HISTORICAL NOTE AND NOMENCLATURE

In 1964 this disorder was differentiated from a group of generalized epilepsies with sudden jerks that included those disorders now termed infantil.

The 1989 revised classification of the International League Against Epilepsy placed the disorder under "cryptogenic or symptomatic generalized epilepsies and syndromes" (Commission on Classification and Terminology of the International League Against Epilepsy 1989).

As described by Doose, this group of patients is supposed to share a genetic predisposition related to idiopathic generalized epilepsy and it was also called "centrencephalic myoclonic-astatic petit mal" (Doose et al 1970). Thus, it consists of an etiological concept, not of a syndrome with homogeneous electroclinical pattern. In fact, it comprises several subgroups, each subgroup consisting of an epilepsy syndrome. These subgroups are reported as "severe myoclonic epilepsy in infancy" (Dravet et al 1992a), "benign myoclonic epilepsy in infancy" (Dravet et al 1992b), and cases that begin later in childhood. Thus, series reported by Doose and coworkers include at least three different syndromes of myoclonic epilepsy.

This article will address the child-age group.


CLINICAL MANIFESTATIONS

Prior to the onset of myoclonic-astatic seizures, 84% of affected children show normal development; the remainder show moderate psychomotor retardation mainly affecting speech. The seizures usually begin between 2 and 5 years of age. Boys (74%) are more often affected than girls (Doose and Baier 1987a).

The first seizure is most often a generalized tonic-clonic seizure and rarely a myoclonic, astatic, myoclonic-astatic, or absence seizure. Generalized tonic-clonic or clonic seizures, occur as the initial symptom in more than half of the cases (Doose and Baier 1987a). They are usually prolonged, recurring frequently and during the daytime. After a period of repeat generalized tonic-clonic seizures lasting several months, so-called "minor motor seizures" appear, consisting of myoclonic seizures, absences, and drop attacks that occur several times a day. This period of frequent seizures lasts 1 to 3 years.

Myoclonic seizures usually involve the arms and shoulders symmetrically and are accompanied by head nodding. The myoclonic jerks are brief and vary in intensity: some may be so violent that the arms are flung upward; some so mild that they are palpable rather than visible. Irregular twitching of facial muscles, especially of the perioral and periocular musculatures, may also be seen. A brief yell, probably a result of contraction of the diaphragm, sometimes accompanies the myoclonic jerks (Doose et al 1970).

Drop attacks may result from pure astatic, myoclonic-astatic, or atypical absence seizures. Oguni and colleagues studied the nature of the drop attacks with video and slow-motion analysis and found myoclonic flexor jerks in 9 of 36 attacks, myoclonic-atonic in 2, and atonic, with or without brief preceding events, in 25. They concluded that atonic drop attacks were a common cause of ictal epileptic falling in myoclonic-astatic epilepsy (Oguni et al 1992).

Pure astatic seizures with abrupt loss of muscle tone may occur. Astatic seizures cause either drop attacks or merely brief head nodding or slight knee bending, depending on the extent of hypotonia. Consciousness usually remains clear during pure astatic seizures, and the child can resume the original posture immediately. Pure astatic seizures occur only rarely as the only manifestation of the disorder (Doose et al 1970).

The most common and characteristic seizure type, however, is the myoclonic-astatic seizure with symmetrical myoclonic jerks immediately followed by loss of muscle tone (postmyoclonic atonia). Lapse of consciousness accompanied by myoclonic and/or astatic seizures occurs in 62% of the cases. The pure myoclonic, pure astatic, or combined myoclonic-astatic seizures occur in 100% of the affected children (Doose 1992a).

Status epilepticus affects 36% of the patients with myoclonic-astatic seizures, but the consequences are variable. It may last for several hours or a few days without major consequences; it may last several weeks; or it may be repeated several times during a period of 1 to 2 years. During each episode, features of atypical absences, myoclonus, and astasia are present in varying degrees. The child appears apathetic, hypokinetic, and stuporous. Barely discernible myoclonic contractions and irregular twitching of facial muscles and the hands can be detected (Doose et al 1970; Dulac et al 1998).

Following these episodes of status, the general condition improves, and the patient may become seizure-free after a period with only generalized tonic-clonic seizures. However, for patients who exhibited long-lasting episodes of status, the general condition worsens, and tonic seizures occur during sleep and may remain as the only type of seizure the patient experiences after the age of 10. Thus, tonic seizures are not a regular component of the disorder. However, if they occur (usually appearing later in the course of the disorder and during sleep), prognosis is poor.


ETIOLOGY

Myoclonic-astatic epilepsy usually begins in previously normal children, and there is a high incidence of familial antecedents of idiopathic generalized epilepsy. Familial occurrence of seizure disorders can be detected in about one third of those cases (Doose and Baier 1987a). The prevalence is higher in siblings (16%) than in parents (6%). The prevalence of abnormal EEG patterns (photosensitivity, 4- to 7-Hz rhythms, spike and wave) without clinical seizures among the relatives is even higher. EEG abnormalities can be detected in 46% of siblings. The type of seizure in the affected relatives is variable; febrile or afebrile generalized tonic-clonic seizure predominates, followed by absence, myoclonic, or myoclonic-astatic seizures. Cases associated with generalized tonic-clonic seizures have an even higher prevalence (36%) of seizures among their parent or siblings than those without the generalized tonic-clonic seizures (12%) (Doose and Baier 1987a). These data suggest that a similar genetic predisposition could play a role as opposed to another syndrome of generalized epilepsy that begins in the same age range, Lennox-Gastaut syndrome.

However, some age-related modifying factor also seems to contribute, facilitating an unfavorable outcome by producing a pattern that resembles a more symptomatic or cryptogenic (ie, Lennox-Gastaut) syndrome than idiopathic epilepsy. The significance of subcortical atrophy reported in some patients by Langenstein and colleagues is difficult to determine (Langenstein et al 1979). It may result from repeat seizures or episodes of status or from the treatment.

It is suggested that myoclonic-astatic epilepsy of early childhood is inherited in a polygenic fashion with variable penetrance (Doose and Baier 1987b; Doose 1992b).


BIOLOGICAL BASIS

The pathology and pathogenesis of cryptogenic epilepsy with myoclonic-astatic seizures are not known, although genetic factors are likely.


EPIDEMIOLOGY

The prevalence and incidence of myoclonic-astatic epilepsy are not known. The condition is estimated to occur in 1% to 2% of all childhood epilepsies (Doose and Baier 1987a).


PREVENTION

No information is available.


DIFFERENTIAL DIAGNOSIS

The main disorders to be differentiated from epilepsy with myoclonic-astatic seizures include late-onset infantile spasms, Lennox-Gastaut syndrome, and continuous spike waves in slow sleep.

The seizures of late-onset infantile spasms are brief spasms of trunk flexion or extension occurring in a cluster. Salaam movement (trunk flexion) is characteristic. The interictal tracing may show more synchronous slow spike-wave activity than infantile spasms starting in infancy (Bednarek et al 1998). Epilepsy with myoclonic-astatic seizures, on the other hand, has a more polymorphous seizure pattern (myoclonic, astatic, myoclonic-astatic, absence, generalized tonic-clonic, clonic and tonic seizures). The seizures are more prolonged, and the EEG shows regular and irregular bilaterally synchronous 2- to 3-Hz spike-waves and polyspike patterns with a 4- to 7-Hz background.

Although drop attacks are common to both Lennox-Gastaut syndrome and epilepsy with myoclonic-astatic seizures, the predominant seizure type in Lennox-Gastaut syndrome is tonic. Tonic seizures are less common in epilepsy with myoclonic-astatic seizures and, if this develops, it occurs mainly during sleep. Atypical absence may occur independently in Lennox-Gastaut syndrome, whereas the absence in epilepsy with myoclonic-astatic seizures usually occurs accompanying myoclonic and/or astatic episodes. The EEG of Lennox-Gastaut syndrome shows a pattern of diffuse slow (2-Hz) spike-waves and polyspike-waves superimposed on a slow background activity, whereas epilepsy with myoclonic-astatic seizures shows more rapid (2- to 3-Hz) spike-waves on a 4- to 7-Hz background.

Continuous spike waves in slow sleep produce drop attacks due to atypical absences or negative myoclonus, characterized by lapses of muscle tone that appear when the patient stretches the arm in front but that do not show when the patient is lying down (Guerrini et al 1993). Sleep EEG shows continuous spike-wave activity from the beginning of slow wave sleep.


DIAGNOSTIC WORKUP

The EEG may initially show only an abnormal 4- to 7-Hz rhythm. Later, regular or irregular bilaterally synchronous 2- to 3-Hz spike-waves and/or polyspike-waves will be superimposed on the background activity. Sleep can facilitate the appearance of spike-wave discharges.


PROGNOSIS AND COMPLICATIONS

Epilepsy with myoclonic-astatic seizures has a variable course and outcome. Spontaneous remission with normal development has been observed in a few untreated cases. Complete seizure control can be achieved in about half of the cases with antiepileptic drug treatment (Doose and Baier 1987b; Dulac et al 1990). In the remainder of cases, the level of intelligence deteriorates and the children become severely retarded. Other neurologic abnormalities such as ataxia, poor motor function, dysarthria, and poor language development may emerge (Doose 1992b). However, this proportion may not be representative because in this series the data were collected in an institution for children with severe epilepsy.

The outcome is unfavorable if generalized tonic-clonic, tonic, or clonic seizures appear at the onset or occur frequently during the course. Generalized tonic-clonic seizures usually occur during the daytime in this disorder, at least in the early stages. Nocturnal generalized tonic-clonic seizures, which may develop later, are another unfavorable sign. If tonic seizures appear, prognosis is poor.

Status epilepticus with myoclonic, astatic, myoclonic-astatic, or absence seizures is another ominous sign, especially when prolonged or appearing early.

Failure to suppress the EEG abnormalities (4- to 7-Hz rhythms and spike-wave discharges) during therapy and absence of occipital alpha-rhythm with therapy also suggest a poor prognosis (Doose 1992a).


MANAGEMENT

Therapy for epilepsy with myoclonic-astatic seizures in early childhood remains empirical. Some compounds should never be given because they contribute to worsen the condition: carbamazepine, phenytoin, and vigabatrin (Perucca et al 1998). In addition, phenobarbital should be avoided because of its metabolic interaction with valproate. Indeed, valproate, ethosuximide and benzodiazepine, and clobazam more than clonazepam, have been used successfully (Doose and Baier 1987b). However, the most efficient combination seems to be valproate with lamotrigine, since these two compounds exhibit beneficial potentiation (Panayiotopoulos et al 1993). In practice, the best therapy seems to begin with valproate followed by the addition of lamotrigine in case of resistance to valproate, whereas benzodiazepines should be restricted to episodes of status epilepticus. It remains to be determined whether there is any benefit in the use of steroids.


PREGNANCY

No information is available.


ANESTHESIA

No information is available.


REFERENCES CITED

Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-99.

Doose H. Das akinetische petit mal. Arch Psychiatr Nervenkr 1964;205:637-54.

Doose H. Myoclonic astatic epilepsy of early childhood. In: Roger J, Dravet C, Bureau M, Dreifuss FE, Perret A, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey; 1992a:103-14.

Doose H. Myoclonic-astatic epilepsy. In: Dyen R, Dreifuss FE, editors. Benign localised and generalized epilepsies of early childhood. Epilepsy Res 1992b;Suppl 6:163-8.

Doose H, Baier WK. Genetic factors in epilepsies with primary generalized minor seizures. Neuropediatrics 1987a;18(Suppl 1):1-64.

Doose H, Baier WK. Epilepsy with primary generalized myoclonic-astatic seizures: a genetically determined disease. Eur J Pediatr 1987b;146:550-4.

Doose H, Gerken H, Leonhardt R, Volzke E. Centrencephalic myoclonic-astatic petit mal. Clinical and genetic investigation. Neuropadiatrie 1970;2:59-78.

Dravet C, Bureau M, Guerrini R, Giraud N, Roger J. Severe myoclonic epilepsy in infants. In: Roger J, Bureau M, Dravet C, Dreifuss F, Perret A, Wolf P. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey; 1992a:75-88.

Dravet C, Bureau M, Roger J. Benign myoclonic epilepsy in infants. In: Roger J, Bureau M, Dravet C, Dreifuss F, Perret A, Wolf P. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey; 1992b:67-74.

Dulac O, Plouin P, Chiron C. [Benign form of myoclonic epilepsy in children]. [French]. Neurophysiol Clin 1990;20:115-29.

Dulac O, Plouin P, Shewmon A. Myoclonus and epilepsy in childhood: 1996 Royaumont meeting. Epilepsy Res 1998;30(2):91-106.

Guerrini R, Dravet C, Genton P, et al. Epileptic negative myoclonus. Neurology 1993;43:1078-83.

Langenstein I, Kuhne D, Sternowsky HJ, Rothe M. Computerized cranial transverse axial tomography (CTAT) in 145 patients with primary and secondary generalized epilepsies. West syndrome, myoclonic-astatic petit mal, absence epilepsy. Neuropediatrie 1979;10:15-28.

Oguni H, Fukuyama Y, Uehara T. Video-EEG analysis of drop seizures in myoclonic-astatic epilepsy of early childhood [Doose syndrome]. Epilepsia 1992;33:805-13.

Panayiotopoulos CP, Ferrie CD, Knott C, Robinson RO. Interaction of Iamotrigene with sodium valproate. Lancet 1993;341(8842):445.

Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998;39(1):5-17.

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