Dravet's Syndrome (severe myoclonic epilepsy in infancy)

Dravet's Syndrome (severe myoclonic epilepsy in infancy)

Dravet C

2003

Disease Specific

HISTORICAL NOTE AND NOMENCLATURE Severe myoclonic epilepsy in infancy was described by Dravet in 1978 (Dravet 1978). In 2002 Dravet and colleagues found at least 445 published cases. The 1989 revised classification of the International League Against Epilepsy places this syndrome under "epilepsies and syndromes undetermined as to whether they are focal or generalized," since the syndrome shows both generalized and localized seizure types and EEG paroxysms (Commission on Classification and Terminology of the International League Against Epilepsy 1989). Many children have been reported to have symptoms similar to Dravet syndrome only without myoclonias (Sugama et al 1987; Ogino et al 1989; Kanazawa 1992; Yakoub et al 1992). This has also been mentioned by Dravet (Dravet et al 1992). These patients may have different EEG features but they share the same course and outcome as the patients with myoclonias. Thus, they can be included in Dravet syndrome. This seems to be supported by the genetic studies performed by Doose and colleagues (Doose et al 1998). Thus it has been proposed to change its name, first to “epilepsy with polymorphic seizures” and then to “Dravet syndrome." CLINICAL MANIFESTATIONS Severe myoclonic epilepsy begins during the first year of life. Development is normal prior to the onset of seizures. Affected infants develop either generalized or unilateral clonic seizures without prodromal signs. Myoclonic jerks and partial seizures usually appear later. Psychomotor retardation and other neurologic deficits occur in affected children. The first seizure type that appears is a clonic seizure, either generalized or unilateral, often changing sides These seizures may be brief or long in duration. In many cases, the first seizure appears in association with fever. The febrile seizures in these cases often recur in 6 to 8 weeks and may be prolonged, leading to status epilepticus. Later in the course, the seizures may recur without rise of body temperature (Dravet et al 1992). These convulsive seizures, carefully analyzed with video-EEG recordings performed along the course, are polymorph. They can be clearly generalized, clonic and tonic clonic, or unilateral, hemiclonic.|{diagram:cdds1.bmp}{caption:Polygraphic recording of a convulsive seizure during sleep}{label:Association of asymmetric tonic-clonic components demonstrating a short hemiclonic seizure are seen in this 7-year-old girl. Onset occurs with a right discharge of polyspikes and polyspike waves. Then, the discharge involves the right hemisphere, spreading to the opposite side. Postictal right depression and slow waves are shown.}| More often, they have peculiar clinical and EEG features that do not permit classification under generalized clonic or tonic-clonic seizures. They are characterized by clonic or tonic components, initially predominating in the head and the face, evolving to variable, bilateral localization, and loss of consciousness. When they are short in duration there are no autonomic symptoms. They were named “falsely generalized” or “unstable” (Dravet et al 2002). The second seizure type is myoclonic seizures. Typically they are generalized, involving the body axis and the proximal part of the limbs. They are accompanied by generalized spike-waves and polyspike waves in the EEG.|{diagram:cdds2.bmp}{caption:Polygraphic recording of massive myoclonias}{label:Numerous myoclonic jerks are associated with generalized spike-waves and polyspike-waves in the 5-year 10-month-old boy.}| Sometimes, they begin focally and are limited to one limb or the head prior to becoming generalized seizures (Dravet et al 2002). The myoclonic jerks are usually frequent, occurring several times a day. These myoclonic seizures are often associated with interictal segmental myoclonus.|{diagram:cdds3.bmp}{caption:Polygraphic recording of interictal myoclonias increased by movements}{label:The left side shows the patient at rest; the right side shows her in movement. Myoclonias are not associated with spike-waves.}| The third seizure type is absence seizures, which are atypical and of rather short duration, with more or less rhythmical generalized spike-waves in the EEG. The fourth seizure type is complex partial seizures with atonic or adversive and autonomic phenomena as well as automatisms. Occasionally they secondarily generalize. The occurrence of status epilepticus is frequent, either convulsive (often febrile), or as obtundation status (Dravet et al 2002). The latter consist of an impairment of consciousness, variable in intensity, the presence of fragmentary and segmental erratic myoclonias, sometimes associated with a slight increase of the muscular tone. Convulsive seizures can either initiate or occur during or terminate these status. They are prolonged for several hours or days. The EEG shows a diffuse dysrhythmia of slow waves, intermixed with focal and diffuse spikes. Psychomotor retardation is observed usually during the second year after the onset of seizures. Progressive neurologic deficits such as ataxia and corticospinal tract signs subsequently develop. The interictal EEGs are characterized by the association of generalized and focal and multifocal anomalies |{diagram:cdds4.bmp}{caption:Interictal EEG abnormalities}{label:From left to right: Left posterior temporal spike-waves; left temporal posterior spike-waves spreading to the left hemisphere; right posterior temporal spike-waves spreading to the right hemisphere and vertex; left posterior temporal spike-waves associated to one right hemispheric spike-wave spreading to the left frontal area and vertex.}| as well as by a strong photosensitivity in a large proportion of cases (more than 40%) (Dravet et al 2002). The background is variable, often with an either transitory or permanent. CLINICAL VIGNETTE The patient was born on March 1, 1994. There was no family history of epilepsy, febrile convulsions, or pathological antecedents. The patient demonstrated normal psychomotor development. The first unilateral febrile seizure occurred at 10 months on the left side for about 10 minutes. EEG was normal, and the patient was treated with phenobarbital. Other convulsive seizures, febrile and afebrile, occurred in the following months, either generalized or lateralized on the left. At 13 months, myoclonias and brief atypical absences with progressive and jerky head fall or complete fall appeared several times a day. The child then started to self-stimulate by pattern fixation. She began walking at 10 months and talking at 11 months. Psychomotor development and hyperkinetic behavior then began to slow. CT and MRI scans were then performed, and biological investigations are normal. The EEGs showed numerous generalized spike-waves and polyspike waves. Different antiepileptic drugs were prescribed, but without success. Lamotrigine triggers a worsening of the seizures. The child was referred to our center at 2 years 9 months of age. She had daily seizures consisting of atypical absences and clonic seizures, lateralized either on the left or on the right. She presented with a slight ataxia, diffuse hypotonia, and mild psychomotor retardation. She spoke in sentence fragments and played in a stereotyped manner, but interacted well socially. EEGs showed numerous generalized spike-waves and polyspike waves: background at 5 Hz to 6 Hz, generalized spike-waves and polyspike waves that increased during sleep, associated with multifocal anomalies. No effect of intermittent photic stimulation. Numerous atypical absences were recorded that were spontaneous or elicited by patterns. One right hemiclonic seizure was recorded during 1 minute, followed by a brief right motor deficit, which is typical for severe myoclonic epilepsy in infancy. The slight degree of mental deficit may be explained by the epileptic status as well as the absence of prolonged seizures during the course of the disease. ETIOLOGY Severe myoclonic epilepsy in infancy is not associated with previous significant brain pathology. Neuroimaging studies have occasionally shown diffuse atrophy, but no specific abnormalities have emerged and the majority of patients have shown no abnormalities on CT or MR scanning. Although the first neuropathologic description of severe myoclonic epilepsy of infancy revealed microdysgenesis of cerebral cortex and cerebellum and malformation of the spinal cord (Renier and Renkawek 1990), no other such abnormalities have subsequently been reported. When performed muscular and skin biopsies were negative (Guerrini and Dravet 1998). The most probable etiological background is of genetic nature. PATHOGENESIS AND PATHOPHYSIOLOGY In 15% to 25% of cases there is a family history of either epilepsy or febrile convulsions, suggesting a genetic basis for this disorder. Four pairs of affected monozygotic twins (Fujiwara et al 1990; 1992; Musumecci et al 1992; Ohki et al 1997) and one pair of dizygotic twins (Ohtsuka et al 1991) were reported. Three families with 2 affected sibs were also reported (Ogino et al 1989; Dravet et al 2002). In 2001 Claes and colleagues found new mutations in the sodium-channel gene SCN1A in all of the studied 7 probands with severe myoclonic epilepsy in infancy (Claes et al 2001). Other publications have confirmed these data, but the mutation rates are not so high as in the first study (Ohmori et al 2002; Sugawara et al 2002; Yamakawa 2002). EPIDEMIOLOGY Severe myoclonic epilepsy in infancy is a rare disease, with an incidence probably less than 1 per 40,000 (Hurst 1990). Almost the same figure (1 per 20,000 or 30,000) was later reported (Yakoub et al 1992). Males are more often affected than females in the ratio of 2 to 1. PREVENTION No information was provided by the author. DIFFERENTIAL DIAGNOSIS Since the first clonic seizures in severe myoclonic epilepsy are often associated with fever, distinction from febrile convulsions is important. In severe myoclonic epilepsy, (1) the onset is earlier (before 1 year of age) than in febrile convulsions, where the age of onset is between 18 and 22 months; (2) the seizure type is clonic and often unilateral instead of generalized tonic-clonic; and (3) the seizure episodes are more prolonged and frequent, even when treated. The diagnosis can be established if other seizure types, particularly myoclonic jerks and photically-induced spike-waves, are observed (Dravet et al 2002). When no myoclonias occur but the other seizure types appear (atypical absences, partial seizures, obtundation status), the diagnosis is also that of severe myoclonic epilepsy but in its variant without myoclonias. Lennox-Gastaut syndrome is virtually excluded by a history of febrile clonic seizures in the first year of life and is characterized by drop attacks, atypical absences, axial tonic seizures, and specific electroencephalographic abnormalities. Difficulties may arise in differentiating severe myoclonic epilepsy from myoclonic-astatic epilepsy. In some cases of the latter, there is an early onset with febrile convulsive seizures but during the course of the epilepsy there are neither partial seizures nor focalization on the EEGs, and the main seizure type is myoclonic-astatic (Doose et al 1998; Guerrini et al 2002). The progressive myoclonic epilepsies due to storage could be evoked, but at this age run a different course and can be eliminated by biological and neurophysiological investigations and by fundus. An early cryptogenic focal epilepsy may have the same onset with febrile convulsions rapidly associated with focal seizures; these patients will not present atypical absences and myoclonic jerks. This diagnosis is improbable when the hemiclonic seizures are alternating and when partial motor seizures affect different parts of the body (Sarisjulis et al 2000). DIAGNOSTIC WORKUP The diagnosis is based on the clinical findings described above. One must underline the great value of the hyperthermia as a triggering factor, even when the elevation of temperature is not very high, as well as hot bath and physical efforts (Awaya et al 1989; Dravet et al 2002). In the initial stage of severe myoclonic epilepsy, the EEG may not show any abnormal patterns. As the syndrome evolves, generalized spike-waves and polyspike-waves become apparent. The paroxysmal discharges may occur either in single episodes or in clusters, and there is usually a predominance on one side of the hemispheres. Intermittent photic stimulation and drowsiness may facilitate the appearance of EEG paroxysms. In addition to the generalized discharges, localized paroxysms of spikes and spike-waves are also common and mostly multifocal (Dravet et al 2002). The interictal background activity is normal at onset and has a tendency to deteriorate afterwards. Paroxysmal activities tend to disappear on awake EEGs and be prominent on sleep EEGs. Laboratory tests are usually within normal limits. CT and MRI are usually normal except for a few cases with dilatation of the cisterna magna or slight diffuse atrophy (Dravet et al 2002). PROGNOSIS AND COMPLICATIONS The outcome of severe myoclonic epilepsy in infancy is unfavorable. The affected children will persistently be affected with seizures. Partial seizures disappear and myoclonic jerks disappear or attenuate. Convulsive seizures are mainly localized at the end of the night. Fever remains a triggering factor and can still provoke epileptic status. Neurologic abnormalities remain stable. All patients are cognitively impaired (severely in 50%) but without deterioration after the age of 4 years (Guerrini and Dravet 1998). Many also have behavioral disorders, including psychosis. The mortality rate is very high, from 15.9% to 18% (Dravet et al 2002). The cause of death is variable, including drowning, accident, seizure, status epilepticus, infection, and sudden unexpected death. MANAGEMENT Treatment is disappointing. Valproate and benzodiazepines (clonazepam, lorazepam) are the most useful drugs. Phenobarbital, potassium bromide (convulsive seizures), and ethosuximide (myoclonic seizures and absences) can help some children. The effect of vigabatrin is variable. Carbamazepine and lamotrigine often have an aggravating effect (Guerrini et al 1998; Wallace 1998). The helpfulness of ketogenic diet needs to be proven (Caraballo et al 1998). Recently, stiripentol (Chiron et al 2000) and topiramate (Coppola et al 2002; Villeneuve et al 2002) have been shown to be effective against the convulsive seizures and the status. It is important is to avoid the long, generalized, unilateral seizures by preventing infectious diseases and hyperthermia, which are their triggering factors. PREGNANCY Not applicable. ANESTHESIA Not applicable. REFERENCES Caraballo R, Tripoli J, Escobal L, Cersosimo R, et al. Ketogenic diet: efficacy and tolerability in childhood intractable epilepsy. Rev Neurol 1998;26:61-4. Chiron C, Marchand MC, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomized placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet 2000;356(9242):1638-42. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001;68(6):1327-32.** Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:289-99. Coppola G, Capovilla G, Montagnini A, et al. Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial. Epilepsy Res 2002;49(1):45-8. Doose H, Lunau H, Castiglione E, Waltz S. Severe idiopathic generalized epilepsy of infancy with generalized tonic-clonic seizures. Neuropediatrics 1998;2:229-38.** Dravet C. Les epilepsies graves de l'enfant. Vie Med 1978;8:543-8. Dravet C, Bureau M, Guerrini R, Giraud N, Roger J. Severe myoclonic epilepsy in infants. In: Roger J, Dravet C, Bureau M, Dreifuss FE, Perret A, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. 2nd ed. London: John Libbey, 1992:75-88.** Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy (Dravet syndrome). In: Roger J, Bureau M, Dravet Ch, Genton P, Tassinari CA, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. 3rd ed. London: John Libbey, 2002:81-103.** Fujiwara T, Nakamura H, Watanabe M, Yagi K, Seino M, Nakamura H. Clinicoelectrographic concordance between monozygotic twins with severe myoclonic epilepsy in infancy. Epilepsia 1990;31:281-6. Guerrini R, Dravet C. Severe epileptic encephalopathies of infancy, other than West syndrome. In: Engel J and Pedley TA, editors. Epilepsy. A comprehensive textbook. Vol. 3, Philadelphia-New-York: Lippincott-Raven, 1998:2285-302. Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 1998;39:508-12.** Guerrini R, Parmeggiani L, Kaminska A, Dulac O. Myoclonic astatic epilepsy. In: Roger J, Bureau M, Dravet Ch, Genton P, Tassinari CA, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. 3rd ed. London: John Libbey, 2002:106-12.** Hurst DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia 1990;31;397-400. Kanazawa O. Medically intractable generalized tonic-clonic or clonic seizures in infancy. J Epilepsy 1992;5:143-8.** Ogino T, Ohtsuka Y, Yamatogi Y, Oka E, Ohtahara S. The epileptic syndrome sharing common characteristics during early childhood with severe myoclonic epilepsy of infancy. Jpn J Psychiatry Neurol 1989;43:479-81. Ohki T, Watababe K, Negoro T, et al. Severe myoclonic epilepsy in infancy: evolution of seizures. Seizure 1997;6(3):219-24. Ohmori I, Ouchida M, Ohtsuka Y, Oka E, Shimizu K. Significant correlation of the SCN1A mutations and severe myoclonic epilepsy in infancy. Biochem Biophys Res Commun 2002;295(1):17-23. Ohtsuka Y, Maniwa S, Ogino T, Yamatogi Y, Ohtahara S. Severe myoclonic epilepsy in infancy: a long-term follow-up study. Jpn J Psychiatry Neurol 1991;45(2):416-8. Renier WO, Renkawek K. Clinical and neuropathologic findings in a case of severe myoclonic epilepsy of infancy. Epilepsia 1990;31:287-91. Sarisjulis N, Gamboni B, Plouin P, Kaminska A, Dulac O. Diagnosing idiopathic/cryptogenic epilepsy syndromes in infancy. Arch Dis Child 2000;82:226-30. Sugama M, Oguni H, Fukuyama Y. Clinical and electroencephalographic study of severe myoclonic epilepsy in infancy (Dravet). Jpn J Psychiatry Neurol 1987;41:463-5. Sugawara T, Mazaki-Miyazaki E, Fukushiman K, et al. Frequent mutations of SCN1A in severe myoclonic epilepsy in infancy. Neurology 2002;58(7):1122-4. Villeneuve N, Portilla P, Ferrari AR, Dulac O, Chauvel P, Dravet C. Topiramate (TPM) in severe myoclonic epilepsy in infancy (SMEI): study of 27 patients. Epilepsia 2002;43(suppl 8):155. Wallace SJ. Myoclonus and epilepsy in childhood: a review of treatment with valproate, ethosuximide, lamotrigine and zonisamide. Epilepsy Res 1998;29:147-54. Yakoub M, Dulac O, Jambaque I, Chiron C, Plouin P. Early diagnosis of severe myoclonic epilepsy in infancy. Brain Dev 1992;14;299-303.** Yamakawa K. Mutations of sodium-channels in GEFS+ and SMEI. Brain Dev 2002;24(6):358. ILAE ILAE Copyright Notice ABBREVIATIONS CT:computed tomography EEG:electroencephalogram ILAE:International League Against Epilepsy MR:magnetic resonance ICD CODE 345.1 SYNONYMS Dravet’s syndrome Epilepsy with polymorphic seizures SME SMEI ASSOCIATED DISORDERS Febrile convulsions Severe idiopathic generalized epilepsy of infancy with generalized tonic-clonic seizures MAJOR KEYWORD DESCRIPTORS clonic seizures cognitive impairment complex partial seizures epilepsy febrile convulsions myoclonus photic stimulation psychomotor retardation seizures status epilepticus MINOR KEYWORD DESCRIPTORS behavioral disorders infancy neurologic deficits pyramidal signs slow waves spike-waves AGE OF PRESENTATION 01-23 months AGE OF TYPICAL PRESENTATION 01-23 months POPULATION GROUP(S) PREFERENTIALLY AFFECTED none selectively affected OCCUPATION GROUP(S) PREFERENTIALLY AFFECTED none selectively affected SEX male>female, >1:1 FAMILY HISTORY family history may be obtained HEREDITY heredity may be a factor GLOSSARY Dravet syndrome (severe myoclonic epilepsy in infancy):Epileptic syndrome characterized by infantile onset, multiple seizure types, and progressive cognitive decline. ILLUSTRATION CAPTIONS Figure 1 Title: Polygraphic recording of a convulsive seizure during sleep. Legend: in this girl of 6 years 11 months, association of asymmetric tonic and clonic components, realizing a short hemiclonic seizure. Onset by a right discharge of polyspikes and PSW. Then, the discharge involves the right hemisphere, spreading to the opposite side. Postictal right depression and slow waves. OCULO: oculogram R. EXT: right wrist extensor muscle R. FLEX: right wrist flexor muscle L. DELT: left deltoid muscle L. EXT: left wrist extensor muscle L. FLEX: left wrist flexor muscle Figure 2. Title: polygraphic recording of more or less massive myoclonias. In this boy of 5 years 10 months, numerous myoclonic jerks are associated with generalized SW and PSW. R. DELT: right deltoid R. EXT: right wrist extensor muscle R. FLEX: right wrist flexor muscle L. DELT: left deltoid muscle L. EXT: left wrist extensor muscle L. FLEX: left wrist flexor muscle Figure 3 Title: polygraphic recording of interictal myoclonias increased by movements Legend: myoclonias recorded in the same girl as in figure 1.On the left she is at rest; on the right she moves. Myoclonias are not associated with SW. DELT R: right deltoid L. DELT: left deltoid L. EXT: left wrist extensor Figure 4. Title: interictal EEG abnormalities. Legend: in the same girl as in figure 1, at 4 years 2 months. From left to right: left posterior temporal SW; left temporal posterior SW spreading to the left hemisphere; right posterior temporal SW spreading to the right hemisphere and vertex; left posterior temporal SW associated to one right hemispheric SW spreading to the left frontal area and vertex. Video clip 1. Title: polygraphic recording of different seizure types in a girl of 2 years 9 months. Legend: EEG montage from the top to the bottom: right longitudinal derivations; right wrist extensor muscle; left longitudinal derivations; left deltoid muscle; two vertex derivations. First sequence. Five spontaneous brief atypical absences. The girl plays, sitting on the bed. She bents forward by a slightly jerking movement, without obvious myoclonias on the polygraphy. EEG: very high amplitude generalized PSW followed by slow waves (2 to 3 seconds). Second sequence. A / two successive atypical absences during the presentation of striped patterns. She lies on the bed. There is only a small change in the mimic and a slight chewing, accompanied by PSW. B / the third absence is followed by a right hemiclonic seizure, with head and eyes turning to the right, low amplitude myoclonias involving the face and the right limbs. Discrete cyanosis of the lips and pupillary dilatation (1 minute duration). At the end, the girl closes her eyes and has a large inspiration. Then, she remains confused with a transitory motor deficit of the left arm. EEG: apparently generalized PSW. T the 20th second the gain is decreased and the discharge appears asymmetric, higher on the left hemisphere. Asymmetric slow waves during the postictal phase. PERMUTED TOPIC, SYNONYMS, VARIANTS Dravet syndrome (severe myoclonic epilepsy in infancy) severe myoclonic epilepsy in infancy, Dravet syndrome myoclonic epilepsy in infancy, Dravet’s syndrome seizures, Epilepsy with polymorphic polymorphic seizures, Epilepsy syndrome, Dravet syndrome, Dravet’s RELATED TOPICS Epilepsia partialis continua Epilepsy Myoclonic status Myoclonic-astatic epilepsy of childhood Myoclonus DIFFERENTIAL DIAGNOSIS febrile convulsions Lennox-Gastaut syndrome progressive myoclonic epilepsies due to storage diseases early cryptogenic focal epilepsy

2003

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