Myoclonic status in nonprogressive encephalopathies: An update

Authors

  • Maurizio Elia

    1. Unit of Neurology and Clinical Neurophysiopathology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina (EN), Italy
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Address correspondence to Maurizio Elia, MD, Unit of Neurology and Clinical Neurophysiopathology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via Conte Ruggero, 73 94018 Troina (EN), Italy. E-mail: melia@oasi.en.it

Summary

Myoclonic status in nonprogressive encephalopathies (MSNE) is an epileptic syndrome in development, characterized by the early onset of continuous diffuse epileptiform abnormalities, accompanied by positive and/or negative phenomena correlated with transient and recurring motor, cognitive, or behavioral disturbances. Outcome of MSNE is poor and may determine progressive neurologic deterioration. MSNE is not easy to recognize and should be distinguished from progressive myoclonic epilepsies and other rarely reported infantile myoclonic epilepsies. The identification of MSNE may guide the diagnostic work-up, suggesting the presence of a genetic defect, such as Angelman syndrome, hypoxic–ischemic encephalopathy, or brain malformation.

Historical Background

Aicardi and Chevrie (1971) first reported a myoclonic epilepsy in a group of children with nonprogressive encephalopathy. This observation was later confirmed by Cavazzuti et al. (1979) However, these authors did not describe the characteristics of this myoclonic epilepsy or the type of encephalopathy; moreover, they included in their series some cases in whom myoclonus was not correlated with electroencephalography (EEG) paroxysmal abnormalities.

Dalla Bernardina et al. (1980) described a peculiar clinical and EEG picture of myoclonic epilepsy in seven children presenting cerebral palsy due to severe prenatal or neonatal cerebral damage. These authors called this new entity “myoclonic status in non progressive encephalopathies” (MSNE), characterized by early appearance and recurrence of long-lasting myoclonic status in infants and young children with nonprogressive encephalopathy with a poor prognosis.

The term “minor epileptic status” was proposed by Brett (1966). He reported 22 patients with “pseudo-dementia” and “pseudo-ataxia,” previously healthy or, more frequently, epileptic and with normal or retarded developmental milestones. This condition may last for hours, days, or weeks and is characterized by dulling of consciousness and responsiveness, drooling, and absent or slurred speech. During this state, symmetric and asymmetric jerks may be present involving limbs, trunk, and face. Sudden atonia may occur, with head nodding, flexion of the trunk, or fall. The gait is unsteady. The EEG picture is characterized by multifocal continuous spikes, sharp waves, or continuous slow waves. The outcome is poor and adrenocorticotropic hormone (ACTH) is the most effective treatment. However, “minor epileptic status” is a heterogeneous condition and in the Brett’s series possibly four patients had an underlying progressive brain disease, including neurolipidosis and Unverricht-Lundborg disease (Brett, 1966).

The subsequent descriptions of MSNE in the literature are rare, probably due to the fact that EEG and electromyography (EMG) polygraphic recordings have not been performed frequently or the difficult recognition of this peculiar electroclinical pattern. Dalla Bernardina et al. (2002), and, more recently, Caraballo et al. (2007) reported two large series including 45 and 29 children with MSNE.

On the basis of the literature reports, MSNE has been included in the group of epileptic encephalopathies as a syndrome in development in the recent ILAE classification (Engel, 2001), but more recently it has been stated that there is sufficient evidence to support MSNE as a syndrome (Engel, 2006).

Clinical and EEG Features

According to the clinical and EEG analyses of the cases reported until now, MSNE is divided into three different subgroups (Dalla Bernardina et al., 2002; Caraballo et al., 2007). The first subgroup (49–62% of cases) recognizes a predominant genetic etiology and is characterized by the association of absences, subcontinuous jerks (rhythmic or arrhythmic), and brief myoclonic absences. On EEG, these seizures are eventually followed by a brief silent period with a subcontinuous theta–delta activity involving the central areas, or there are brief sequences of rhythmic delta waves with superimposed spikes, mainly involving the parietooccipital regions, often activated by eye closure (Fig. 1).

Figure 1.


A 7-year-old girl with AS. Awake electroencephalography (EEG) shows a slow background activity and quasicontinuous high-voltage, diffuse spike-and-wave complexes, prevalent over the frontal regions. Surface electromyography (EMG) of extensor and flexor muscles of the forearms shows that myoclonic jerks are present, which are rarely correlated with the paroxysmal abnormalities (R, right; L, left; EXT, extensor muscle of the forearm; FLEX, flexor muscle of the forearm).

The EEG picture persists during drowsiness and the first night sleep cycle, but during sleep stages 2 and 3 of the following sleep cycles, epileptiform abnormalities are less active, and during slow wave sleep the myoclonic jerks disappear. MSNE is usually recognized during the first year of age. Children appear unable to walk or are very unsteady, with continuous jerks of the limbs and hyperactivity. The evolution is characterized by sporadic or frequent recurrence even for years.

In this subgroup, MSNE appears resistant to the different antiepileptic treatments, including benzodiazepines and ACTH; only the association ethosuximide–valproic acid determines a significant clinical and EEG improvement in one-third of patients (Caraballo et al., 2007).

This subgroup includes some definite etiologies, namely Angelman syndrome (AS) and Prader-Willi syndrome, with an imprinted genetic defect on chromosome 15q11–13, Wolf-Hirschhorn syndrome due to the deletion of the short arm of the chromosome 4, and Rett syndrome associated with the MECP2 gene mutation (Dalla Bernardina et al., 2002; Caraballo et al., 2007).

MSNE may be present in all children with AS, although the prevalence is rather different in its different genetic types. In particular, we found MSNE in 9 of 20 patients (45%) with chromosome 15q11–13 deletion and in 3 of 10 cases (30%) with UBE3A mutation. On the other hand, none of our four subjects with uniparental disomy presented MSNE (Elia M, Romeo A, Ferri R, Russo S, Cavalleri F, Schinzel A, Viri M, Musumeci SA, unpubl. data). These findings seem to confirm also for MSNE the well-known correlation between epilepsy phenotypes and genotypes in AS (Minassian et al., 1998; Moncla et al., 1999).

The second subgroup (17–31% of cases) comprises patients with a pattern characterized by marked predominance of inhibitory phenomena or the alternance of bilateral positive myoclonic jerks and long-lasting negative myoclonus. On EEG, sometimes a long-lasting status is evident, which is characterized by the recurrence of very ample and diffuse rhythmic slow spike-waves associated with rhythmic and generalized myoclonus followed by inhibitory phenomena; when the status is less structured, subcontinuous multifocal slow spike-waves or theta–delta activity predominant on the frontocentral regions, which are very difficult to correlate with the positive and negative myoclonic phenomena. Positive phenomena may also be present as violent uncontrolled dyskinetic movements.

MSNE is usually recognized early, before 6 years of age, and patients are often resistant to different therapies, including intravenous benzodiazepines, and the status may become a life-threatening event. In many cases it persists into adulthood and the final outcome is very poor, with aposturality and severe intellectual disability (Caraballo et al., 2007).

The patients with this particular electroclinical pattern are mostly females affected by a nonprogressive encephalopathy of unknown etiology or sustained by brain malformations, such as polymicrogyria, colpocephaly, vermis hypoplasia, or partial corpus callosum agenesia (Dalla Bernardina et al., 2002; Caraballo et al., 2007).

The third subgroup includes children who present at onset a mild neurologic impairment, and focal motor seizures of the face. MSNE usually starts between 7 months and 5 years of age.

The status is characterized by subcontinuous discharges of generalized spike-wave–type paroxysms or bilateral continuous slow-wave complexes, apparently related to rhythmic myoclonic jerks of face and limbs. After 1–3 weeks, a progressive change is evident on EEG with deterioration of the morphology of paroxysmal abnormalities, which become sharp theta waves with very slow pseudorhythmic continuous spikes in the central regions and vertex. At the same time, the clinical motor picture progressively worsens, and pyramidal signs and intentional tremors appear. Furthermore, continuous myoclonic inhibitory phenomena may appear (Fig. 2).

Figure 2.


A 6-year-old boy with dystonic tetraplegia. Awake electroencephalography (EEG) shows multifocal spikes, prevalent over the central and temporal regions. At the surface electromyography (EMG) of the forearms, myoclonic jerks are evident, which sometimes are synchronous with the paroxysmal abnormalities (dx, right; sx, left; ext, extensor muscle of the forearm, flex, flexor muscle of the forearm.).

The patients may present a severe and progressive neuropsychological impairment, and the myoclonic epilepsy is drug-resistant. The etiology, as confirmed by brain neuroimaging showing corticosubcortical and cerebellar atrophy, and consists invariably in a pre-, peri- or neonatal anoxic injury.

Conclusions

MSNE is an epileptic encephalopathy, with onset in the first years of life, characterized by continuous diffuse discharges of spike-and-wave complexes or delta–theta waves, accompanied by positive synchronous or asynchronous myoclonic jerks and/or inhibitory phenomena, which correlate with transient and recurring motor, cognitive, or behavioral disturbances. Because of its frequent recurrence and its drug resistant, the outcome of MSNE is poor and may determine a progressive deterioration of the neurologic picture, although the underlying disease is always nonprogressive. MSNE is not easy to recognize, and polygraphic EEG recording is mandatory for a correct diagnosis and to differentiate this condition from progressive myoclonic epilepsies and other rare epileptic conditions, such as newborn continuous partial epilepsy (Dalla Bernardina et al., 1987), early onset progressive encephalopathy with migrant continuous myoclonus (Gaggero et al., 1996), and migrating partial seizures of early infancy (Coppola et al., 1995).

Acknowledgment

I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Disclosure: The author has no conflicts of interest to declare.

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