Dravet Syndrome: from Electroclinical Characteristics to Molecular Biology Alexis Arzimanoglou

Epilepsia, 50(Suppl. 8):3–9, 2009 doi: 10.1111/j.1528-1167.2009.02228.x DIFFICULT-TO-TREAT SYNDROMES

Dravet syndrome: From electroclinical characteristics to molecular biology Alexis Arzimanoglou

Epilepsy, Sleep and Pediatric Neurophysiology Department, Institute for Children and Adolescents with Epilepsy – IDEE, University Hospitals of Lyon (HCL) and Inserm U821, Lyon, France

although mental deterioration occurs in infancy, SUMMARY usually leaving patients with severe mental The onset of Dravet syndrome typically occurs impairment, further deterioration does not within the first year, with prolonged, generalized, occur. The identification of genes associated with or unilateral clonic seizures triggered by fever. In Dravet syndrome and related syndromes hints at the early stages, other types of refractory sei- the complexity of the etiology of such epilepsies. zures usually present that include myoclonic sei- Identifying SCN1A mutations has become useful zures, atypical absences, and partial seizures. as a means to support an early diagnosis of Dra- Electroencephalography (EEG) findings are not vet syndrome, to benefit counseling, and to avoid pathognomonic, and signs of cognitive arrest or use of antiepileptic drugs (AEDs) that may have deterioration progressively appear. In contrast, adverse effects. However, the defining character- in adults, myoclonic seizures, atypical absences, istics of seizure type and EEG patterns initially and focal seizures tend to disappear, and short identified by Dravet remain fundamental to diag- tonic–clonic seizures, often associating a focal nosis. component, persist particularly during sleep. The KEY WORDS: Severe myoclonic epilepsy of sensitivity to fever persists into adulthood, and infancy, SCN1A, Fever, Ion channel.

Charlotte Dravet provided the first description of what tal stages. In particular, characteristics include the pres- would later become ‘‘Dravet syndrome’’ in a French pub- ence of early unilateral clonic seizures, often precipitated lication on severe epilepsies of childhood. She under- by fever, and the subsequent appearance of myoclonic scored that her attention was drawn to some very severe seizures (with variable severity), atypical absences, and cases of epilepsy beginning early in life which, despite partial seizures. There are few clues as to the etiology of certain similarities, could not be categorized as Lennox- the syndrome, which is considered to be an epileptic Gastaut syndrome for several reasons, especially their encephalopathy, as it almost invariably features cognitive ‘‘stereotyped mode of onset and the absence of axial arrest or deterioration. Dravet syndrome is rare: approxi- tonic seizures’’ (Dravet, 1978). She used the designation mately 500 cases have been reported to date worldwide ‘‘severe myoclonic epilepsy of infancy (SMEI)’’ in a (Dravet et al., 1992; Dravet & Bureau, 2004). chapter on myoclonic epilepsies published in Advances The designation of the syndrome as ‘‘severe myoclonic in Epileptology (Dravet et al., 1982). The description epilepsy of infancy’’ was considered misleading by some was based on both clinical and electroencephalographic authors (Aicardi, 1994), who underscored the fact that features. myoclonic seizures are uncommonly the first manifesta- The defining characteristics of the syndrome typically tion, and they are usually overshadowed by other types consist of different seizure types—that can be unilateral, of seizures. Subsequent reports indicated that myoclonic focal, or generalized—occurring at specific developmen- seizures could be absent (referred to as ‘‘borderline severe myoclonic epilepsy,’’ or SMEB). Moreover, there was also Address correspondence to Alexis Arzimanoglou, Associate Professor variation in the severity of myoclonic seizures reported, of Neurology and Child Neurology, Head Institute for children and ado- being either massive and/or erratic. It is for these reasons lescents with epilepsy IDEE, 59 Boulevard Pinel, 69677 Lyon, France. E-mail: [email protected] that it is accepted that the term SMEI is misleading and thus the original term ‘‘Dravet syndrome’’ is now preferred Wiley Periodicals, Inc. ª 2009 International League Against Epilepsy (Kanazawa, 2001; Oguni et al., 2001; Dravet et al., 2002),

3 4 A. Arzimanoglou and included as such in the International League of Epi- Myoclonic seizures lepsy (ILAE) classification (Engel, 2001). As suggested One defining characteristic of Dravet syndrome is the initially by clinical observations (Veggiotti et al., 2001), presence of myoclonic seizures that may occur in different recent progress in molecular biology has confirmed that forms. Massive myoclonias have been reported for 77% of Dravet syndrome is part of a continuum, and can be con- patients (total 56; Dravet et al., 1992) and erratic myoclo- sidered as the most severe epilepsy syndrome within the nias for about one-third of patients studied (Dravet et al., spectrum of syndromes described in families with general- 1982; Doose et al., 1998; Oguni et al., 2001); some ized epilepsy with febrile seizures plus (GEFS+). What is patients may experience both massive and erratic myoclo- intriguing about this commonality is that, in recent years, nia (Dravet et al., 1992). In some cases, however, patients the marked severity of Dravet syndrome, relative to other with Dravet syndrome appear not to present any myo- syndromes, is paralleled by a strong genetic association. clonic seizures (Sugama et al., 1987; Ogino et al., 1989; Identification of gene mutations is useful as a means to Dravet et al., 1992; Kanazawa, 1992; Yakoub et al., 1992; support an early diagnosis of Dravet syndrome; however, Dravet et al., 2005). Such cases have been grouped as the defining characteristics of seizure type and electroen- ‘‘borderline cases of SMEI’’ (SMEB). cephalography (EEG) as well as the pattern of evolution The massive myoclonias, which involve predominantly identified by Dravet remain fundamental to diagnosis. axial muscles, may be either violent and cause drop attacks, or far more subtle with small forward or backward Onset movements of the head, shoulders, or trunk. The myoclonias tend to occur in isolation or in brief bursts consisting Typically, the occurrence of prolonged (10–90 min), of two to three jerks. Myoclonias may occur frequently generalized, or unilateral clonic febrile seizures, between and are often reported only in the minutes preceding a 2 and 12 months of age, is indicative of the onset of Dra- convulsion, predominantly on awakening, and disappear vet syndrome (Dalla Bernardina et al., 1982; Giovanardi during slow sleep. Myoclonias may be precipitated by Rossi et al., 1991; Dravet et al., 1992; Doose et al., 1998). variations in ambient light intensity (Dravet et al., 1992, This is further indicated by the presence of subsequent 2002) or continuous stimulation (Oguni et al., 2001). seizures in a febrile context that occur within the next few Approximately 25% of patients are able to induce seizures months of the first seizure. In some cases, febrile seizures themselves, either by interfering with a light source or are associated with only a mild fever, and afebrile seizures observing patterns (Dalla Bernardina et al., 1987; Hurst, (isolated episodes of focal myoclonic jerking) account for 1987a; Aicardi & Gomes, 1988; Aicardi, 1991; Dravet 28–35% seizures and may be triggered by vaccinations, et al., 1992). Dravet et al. (1992) reported that the majority minor infections, or hot baths (Doose et al., 1998). In rare of massive myoclonias were associated with bursts of cases, myoclonic seizures may present at the onset, hours irregular spike-waves or polyspike-waves. However, (or even days or weeks) before the first convulsion (Dravet although this was the case for approximately half the indi- et al., 1992, 2002). viduals studied by Doose et al. (1998), it was less com- Characteristic to Dravet syndrome is the observation monly observed by others (Ogino et al., 1986; Watanabe that lateralization often changes from one unilateral clonic et al., 1989a,b; Fujiwara et al., 1990; Kanazawa, 1992; seizure to another or even within the same attack (Doose Oguni et al., 1994; Dravet et al., 2002). et al., 1998). Seizure sensitivity to photic stimulation is Erratic (or segmental) myoclonias predominantly also positive in approximately 40% of patients, particu- involve the limbs in a narrowly limited, mainly distal, area larly in very young children. of the face and cause mostly mild muscle jerks. Movement enhances erratic myoclonias and they are particularly Early Progression common during periods of severe and frequent convulsions; however, they also occur at rest. The seizures are The second and third years of life are marked by the seldom intense, and may be more palpable than visible; emergence of brief attacks of different seizure types: myo- however, imbalance and disturbances of fine coordination clonic seizures (either massive or erratic), atypical may occur. Unlike massive myoclonias, erratic myoclo- absences, convulsive generalized tonic–clonic or clonic nias are not reported to be associated with EEG seizures, uni- or bilateral seizures, focal seizures (with or paroxysms. without secondary generalization), and episodes of obtundation status (nonconvulsive status epilepticus with or Atypical absences without erratic myoclonus). Tonic seizures are only Atypical absences are common in patients with Dravet exceptionally present and may render a differential diag- syndrome, with a frequency of between 40% and 93% nosis for Lennox-Gastaut syndrome difficult. However, (Ogino et al., 1986; Sugama et al., 1987; Dravet et al., the presence of the predominant clinical features and EEG 1992). These appear as absence seizures with myoclonic characteristics allows differentiation. jerks of the upper limbs, a simple fall of the head, or drop

Epilepsia, 50(Suppl. 8):3–9, 2009 doi: 10.1111/j.1528-1167.2009.02228.x 5 Dravet Syndrome: A Success Story attacks. EEG recordings identify brief discharges or irreg- acute psychiatric episodes are rare (Dravet et al., 1992; ular spike-waves. Atypical absences may occur in groups Doose et al., 1998). during episodes of nonconvulsive status epilepticus that last for several hours or even days, usually with erratic EEG Features myoclonus (Dravet et al., 1992, 2002). Accompanying imbalance, dribbling, or frank ataxia may wrongly suggest Interictal EEG recordings are generally normal during the presence of a degenerative disease. Obtundation of a the first months of the disease, despite the frequent sei- variable, often fluctuating degree is a major feature. zures (unlike the slow spike-waves observed for Lennox- Gastaut syndrome). However, EEG findings subsequently Focal seizures appear to change progressively with the appearance of Focal seizures are reported to occur in at least half of generalized, focal, and multifocal abnormalities. Back- patients studied. These may become generalized or remain ground EEG activity varies between normal and slow, and unilateral. a theta rhythm (of 5–6 Hz) in the central and vertex regions is present (Hurst, 1987a; Dravet et al., 1992; Psychomotor development and neurologic features Doose et al., 1998). Initially, despite the frequent seizures, the child appears From the second year of life, generalized discharges of to develop normally. However, during the second or third fast spike-wave or polyspike-wave complexes appear in year of life, developmental progression deteriorates sig- bursts or in isolation, sometimes with a unilateral predom- nificantly. Walking is normal but gait is unsteady. Associ- inance. Focal or multifocal spikes are often observed. ated neuropsychological disturbances are common, and In later life, the EEG patterns observed are variable. the extent is often related to the severity of the epilepsy Multifocal spikes or sharp-wave discharges become during the first 2 years of life (Wolff et al., 2006). Ataxia more common, and background tracings become slower, and pyramidal signs are common; in 59% and 22% of especially during seizure clusters. Paroxysmal abnormal- cases, respectively. Language progresses slowly and many ities tend to increase with slow sleep, and epileptiform children are unable to formulate sentences. Behavior often discharges later tend to occur less frequently and the deteriorates and attention deficit/hyperactivity disorder theta rhythm is replaced by diffuse polymorphic or (ADHD) is common. rhythmic slowing. In a recent report by Nabbout et al. (2008), atypical EEG patterns were reported in a minor- Late Progression ity of adolescents with Dravet syndrome; frontal slow bi–tri spikes were sometimes followed by slow waves Virtually all affected individuals continue to present when awake and activated by sleep with 5–10 s dis- seizures, sometimes with a period of very active epilepsy, charges of 8–9 Hz spikes. The authors suggested that up to age 12–13 years of age. Whereas myoclonic and although these patterns could suggest Lennox-Gastaut focal seizures, as well as atypical absences, tend to dis- syndrome, they more likely represent a previously appear after 4–7 years, short tonic–clonic seizures, often overlooked EEG pattern in adolescents with Dravet with a focal component, persist, particularly during sleep. syndrome. Episodes of nonconvulsive status epilepticus are common, and these may play a role in increasing the degree of cog- Treatment nitive and behavioral deterioration. Clonic seizures alternating from side to side, or complex partial seizures, may Treatment options for patients with Dravet syndrome also persist (Arzimanoglou et al., 2004). are rather limited. As a preventative measure, hot baths The sensitivity of seizures to fever or afebrile infections should be avoided in young children and sunglasses or any is still marked in late infancy and adolescence, and the other method to reduce photo- and pattern-sensitivity, photo- and pattern-sensitivity of seizures persists (Dravet when present, may prove useful. Vigorous treatment of et al., 1992, 2002). Neurologic anomalies tend to fluctuate febrile diseases is recommended but is of uncertain value. with the occurrence of seizures, but do not progress after In general, there is a lack of controlled trials regarding the age of 4–5 years. Motor function, however, remains the efficacy of available antiepileptic drugs (AEDs). Many poor, and erratic myoclonus and a persistent tremor are AEDs have no effect and may be at the origin of adverse common (Dravet et al., 1992, 2002). effects, such as carbamazepine (Ernst et al., 1988) and In general the ultimate outcome is poor. In one report vigabatrin (Dravet et al., 1992; Arzimanoglou, 1994) by Dravet et al. (1992) 16% of patients (total 63) died at a which can favor or even induce myoclonic seizures and mean age of 11 years, and 100% of patients older than lamotrigine (Genton & McMenamin, 1998; Guerrini 10 years (37 patients) were institutionalized. Most et al., 1998), particularly for young patients. For older patients in later life are reported to be severely mentally patients, polytherapy should be avoided, and the specific impaired and have low IQs, although aggressiveness and action of each AED should be considered.

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AEDs that have been shown to have therapeutic value predominance of myoclonic–astatic seizures indicates against Dravet syndrome include valproate (Hurst, MAE (Doose et al., 1998; Guerrini & Aicardi, 2003). 1987a,b), levetiracetam (Labate et al., 2006; Striano et al., In the case of Lennox-Gastaut syndrome (Arzimano- 2007), zonisamide (Wallace, 1998), and topiramate glou et al., 2009), the occurrence of drop attacks is mis- (Nieto-Barrera et al., 2000; Coppola et al., 2002; Grosso leading; however, a history of febrile clonic seizures and et al., 2005), especially in patients who were unsatisfacto- absence of axial tonic seizures and specific EEG abnor- rily treated with stiripentol alone (Krçll-Seger et al., malities is indicative of Dravet syndrome. 2006). Stiripentol is a new AED that recently received condi- Common genotypes tional approval from the European Medicines Agency The genotypes of patients belonging to GEFS+ families (EMEA) to be used throughout the European Union, in are heterogeneous (Lerche et al., 2001; Scheffer et al., conjunction with clobazam and valproate as adjunctive 2005). In 10–15% of GEFS+ families, autosomal domi- therapy for refractory generalized tonic–clonic seizures in nant genes have been identified and include mutations in patients with Dravet syndrome (Chiron, 2007). When the genes for: the sodium channel a subunit (SCN2A), reg- administered as ‘‘add-on,’’ stiripentol demonstrates a posi- ulatory b1 subunit (SCN1B), c-aminobutyric acid tive effect on reducing the frequency of seizures (Perez (GABA)-A receptor c2 subunit (GABRG2), and d subunit et al., 1999; Chiron et al., 2000, 2001). Kassa et al. (2008) (GABRD), and most significantly, the sodium channel performed a systematic review and meta-analysis of indi- subunit a1(SCN1A). vidual data that demonstrated a positive effect of stiripen- In 2001, Claes et al. demonstrated the presence of muta- tol in patients with Dravet syndrome using 23 tions in SCN1A in patients with Dravet syndrome (Claes uncontrolled studies and two randomized controlled trials. et al., 2001). However, unlike other syndromes within the Of the 64 children (aged between 3 and 20 years), stirip- GEFS+ spectrum, Dravet syndrome is highly associated entol reduced seizure rate on average by 70%, relative to with mutations in SCN1A. More intriguingly, SCN1A placebo. Stiripentol may prove to be useful as a treatment mutations appear to be largely directly proportional to the against Dravet syndrome in the future. severity of syndromes across the spectrum. SCN1A muta- Alternative treatments include the implantation of a tions were identified in 11.5% patients with GEFS+ (Ma- vagus nerve stimulator (VNS); the use of steroids, adreno- rini et al., 2007), 23% in patients with cryptogenic corticotropic hormone, and immunoglobulins (Aicardi, generalized and focal epilepsies (Harkin et al., 2007), 25% 1991; Dravet et al., 1992); bromides (Tanaka et al., 1990; in patients with Dravet syndrome but without myoclonias Woody, 1990; Steinhoff & Kruse, 1992; Oguni et al., (SMEB; Fukuma et al., 2004), and 70% in patients with 1994; Tanabe et al., 2008); and use of the ketogenic diet Dravet syndrome with myoclonias (Ohmori et al., 2002; (Caraballo et al., 2005; Fejerman et al., 2005). Most of the Sugawara et al., 2002; Fujiwara et al., 2003; Nabbout preceding reports refer to anecdotal cases or to open et al., 2003; Wallace et al., 2003; Korff et al., 2007; Marini studies. et al., 2007), similar to that observed for intractable childhood epilepsies with generalized tonic–clonic seizures Dravet and Other Syndromes (Fujiwara, 2006). Most SCN1A mutations in patients with Dravet syn- Common phenotypes drome give rise to truncations (frameshift or deletion) The presence of early febrile seizures may confuse rather than missense (Mulley et al., 2005); the type of diagnosis of febrile convulsions or early cryptogenic focal mutation does not appear to relate to the severity of epilepsy. Unlike benign febrile convulsions, the early feb- symptoms (Wang et al., 2008). However, when compared rile seizures of Dravet syndrome occur at an early age with patients who have febrile seizures, those with Dravet (<1 year), are more frequent, persist for longer periods, syndrome possessed a higher proportion of point muta- are clonic and unilateral (rather than generalized tonic– tions within the pore region of SCN1A (Kanai et al., 2004). clonic), and are resistant to treatment. The diagnosis is Dravet syndrome is associated with a family history of usually confirmed by the presence of other seizure types, seizures in 50% of patients. Familial SCN1A mutations notably myoclonic jerks (Dravet et al., 2002). Although have been reported to be inherited from mildly affected the onset of early cryptogenic focal epilepsy may involve parents (Fujiwara et al., 2003; Nabbout et al., 2003; febrile convulsions rapidly associated with focal seizures, Kimura et al., 2005). However, most SCN1A mutations atypical absences and myoclonic jerks are absent, and in patients with Dravet syndrome arise de novo. More alternating hemiclonic seizures and varied partial motor recently, SCN1A mutations have been shown to be seizures confirm diagnosis (Sarisjulis et al., 2000). Like inherited from unaffected or weakly affected parents, via Dravet syndrome, the onset of myoclonic astatic epilepsy parental somatic and germline mosaicisms (Depienne (MAE) may occur within the first 2 years of life. How- et al., 2006; Gennaro et al., 2006; Marini et al., 2006; ever, the lack of partial seizures or EEG focalization and Morimoto et al., 2006).

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A large series of 333 patients was screened (Depienne ated genes, could only be a combination of comprehensive et al., 2009) using both direct sequencing and multiplex analysis of existing data and fortuity. Integration of cur- ligation-dependent probe amplification (MLPA). Noncod- rent diagnostic tools to confirm diagnosis or recognition ing regions of the gene that are usually not investigated that patients with a similar genotype may have different were also screened. SCN1A point mutations were identi- phenotypes will generate new questions for further fied in 228 patients, 161 of which had not been previously research. reported. MLPA analysis of the 105 patients without point mutation detected a heterozygous microrearrangement of Acknowledgment SCN1A in 14 additional patients. These findings widely expand the SCN1A mutation spectrum identified and high- Disclosure: The author has acted as a paid consultant to UCB, Pfizer light the importance of screening the coding regions with (France), Sanofi-Aventis, Eisai, and GlaxoSmithKline (France). both direct sequencing and a quantitative method. Accord- ing to the authors (Depienne et al., 2009), this mutation References spectrum, including whole gene deletions, argues in favor of haploinsufficiency as the main mechanism responsible Aicardi J, Gomes AL. (1988). The Lennox-Gastaut syndrome: clinical and electroencephalographic features. In Niedermeyer E, Degen D for Dravet syndrome. (Eds) The Lennox-Gastaut syndrome. Alan R. Liss, New York, pp. The familial element and high frequency of de novo 25–46. SCN1A mutations in patients with Dravet syndrome Aicardi J. (1991) Myoclonic epilepsies in childhood. Int Pediatr 6:195– 200. emphasize the importance of the different genetic back- Aicardi J. 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