INTRODUCTION

The possible occurrence of myoclonic epilepsy in children with nonprogressive encephalopathy has been reported in the literature for many years by various authors (1–5).

However, in the majority of these cases, the authors did not fully describe the electroclinical features of the myoclonic epilepsy or the type of encephalopathy. Moreover, they included in their series some cases in which myoclonus was not correlated with overt EEG paroxysmal activity.

Additionally, there is proof in the literature, in different forms of epilepsy, of absence status with myoclonias of variable duration defined as “minor epileptic status,” “minor motor status” (1), “obtundation with myoclonia,” and “nonconvulsive status with ataxia” (5,6).

Nevertheless, the deription of an epileptic syndrome characterized by the recurrence of long-lasting myoclonic status (MSNPE) in children with a nonprogressive encephalopathy is relatively scarce (7–19), probably because polygraphic EEG recordings are usually not routinely performed in clinical practice. A similar electroclinical picture has been described by many authors in children with nonprogressive encephalopathy, Angelman syndrome, and other genetic entities such as 4p- syndrome and Rett syndrome (20–26). However, only a few authors have stressed how, in some of these cases, the electroclinical features were typically those of an MSNPE (27–32). Recently, the MSNPE was first proposed in the scheme of the ILAE Task Force on Classification and Terminology (33) as a “syndrome in development” and later recognized as a well-defined epileptic syndrome in the group of epileptic encephalopathies (34,35).

GENERAL CHARACTERISTICS

Gender

There is a relative predominance of females with a M/F sex ratio of 1/1.7.

Familial Antecedents for Epilepsy

A family history of epilepsy is present in about 15% of the cases.

Etiology

According to the etiology, the population can be divided in three groups.

A genetic disorder is documented in nearly two-thirds of the cases. Most often (more than 70% of the genetic cases) it is due to a defect in chromosome 15q 11-q13 (Angelman syndrome) but also different genetic conditions such as Rett syndrome, Wolf–Hirschhorn or 4p- syndrome, Prader–Willi syndrome, and CDKL 5 syndrome have been documented. More recently, we documented a 17q12 duplication in a boy, and a SCN8A mutation in a girl (personal observations).

In these cases, the neuroradiologic findings at onset were normal.

A pre-perinatal anoxic injury was found in 15% of the cases. In the majority of these cases, the neuroradiologic (TAC and MRI) investigations show a cerebral atrophy of variable degree.

The etiology is unknown (cases affected by an assessed symptomatic form where the underlying mechanism remains undefined) in almost one-third of the cases. However, in more than two-thirds of these cases, the neuroradiologic investigations document malformations of cortical development as focal unilateral or bilateral micropoligyria, vermis hypoplasia with microcephaly, bilateral hippocampal dysgenesis with partial callosal agenesis, or hemimegalencephaly. Some familial cases have been reported (14). Therefore, in a consistent number of cases the pathology appears to be constituted by a cortical dysplasia, probably genetically determined in several cases.

Neurologic Picture at Onset

The most constant clinical picture at onset is that of an axial hypotonia (observed in more than 80% of the cases) of variable degree inducing a simple delay in postural acquisitions or aposturality. In the other cases, the neurologic picture is that of a hypotonic “ataxic” cerebral palsy. In more than half of the cases, there are associated polymorphous abnormal movements realizing a dystonic-dyskinetic syndrome. Severe cognitive and language impairment is always present. Dysmorphisms evoking a probable genetic etiology are present in about half of the cases, and are often associated with slight microcephaly.

ELECTROCLINICAL FEATURES

The average age of seizure onset is 10 months (range 1 day to 5 years).

In about half of the cases, the epilepsy onset is constituted by a myoclonic status characterized by very frequent/day or subcontinous “absences” associated with rhythmic bursts or arrhythmic myoclonia of distal muscles, often involving the periorbital and perioral regions. In the other subjects, the initial seizures are mostly partial motor seizures, myoclonic absences, or recurrent massive jerks. Generalized or unilateral clonic seizures often occurring only due to a febrile illness are rare. The recurrence of brief massive startles during drowsiness and stages I and II of sleep are also frequently observed.

The mean age when the myoclonic status is recognized is 14 months (range 3 months to 5 years).

Because of severe cognitive and behavioral impairment and abnormal movements, both the paroxysmal attention disturbances (“absences”) and the myoclonia can remain unrecognized for several months. In some cases, the status can be recognized at the time of the first overt seizure. Therefore, it is probable that the age of onset of the status significantly precedes that of its recognition.

More frequently, the myoclonia are subcontinous but asynchronous in different muscles. In this case, their relationship with paroxysmal EEG activity is very difficult to appreciate and the paroxysmal nature of the EEG pattern is also difficult to recognize.

In some cases, the myoclonia are clinically more obvious, rhythmically involving both arms and orofacial muscles, related with ample diffuse spike-and-wave discharges (Figure 25.1). In other cases, the myoclonia are followed by a brief silent period, realizing a mixture of positive and negative phenomena (Figure 25.2). In some other cases, the negative myoclonous is predominant, continuously fragmenting the voluntary movements and inhibiting any fixed antigravity posturing (Figure 25.3).

FIGURE 25.1 A 2-year-old male with Angelman syndrome suffering since the age of 6 months from long-lasting MSNPE status.

On the left, it is possible to see subcontinuous diffuse delta waves of great amplitude with a superimposed spike. Note on the EEG records the subcontinuous rhythmic myoclonia involving the upper limbs and face, related with EEG paroxysms. The myoclonia are partially masked by other abnormal movements.

On the right, at the onset of sleep the EEG discharges persist and the myoclonia become more easily recognizable because the other abnormal movements disappear.

FIGURE 25.2 A 14 months and 11 days old female with bilateral polymicrogyria suffering since the age of 4 months from brief myoclonic absences and recurrent myoclonic status since the age of 9 months.

Note the continuous EEG pseudorhythmic discharges of slow spikes and/or slow waves fluctuating on both hemispheres, accompanied by rhythmic bilateral positive myoclonia and long-lasting negative myoclonia.

In some cases, during wakefulness the EEG is characterized by a slow activity with difficult to recognize paroxysmal abnormalities. These consist of a relatively monomorphous subcontinuous delta-theta activity (3–6 c/s) varying in amplitude that involves more or less asynchronously the centro-parietal regions (Figure 25.4). When the child is agitated, the motor activity can inhibit this EEG activity, making its recognition more difficult (Figure 25.5). It is also possible to observe brief sequences of rhythmic delta waves with superimposed spikes, achieving an unusual spike-and-wave predominant in parieto-occipital regions, which are often elicited by eye closure (Figure 25.5).

More often, the myoclonia are arrhythmic and masked by the subcontinous abnormal movements. They became easier to recognize during motor arrest, for example, during absence or sleep when other abnormal movements cease (Figure 25.1).

The status is typically characterized by a fluctuation of the electroclinical pattern. It is possible to observe, in fact, recurring bursts of spikes and waves or slow waves that are more or less diffuse, synchronous, or asynchronous on both hemispheres associated with a more or less obvious impairment of consciousness. Between these bursts are inserted periods of variable duration without obvious paroxysmal discharges but with pseudorhythmic delta-theta activity of variable amplitude involving subcontinuously both central regions.

The proof that they are not separate ictal events recurring at a more or less high frequency, but a true status, is shown by the observation that, like theta activity, positive and/or negative myoclonia are also subcontinuous even in the absence of an obvious consciousness impairment.

FIGURE 25.3 A 5-year-old female with bilateral polymicrogyria and a posturality showing since the age of 12 months long-lasting myoclonic status with subcontinuous inhibitory phenomena mixed with sudden violent dyskinetic movements.

Note the continuous paroxysmal complex motor activity related with subcontinuous theta-delta activity intermixed by very small spikes.

For periods of variable duration, the status is more easily recognizable because it is characterized by a continuous diffuse, but asynchronous, sequence of spikes and waves of great amplitude on both hemispheres related with continuous rhythmic jerks with or without the following negative phenomena.

FIGURE 25.4 A 10-month-old male with significant development impairment of unknown etiology suffering since the age of 6 months from brief myoclonic absences and long-lasting myoclonic status.

Note on the EEG the subcontinuous fluctuating theta-delta activity, and on the EMG the subcontinuous myoclonia synchronous on agonists and antagonists, which are partially masked by the other abnormal movements.

FIGURE 25.5 A 10-month-old female with severe motor and cognitive impairment of unknown etiology suffering from the age of 1 month with partial seizures and atypical absences with myoclonia. Since the age of 4 months, she has presented with long-lasting myoclonic status.

Note the subcontinuous discharges of diffuse delta waves with superimposed spike asynchronous on two hemispheres (rightside of the picture). The intensive movements inhibit the diffuse discharges while rhythmic spikes persist on the vertex and central regions (leftside of the picture). Also, the myoclonia are asynchronous on two hemisomes.

During drowsiness and slow sleep, spikes and waves become continuous to the point that the spindles are not recognizable (Figure 25.1); they disappear during REM sleep. During slow sleep stages of the following nocturnal cycles, the paroxysms are more fragmented and the spindles are clearly represented. The myoclonia can persist at drowsiness (Figure 25.1) but they vanish during slow sleep, reappearing briefly at arousal and, at times, during REM. In this phase, there is a subcontinuous rhythmic theta activity mainly involving the vertex and the rolandic regions. A similar theta activity, strictly related to myoclonia, can be transitorily observed during waking up.

According to the electroclinical features of the cases previously reported (12–14,17,18), MSNE cases can be divided into three different subgroups.

The first subgroup, recognizing a predominant genetic etiology, is characterized by the association of absences, brief myoclonic absences, and subcontinuous rhythmic and arrhythmic jerks, eventually followed by a brief silent period related to a subcontinuous delta-theta activity involving the central areas; these are followed by brief sequences of rhythmic delta waves with superimposed spikes, mainly involving the parieto-occipital regions often activated by eyeclosure (Figure 25.1). This EEG picture persists during drowsiness and the first night sleep cycle, but during stages II and III of the following sleep cycles, the paroxysms became less active; during slow wave sleep the myoclonia disappear. In this subgroup, the myoclonic status generally occurs and it is recognizable just during the first year of life. The status is of variable duration, lasting few or several days; it recurs sporadically in more than half the cases, whereas it can be more “chronic,” lasting for months or years in one-third of the cases. A majority of the cases are refractory to treatments, and even benzodiazepine and ACTH generally have only a transitory effect. The association of ethosuximide and valproic acid induces an electroclinical-relevant improvement in a significant number of cases. Levetiracetam, in about 10% of the cases, and ketogenic diet in some cases can also induce a significant improvement. When the myoclonic status improves significantly or disappears, the clinical picture improves dramatically; the child who was previously showing a severe instability with continuous disabling jerks in many cases becomes ambulatory. Behavior and contact also improve. In these cases, according to Caraballo et al (18), the myoclonic status disappears entirely during evolution at a mean age of 4 years. In some cases, during evolution the intentional myoclonus becomes more prominent, realizing the picture described by Guerrini et al (29,36) as cortical myoclonus.

This electroclinical picture has been observed in few children with Prader–Willi syndrome; in some children with Wolf–Hirschhorn syndrome, Rett syndrome, or CDKL5 syndrome; and in a large number of children with Angelman syndrome. According to Elia (37), this picture can be observed in cases with 15q11–13 deletion or with UBE3A mutation but not in cases with uniparental disomy. As we previously outlined (38,39), and as confirmed by other authors (7,16,17,27,36,37), this peculiar myoclonic status, in several cases, is the earliest diagnostic indicator of Angelman syndrome.

The second subgroup comprises children with an electroclinical pattern characterized by a marked predominance of inhibitory phenomena, mixed with a severe fragmented dystonic component and sudden irregular jerks of variable intensity (Figure 25.3). At onset, the status is often difficult to recognize because of severe mental impairment and the abundance of continuous polymorphous and rough abnormal movements. The erratic jerks are difficult to distinguish from the violent dyskinetic movements. Moreover, the positive and negative myoclonia are very difficult to correlate with the EEG paroxysmal abnormalities. At the time of a long-lasting status, the EEG is characterized by a continuous recurrence of very ample and diffuse rhythmic slow spikes and waves associated with rhythmic and generalized myoclonia followed by an inhibitory phenomenon (Figure 25.2). This status can be refractory to IV benzodiazepine requiring intensive treatment and it may become a life-threatening event (14,17).

When the status is less structured and less easily recognizable, it is characterized by a subcontinuous, more or less rhythmic delta-theta activity, predominating on the fronto-central regions related with subcontinuous inhibitory phenomena mixed with asynchronous sudden and often violent dyskinetic movements (Figure 25.6). The result is an epileptic status characterized by a complex unregulated motor pattern inducing a peculiar “hyperkinetic motor inhibition,”

The third subgroup includes children with an initially subtle developmental delay with a mild neurologic impairment at onset from partial motor seizures and/or frequent brief myoclonic absences. The partial seizures can be rare or very frequent and they can involve both hemisomes independently; frequently there is a peculiar involvement of the face. The myoclonic status begins progressively; more rapidly in some children, more subtly in others. It is characterized by a subcontinuous sequence of generalized spike-and-wave paroxysms (Figure 25.5) or a bilateral continuous theta activity with notched delta appearance related to rhythmic myoclonia of the face and limbs (Figure 25.7). With time, we could observe a progressive deterioration of the electrical activity and the morphology of the paroxysms that become sharp theta waves with pseudorhythmic continuous spikes in the central regions and vertex (Figure 25.8).

Concomitantly, the clinical motor picture progressively worsens and pyramidal signs and intentional tremors, as well as continuous inhibitory phenomena, appear, often mixed with stereotyped abnormal movements. The inhibitory phenomena often can be recognized clinically only in the presence of an increase of the postural tone. A severe motor inhibition is invariably the result. Equally progressive, there is a severe neuropsychologic impairment in the absence of any detectable progressive pathology. At long term the picture instituted remains unchanged.

FIGURE 25.6 Same female as in Figure 25.3.

Note the subcontinuous rhythmic theta activity predominating on the front-central regions related to subcontinuous myoclonia and inhibitory phenomena.

In many cases, the status is refractory to different treatments and it can persist into adulthood.

Other types of seizures are very rare; some subjects can present brief generalized seizures or tonic seizures, sometimes in clusters.

The subjects with this particular electroclinical pattern are mostly females affected by a nonprogressive encephalopathy of unknown etiology or related to a brain malformation.

FIGURE 25.7 A 7-month-old male with severe developmental delay of unknown etiology suffering from the age of 5 months with a pharmacoresistant subtle myoclonic status.

Note on the EEG the subcontinuous theta activity of small amplitude and on the EEG the continuous fast myoclonia independent of hemisomes.

Partial motor tonic or clonic seizures, sometimes followed by generalization, are frequent, even at long term, while other types of seizures are absent.

The electroclinical picture therefore seems to be one of pharmacoresistant progressive epilepsy not sustained by a progressive disease.

This electroclinical pattern can be observed in some children with Rett syndrome (12–14,26), with SCN2A mutation (personal observation), or having a cortical dysplasia; in others, the etiology consists of a pre-perinatal anoxic injury or is unknown.

FIGURE 25.8 Same male as in Figure 25.7 at the age of 20 months.

Note the persistence of the myoclonic status associated with a significant slowing of the proximal activity with intermixed pseudorhythmic spikes predominating on the front-central regions.

DIFFERENTIAL DIAGNOSIS

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