Dravet Syndrome: Severe Myoclonic Epilepsy or Severe Polymorphic Epilepsy of Infants

Severe myoclonic epilepsy (SME) initially was mistakenly considered a form of the Lennox-Gastaut syndrome because of the occurrence of repeated falls. However, its clinical and electroencephalographic (EEG) features and its treatment clearly differ, and it should thus be distinguished from the other syndromes that can be associated with myoclonic seizures.

Dravet syndrome was initially described as SME of infants (Dravet et al., 1982). Although it does often feature myoclonic phenomena (see Chapter 6 for description), only uncommonly are these the first manifestation of the syndrome, and they are usually overshadowed by other types of seizures (generalized, unilateral, or partial) often precipitated by fever, which suggests the diagnosis of febrile seizures. Moreover, myoclonic phenomena observed in Dravet syndrome are of the following two different types: (a) massive myoclonus with concomitant EEG paroxysmal transients and (b) erratic myoclonus that is usually fragmentary and is often unassociated with EEG paroxysms. The pathophysiologic mechanisms of these two types may well differ, and only one type of myoclonus may be present in a proportion of the cases. Not uncommonly, the myoclonic activity is mild and it may be intermittent, and cases with quite similar features but without myoclonus have been known to occur (Oguni et al., 1994; Kanazawa and Kawai, 1992; Fujiwara et al., 1990; Watanabe et al., 1989a, 1989b). Whether they belong to the syndrome has been disputed (Doose et al., 1998). Recently, however, a consensus that cases with and without myoclonus do not differ in any essential aspect except for the absence of myoclonus (and of other brief seizures in some cases) has been reached (Dravet et al., 2002; Kanazawa, 2001; Oguni et al., 2001). For these reasons, the term SME may be inadequate, and the use of the term Dravet syndrome may seem more appropriate because the first description of the syndrome (Dravet et al., 1982) was given by this investigator. Considering Dravet syndrome as one member of the group of the epileptic encephalopathies of infancy and childhood with West syndrome and Lennox-Gastaut syndrome may also be appropriate because it almost invariably features cognitive arrest or deterioration and, sometimes, neurologic abnormalities in addition to intractable seizures. A progressive course is also consistently observed.

ETIOLOGY

The frequency of Dravet syndrome is not known. Hurst (1990) placed the incidence between 1 in 20,000 and 1 in 40,000, but that figure may vary with the diagnostic criteria used and the populations studied. A significant number of cases likely remain undiagnosed. In tertiary centers, Dravet syndrome is a fairly common problem (Dravet et al., 1992a). In several studies, a variable excess of boys was present (Doose et al., 1998; Dravet et al., 1992a).

Antecedents of prenatal and/or perinatal abnormal events or risk factors, such as toxemia of pregnancy, severe emesis, low birth weight, or twin delivery, were found in 22% of the patients in the study conducted by Dravet et al. (1992a) and in 20% of those studied by Doose et al. (1998), but the significance of this finding is not clear. No metabolic abnormality has been detected in any case thus far (Dravet et al., 1992a). Repeated imaging studies have not demonstrated detectable brain abnormalities, even though a mild degree of atrophy has been demonstrated in some late-onset cases (Dravet et al., 1992a), and lesional factors are not thought to play an important role. In a biopsy specimen, Renier and Renkawek (1990) found typical images of microdysgenesias similar to those described by Meencke (1985) and Meencke and Janz (1984) in cases of idiopathic generalized epilepsy. The significance of this finding is not clear, and most investigators consider
the cause of Dravet syndrome not to be structural brain abnormalities.

Genetic factors seem to play an important role. A family history of epilepsy or convulsions has often been noted, varying from 25% (Dravet et al., 1992a; Sugama et al., 1987; Dalla Bernardina et al., 1984) to 57% (Hurst, 1987b) and 64.4% (Ogino et al., 1986), with an average of about 50% (Scheffer, 2003). Affected monozygotic pairs of twins (Dravet et al., 2002; Doose et al., 1998; Fujiwara et al., 1990), and the occurrence of a similar syndrome in siblings (Doose et al., 1998) have been reported. Doose et al. (1998) studied the EEG in detail in siblings and parents of children with SME and related cases and found a high frequency of abnormalities, including generalized spike-waves, generalized monomorphic alpha rhythm, and photosensitivity. Recently, Claes et al. (2001) found several de novo mutations in the genes for α₁ subunit of the sodium channel SCN1A on chromosome 2q in seven children. Some investigators have suggested that Dravet syndrome represents the most severe end of the spectrum of the syndrome of generalized epilepsy with febrile seizures plus (GEFS+) (see Chapter 14) (Singh et al., 2001; Veggiotti et al., 2001). Indeed, missense de novo mutations in the same gene have been reported in families with the GEFS+ syndrome (Escayg et al., 2001). Interestingly, Veggiotti et al. (2001) found cases of Dravet syndrome in two siblings belonging to a family with a history of GEFS+ syndrome. The frequency of the mutation of this SCN1A channel in cases of SME is not yet clear because the figures vary in different series. Japanese groups found a mutation rate of 77% to 82% (Fujiwara et al., 2003; Ohmori et al., 2002; Sugarawa et al., 2000), whereas other groups found significantly lower rates of around 35%. Truncating mutations are the most common, but missense mutations have also been reported. Fujiwara et al. (2003) found 25 nonsense mutations, two frameshift mutations, and 12 missense mutations in a series of 33 patients with SME. Whether such de novo mutations are present in all patients with Dravet syndrome and are the only mutations found or whether similar, but genetically inherited, mutations can also be responsible for Dravet syndrome remains to be explored.

The possible role of immunizations, especially those against pertussis, has been hotly debated (Menkes and Kinsbourne, 1990). Doose et al. (1998) found that 6 of 33 infants with onset in the first 6 months of life experienced their first seizure within 48 hours of pertussis immunization with a whole-cell vaccine. Given the average age at occurrence, that this is a coincidence seems probable (Robillard et al., 1983).

CLINICAL AND ELECTROENCEPHALOGRAPHIC FEATURES

The following description is based on the classic description by Dravet et al. (1982, 1992a). However, the clinical and EEG features of cases without myoclonus, which present as severe generalized or unilateral convulsive seizures (“hemi-grand mal”) with or without associated partial seizures, are also reviewed because drawing a clear delineation between the latter cases and SME seems difficult. This issue is further discussed.

Clinical Features

The clinical physiognomy and course of Dravet syndrome are highly suggestive, with an early appearance of convulsive seizures that are often prolonged and lateralized in a child with normal development. The onset of seizures occurs between 2 and 12 months of age (Dravet et al., 1992a; Giovanardi Rossi et al., 1991; Dalla Bernardina et al., 1982). The seizures are initially generalized, or they are often unilateral clonic seizures and less commonly tonic-clonic attacks. They are often long lasting (10 to 90 minutes). In the series by Doose et al. (1998), 67% of the attacks lasted more than 15 minutes, and 75% had localized symptoms. In more than three-fourths of infants, the lateralization of the attacks changed from one seizure to the next or even within the same attack. The seizures were related to fever in two-thirds to three-fourths of patients, although the level of fever was often modest, being either at or lower than 38°C. Even when the convulsions were nonfebrile, they were often triggered by minor infections. The precipitating effect of Japanese-style hot baths has been mentioned by Japanese investigators (Fujiwara et al., 1990; Sugama et al., 1987; Ogino et al., 1986), and it is common in the authors’ experience.

The seizures tend to recur even without fever, and, in all cases, afebrile attacks appear. In one-third of infants, afebrile seizures are the presenting symptom (Doose et al., 1998). A rapid recurrence of febrile seizures within 2 months of the first attack is common, and this should make the clinician suspicious of the possibility of this form of epilepsy, especially if further recurrences follow.

In much less common cases, the mode of onset may be myoclonic seizures that usually occur in the hours preceding the first convulsion; rarely, however, they may supervene days or weeks before (Dravet et al., 1992a, 2002).

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