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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 myoclo- nias 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 convul- sions; 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 obtun- dation 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
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