, D, Battaglia, D, Lettori, D, Del Re, M, Brogna, C, Dravet, C, et al. Neuropsychological development in children with Dravet syndrome. Epilepsy Res. 2011;95:86-93.Google Scholar
40. Villeneuve, N, Laguitton, V, Viellard, M, Lépine, A, Chabrol, B, Dravet, C, et al. Cognitive and adaptive evaluation of 21 consecutive patients with Dravet syndrome. Epilepsy Behav. 2014;31:143-148.Google Scholar
41. Nabbout, R, Chemaly, N, Chipaux, M, Barcia, G, Bouis, C, Dubouch, C, et al. Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy. Orphanet J Rare Dis. 2013;8:176.Google Scholar
42. Akiyama, M, Kobayashi, K, Yoshinaga, H, Ohtsuka, Y. A long-term follow-up study of Dravet syndrome up to adulthood. Epilepsia. 2010;51:1043-1052.Google Scholar
43. Catarino, CB, Liu, JY, Liagkouras, I, Gibbons, VS, Labrum, RW, Ellis, R, et al. Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain. 2011;134:2982-3010.Google Scholar
44. Han, S, Tai, C, Westenbroek, RE, Yu, FH, Cheah, CS, Potter, GB, et al. Autistic-like behaviour in Scn1a+/– mice and rescue by enhanced GABA-mediated neurotransmission. Nature. 2012;489:385-390.Google Scholar
45. Bender, AC, Natola, H, Ndong, C, Holmes, GL, Scott, RC, Lenck-Santini, PP. Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol Dis. 2013;54:297-307.Google Scholar
46. Rodda, JM, Scheffer, IE, McMahon, JM, Berkovic, SF, Graham, HK. Progressive gait deterioration in adolescents with Dravet syndrome. Arch Neurol. 2012;69:873-878.Google Scholar
47. Fasano, A, Borlot, F, Lang, AE, Andrade, DM. Antecollis and levodopa-responsive parkinsonism are late features of Dravet syndrome. Neurology. 2014;82:2250-2251.Google Scholar
48. Dhamija, R, Erickson, MK, St Louis, EK, Wirrell, E, Kotagal, S. Sleep abnormalities in children with Dravet syndrome. Pediatr Neurol. 2014;50:474-478.Google Scholar
49. Skluzacek, JV, Watts, KP, Parsy, O, Wical, B, Camfield, P. Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia. 2011;52(Suppl 2):95-101.Google Scholar
50. Kalume, F, Westenbroek, RE, Cheah, CS, Yu, FH, Oakley, JC, Scheuer, T, et al. Sudden unexpected death in a mouse model of Dravet syndrome. J Clin Invest. 2013;123:1798-1808.Google Scholar
51. Cheah, CS, Westenbroek, RE, Roden, WH, Kalume, F, Oakley, JC, Jansen, LA, et al. Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome. Channels (Austin). 2013;7:468-472.Google Scholar
52. Auerbach, DS, Jones, J, Clawson, BC, Offord, J, Lenk, GM, Ogiwara, I, et al. Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLoS One. 2013;8(10):e77843.Google Scholar
53. Ceulemans, B. Overall management of patients with Dravet syndrome. Dev Med Child Neurol. 2011;53(Suppl 2):19-23.Google Scholar
54. Kuchenbuch, M, Chemaly, N, Chiron, C, Dulac, O, Nabbout, R. Transition and transfer from paediatric to adult health care in epilepsy: a family survey on Dravet syndrome. Epilepsy Behav. 2013;29:161-165.Google Scholar
Figure 0

Table 1 Predominant seizure types in Dravet syndrome

Figure 1

Table 2 ILAE guidelines for SCN1A testing22