HISTORICAL NOTE AND NOMENCLATURE

In literature we can find proof, in different forms of epilepsy, of an absence status with myoclonias of variable duration called by various names, such as "minor epileptic status," "minor motor status," "obtundation with myoclonias," "non convulsive status with ataxia," etc. (Brett 1966; Bennett et al 1982; Aicardi and Chevrie 1971).

On the other hand, the reports outlining the existence of an epileptic syndrome essentially characterized by the recurrence of long-lasting or subcontinuous myoclonic status in children with a nonprogressive encephalopathy are very rare (Dalla Bernardina et al 1980; 1995; Chiron et al 1988; Dulac et al 1996).

A similar picture has been described by many authors (Matsumoto et al 1992; Sugimoto et al 1992; Casara et al 1995; Viani et al 1995; Guerrini et al 1996; Laan et al 1997; Rubin et al 1997) in some children with Angelman's syndrome, but only a few authors have outlined how, in some of these cases, the electroclinical picture was typically that of myoclonic status in children with a nonprogressive encephalopathy (Dalla Bernardina et al 1992a; 1992b; 1995; Mizuguchi et al 1994).

A similar picture has also been reported by Sgr˜ and colleagues in some children with 4 p-syndrome (Sgr˜ et al 1995).


CLINICAL MANIFESTATIONS

The average age of seizure onset is 12 months (range: 1 day to 5 years). In 18 cases the epilepsy onset was constituted by myoclonic status; in the others the initial seizures are mostly partial motor seizures, more or less typical, myoclonic absences, massive myoclonias, and more rarely generalized or unilateral clonic seizures recurring in some cases only in the case of a febrile illness.

The average age of myoclonic status recognition is 17 months (range: 4 months to 5 years). Because myoclonic status develops insidiously and can remain unrecognized for several months, the average age of myoclonic status onset is probably lower.

Females predominate with a sex ratio male/female of 1/2.

A neurologic impairment is pre-existing in all subject, appearing in the majority as an encephalopathy characterized by a severe axial hypotonia with polymorphous and subcontinuous mixed abnormal movements and severe mental retardation.

The myoclonic status is clinically characterized by very frequent or subcontinuous "absences" accompanied by frequent or subcontinuous myoclonias involving the face or face and distal muscles.

The myoclonias are mostly erratic and asynchronous on different muscles, becoming, with a variable frequency, more rhythmic and synchronous, especially during the most evident absences.

Because of the severe mental retardation and the continuous abnormal movements, both the absences (especially when subcontinuous) and the myoclonias are difficult to recognize.

Also, in many children, frequent and sudden spontaneous massive startles recur with variable frequency. When the child is observed, especially during action, we can view more or less long-lasting bursts of intentional myoclonus or tremor and again repeated brief and abrupt loss of postural tone. The epileptic or other nature of these startles remains unclear.

During slow sleep the absences and the myoclonias, like other abnormal movements, disappear. Nevertheless, looking at the child during drowsiness, when more important abnormal movements disappear, it is possible sometimes to observe slight subcontinuous myoclonias involving fingers and toes. Always during drowsiness, sudden massive startles or brief sequences of bilateral rhythmic jerks can also be recognized.

With the occurrence of myoclonic status the child progressively regresses. The acquired postural skills are impaired or lost with a concomitant increase of the hyperkinetic behavior. According to a concomitant regression of the cognitive skills the child becomes more listless with long-lasting periods of marked irritability.

In some children the prominent seizures are brief absences with myoclonias or brief myoclonic absences mixed with brief bursts of intentional tremor; the intentional tremor seems to be the predominant feature in some children whereas the inhibitory phenomenon is predominant in others.

Other kinds of seizures are rare; tonic seizures in particular are never observed.


ETIOLOGY

In about half the cases of myoclonic status in nonprogressive encephalopathies there is a chromosomal disorder (Angelman syndrome, 4p-syndrome). In approximately one fifth the anamnestic, clinical, and neuroradiological findings strongly suggest a prenatal anoxia ischemic insult, in some cases associated with a variable migrational disorder. In the remaining one third the etiology in unknown. A family history of seizure disorders can be found in about one fifth of cases.


BIOLOGICAL BASIS

Both the pathogenesis and pathologic basis of myoclonic status in nonprogressive encephalopathies are unknown. Considering that a lot of the patients with Angelman syndrome and some of the patients with 4p-syndrome have a chromosomal deletion eliminating a cluster of GABAA receptor genes, it is possible to hypothesize that a loss of GABAergic inhibition could play a role in the pathogenesis of myoclonic status in nonprogressive encephalopathies.


EPIDEMIOLOGY

This syndrome is rare. Although its incidence and prevalence are unknown it was found in 0.5% to 1% of a selected population of children with epilepsy followed at the Neuropediatric Service of the University of Verona, Italy.


PREVENTION

No information is available.


DIFFERENTIAL DIAGNOSIS

Because of the significant increase of neuropsychological impairment that accompanies the appearance of myoclonic status with a nonprogressive encephalopathy, the eventuality of a progressive disease must be considered and discarded. Particularly in some cases presenting frequent atypical absences with concomitant myoclonic-atonic phenomena, the electroclinical picture can be quite similar to that characterizing one of the evolutive phases of the late infantile form of neuronal ceroid-lipofuscinosis.

A differential diagnosis can also be difficult with some of the cases presenting a "newborn continuous partial epilepsy" (Dalla Bernardina et al 1987), that is a form probably corresponding to that described by Coppola and colleagues as migrating partial seizures in infancy (Coppola et al 1995). Some of these cases can present long-lasting status characterized by continuous discharges of diffuse spikes and waves accompanied by bilateral asynchronous myoclonias with obtundation and drooling.


DIAGNOSTIC WORKUP

Diagnosis needs repeated video EEG-polygraphic recordings.

Although the patient is awake the EEG is characterized by a slow background activity with more or less frequent focal or multifocal abnormalities. These abnormalities are constituted by ample theta-delta waves in bursts, involving more or less asynchronously the fronto-central regions, and by brief sequences of rhythmic delta waves with a superimposed spike realizing an unusual spike and wave, predominant in parieto-occipital regions, often elicited by eye closure.

The ictal manifestations are characterized by brief bursts of diffuse slow spikes and waves accompanied by myoclonias often rhythmic and bilateral, mixed with other continuous and polymorphous abnormal movements. Sometimes the myoclonias are rhythmic and bilateral in bursts or continuous and strictly related to EEG charges, but frequently in the same subjects, myoclonias are continuous but asynchronous in the different muscles. In the first condition the ictal pattern is very similar to that of a myoclonic absence. In the second condition the relationship between myoclonias and paroxysmal EEG discharges is more difficult to appreciate and the paroxysmal nature of the EEG pattern is often difficult to recognize too. In some cases the paroxysmal abnormalities are characterized by a continuous sequence of slow waves relatively monomorphous but varying in amplitude, predominating on the central regions.

In most cases, during all stages of slow sleep, there is a great increase in frequency of the paroxysmal discharges, realizing the picture of a continuous spike and wave during slow sleep. So in some cases, only the sleep record permits an easy identification of the paroxysmal discharges. Like the "absences" the myoclonias are more easily recognized during drowsiness because of the disappearance of other abnormal movements.|{diagram:msbb1.bmp}{caption:Ictal events in myoclonic status}{label:Slow spike-wave discharges in bursts of variable duration at awakening and during drowsiness. Note on the left the stop of abnormal movements related to consciousness disturbances and arrest of motion induced by the discharge and the presence on the EMG of rhythmic myoclonias related with the rolandic rhythmic theta waves. During drowsiness in the absence of other abnormal movements there is a clear relationship between spike waves and myoclonias. Abbreviations: EXT: extensor of the hand; FLEX: flexor of the hand; DEL: deltoid.}|

The EEG pattern of the status is characterized in the majority by a marked fluctuation of the paroxysms; it is possible to observe, in fact, recurring bursts of spikes and waves or slow waves more or less diffuse, more or less synchronous, or asynchronous on both hemispheres. These bursts are intercalated by periods of variable duration without obvious paroxysmal discharges but with theta activity of variable amplitude involving subcontinuously both central regions.|{picture:msbb2.bmp}{caption:EEG of myoclonic status}{label:Continuous "paroxysmal" rhythmic theta activity on the center-frontal region of both hemispheres with frequently recurring, more obvious paroxysmal discharges in bursts. Note the relationship between the rhythmic myoclonias and the diffuse discharges and also the subcontinuous rhythmic myoclonias related with the rhythmic theta activity. Abbreviations: EXT: extensor of the hand; FLEX: flexor of the hand; DEL: deltoid.}|

The proof that they are not separate ictal events recurring at a more or less high frequency, but a true status, is favored by observing that, like the theta activity, the myoclonias also are subcontinuous and often mixed with inhibitory phenomena.

In some cases, for periods of various duration, the status is more easily recognizable because it is characterized by a continuous sequence of slow spikes and waves diffuse but asynchronous on both hemispheres, related with rhythmic myoclonias.


PROGNOSIS AND COMPLICATIONS

Myoclonic status in nonprogressive encephalopathy frequently has a poor prognosis. According to the electroclinical picture two main subgroups (subsets) can be recognized. The first is of subjects showing a mixed pattern of myoclonic absences, inhibitory phenomena, and intentional myoclonus. The second is of subjects showing a pattern characterized by the marked predominance of inhibitory phenomena inducing a complete motor inhibition.

In the first group the status is a limited event of variable duration, recurring sporadically in about half of the cases, whereas it is more "chronic" (for years) in about a quarter of the cases. In some of these, during evolution, the intentional myoclonus becomes preeminent realizing the picture described by Guerrini and colleagues in subjects with Angelman syndrome as cortical myoclonus (Guerrini et al 1996).

In the second group the status is always permanent throughout the evolution. In all of these cases the prognosis is invariably particularly poor.

In the first group are included all the patients with chromosomal aberration; the patients in the second group are all females and affected by a nonprogressive encephalopathy of unknown etiology.


MANAGEMENT

Myoclonic status with a nonprogressive encephalopathy is only temporarily stopped by IV benzodiazepines, the eventual efficacy must be evaluated by a EEG-polygraphic recording anyway because in some cases the IV benzodiazepine stops the myoclonias but not the continuous paroxysmal discharges.

In some cases it is possible to obtain a good result with valproic acid in association with ethosuximide or cobazam, but in many occasions it is necessary to do an ACTH treatment too. The end of the myoclonic status is invariably accompanied by an often dramatic improvement of the motor performances and also of the behavioral and mental status.

Often the results are transitory anyway and the myoclonic status tends to recur, even for years, so the children need correct monitoring during that time.


PREGNANCY

Not applicable.


ANESTHESIA

Precautions must be taken especially during status.


REFERENCES

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Brett EM. Minor epileptic status. J Neurol Sci 1966;3:52-75.

Casara GL, Vecchi M, Boniver C, et al. Electroclinical diagnosis of Angelman syndrome: a study of 7 cases. Brain Dev 1995;17:64-8.

Chiron C, Plouin P, Dulac O, Mayer M, Ponsot G. Epilepsies myocloniques des encephalopathies non progressives avec etats de mal myoclonique. Neurophysiol Clin 1988;18:513-24.**

Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia 1995;36(10):1017-24.

Dalla Bernardina B, Colamaria V, Capovilla V, et al. Epilessia parziale continua del lattante. Boll Lega It Epil 1987;58/59:101-2.

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Dulac O, Plouin P, Shewmon A, Contributors to the Royaumont Workshop. Myoclonus and epilepsy in childhood. 1996 Royamount meeting. Epilepsy Res 1998;30:91-106.**

Guerrini R, De Lorey TM, Bonanni P. Cortical myoclonus in Angelman syndrome. Ann Neurol 1996;40:39-48.**

Laan LA, Renier WO, Arts WF, et al. Evolution of epilepsy and EEG findings in Angelman syndrome. Epilepsia 1997;38(2):195-9.

Matsumoto A, Kumagai T, Miura K. Epilepsy in Angelman syndrome associated with chromosome 15q deletion. Epilepsia 1992;33:1083.

Mizuguchi M, Tsukamoto K, Suzuki Y, et al. Myoclonic epilepsy and a maternally derived deletion of 15pter -> q13. Clin Genet 1994;45:44-7.

Rubin DI, Patterson MC, Westmoreland BF, Klass DW. Angelman's syndrome: clinical and electroencephalographic findings. EEG Clin Neurophysiol 1997;102:299-302.

Sgr˜ V, Riva E, Canevini MP, et al. 4p-syndrome: a chromosomal disorder associated with a particular EEG pattern. Epilepsia 1995;36(12):1206-14.**

Sugimoto T, Yasuhara A, Ohta T, et al. Angelman syndrome in three siblings: characteristic epileptic seizures and EEG abnormalities. Epilepsia 1992;33:1078.

Viani F, Romeo A, Viri M, et al. Seizure and EEG patterns in Angelman's syndrome. J Child Neurol 1995;10(6):461-71.

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