Clinical manifestations

Presentation and course

The cardinal symptoms of epilepsy with myoclonic absence seizures are typical absences characterized by impairment of consciousness (which varies from mild to severe) and rhythmic, bilateral, and severe myoclonic jerks (mainly of the shoulders, arms, and legs) with a concomitant tonic contraction (10). The myoclonic absences have an abrupt onset and termination. During the event, the patient’s eyes open, if closed, and the eyeballs usually deviate upward but may also turn to the side. The onset of the absence is almost synchronous with myoclonic jerks that usually involve shoulders and arms. Simultaneous jerks of the head and legs can also be seen. The concomitant tonic contraction causes the arms to raise and start jerking rhythmically. The seizures may start .5 to 1 second after discharge onset, and the child may seem to regain consciousness and stop jerking about 1 second before the discharge ends. The child may recall some numbers given by the technician during the seizure or may even be aware of the jerking that accompanies the absence by 1 to 2 seconds. Some facial, particularly perioral, myoclonias may be seen. Eyelid twitching is absent or occurs rarely. The clinical phenomena may differ slightly depending on the position of the child. The events are usually milder when the patient lies in bed and more pronounced when standing (10). On standing, the myoclonic jerks and the tonic contraction are sometimes unilateral or clearly asymmetric, with a jerky rotation of the head and body and a concomitant, rhythmic bending of the body towards the ground. The patient may show unsteadiness or staggering. Falling is uncommon.

The ictal polygraphic EEG shows a bilateral rhythmic generalized spike-wave discharge at 3 Hz that is bilateral, synchronous, and symmetric even in those cases with asymmetric clinical manifestations. Each jerk coincides with the spike and the silent period with the tonic phase. Some slow rhythmic waves in the frontal or posterior regions may precede or follow the generalized spike-wave discharge (10).

Myoclonic absences occur frequently, often tens of times per day. The duration varies from 6 to 60 seconds. Myoclonic absences are often provoked by hyperventilation and can occur during light sleep or awakening and, in 14% to 17% of cases, can be elicited by intermittent photic stimulation (05; 10). Photic stimulation may evoke a brief discharge associated with the eyes opening and turning to the side, with or without a concomitant head-turning, or may evoke rhythmic jerking of the upper part of the body (10). During sleep, some generalized spike-wave discharges at 2 Hz followed by a few slow spike-wave complexes frontally may be seen, which are rarely associated with massive myoclonias. Myoclonic absences can occur during stage 1 of sleep, sometimes awakening the patient. Generalized spike-wave discharges of variable duration, which are sometimes associated with bursts of myoclonias, can be observed during stages 2 and 3 (05). In some cases, automatisms and autonomic signs can be noted, such as respiratory changes, loss of urine (28; 05), or complex gestural automatisms (24).

A 5-year-old boy presented with a month’s history of sudden episodes of abnormal movement of the upper part of his body, poor response, and movements of mainly the right upper limb. He was diagnosed with focal impaired awareness seizures and was given a sodium channel blocking antiseizure drug. As a consequence, seizures increased in frequency to many episodes daily.

In a study of 10 patients with epilepsy with myoclonic absences, phenotypic heterogeneity was evident based on seizure semiologies, comorbidities, seizure frequency, and response to antiseizure medications and nonmedication treatments (06). This group included twins with myoclonic absence status epilepticus, 40% had an atonic component, 20% presented with myoclonic absence status epilepticus, and 60% had incomplete control of seizures. Two patients with epilepsy with myoclonic absences with atonia underwent corpus callosotomy; one patient was seizure free eight months after surgery, and the other had greater than 50% seizure reduction over a five-month period (06). The authors of the study stressed that the efficacy of this treatment should be further evaluated in a larger study.

Generalized tonic-clonic seizures, clonic seizures, brutal falls, and absence status have rarely been described. In one third of cases, myoclonic absences are the only seizure type observed throughout the evolution; in the other two thirds of cases, additional seizures are present either before the onset or in association with myoclonic absences (28; 05). Focal seizures are exclusionary (27).

About half of affected children are normal and half are intellectually disabled prior to the onset of seizures (28; 29).

Prognosis and complications

A longitudinal study of long-term prognosis performed in 40 cases showed that myoclonic absences disappeared in 37.5% of the cases, and the other 62.5% persisted or their epilepsy changed to other seizure types (05). The unfavorable evolution was attributed primarily to the existence of associated generalized tonic-clonic seizures. Additionally, the appearance or worsening of psychomotor retardation was observed in the two groups, but it was more severe and occurred more frequently in children with associated generalized tonic-clonic seizures or an electroclinical picture of Lennox-Gastaut syndrome (05). The appropriate and adequate treatment in this study was not confirmed as a favorable predictive factor.

Generally, epilepsy with myoclonic absences, like any other idiopathic (genetic) epilepsy syndrome, is characterized by genetic and phenotypic heterogeneity, is expressed either as myoclonic absence only or myoclonic absences associated with other seizures, and evolves to more severe forms of epilepsy, such as Lennox-Gastaut syndrome (10). These assumptions would explain previous reports that (1) about 45% of patients have educational difficulties at the start and almost 70% eventually; (2) children with only myoclonic absences have a more favorable outcome than those who have additional seizures, particularly generalized tonic-clonic seizures; and (3) seizures persist in about half of the cases, and these patients may deteriorate cognitively and evolve toward a more severe form of epilepsy, including the Lennox-Gastaut syndrome (10; 17). Furthermore, an early diagnosis and more appropriate and effective treatment will lead to better cognitive evolution (10).

Biological basis

Etiology and pathogenesis

Myoclonic absences are the hallmark seizures of the genetic (idiopathic) syndrome of epilepsy with myoclonic absences. The etiology of the syndrome is unknown but presumed to be genetic, with a family history positive for epilepsy in approximately 25% of cases (10). The etiology of myoclonic absences in general, not the syndrome, may be idiopathic and probably symptomatic. SPECT analysis in myoclonic absence seizures shows that in addition to the thalamus and basal ganglia, the perirolandic cortical motor area is also involved (22). This may represent key features of the pathophysiological mechanisms underlying myoclonic absence seizures. In the symptomatic group, variable etiological factors have been found, such as prematurity, perinatal hypoxia, congenital hemiplegia, and partial trisomy of the long arm of chromosome 14 (05). Other atypical myoclonic absences have been associated with chromosomal abnormalities in cases with mental retardation and myoclonic absence seizures (Angelman syndrome, 12p trisomy, inv-dup 15) (12; 13), glutamate dehydrogenase mutation (02), and mutation in the gene (SLC2A1) encoding glucose transporter 1 (19). Hiraide and colleagues reported that de novo variants in SETD1B may cause syndromic neurodevelopmental disorders with epilepsy, including epilepsy with myoclonic absences (21). However, further accumulation of cases and functional analyses are necessary for clarifying the phenotypic spectrum and the pathogenesis of SETD1B-related disorders. Frydson and colleagues reported a case of epilepsy with myoclonic absences admitted to the intensive care unit in super-refractory status epilepticus and was found to have a FOXP1 gene pathogenic variation and a variance of unknown significance in the MBD5 gene (16). Furthermore, an 11-year-old girl with a history of generalized tonic-clonic seizures (GTCS) and four to five daily episodes of loss of consciousness associated with jerking of the left upper limb was assessed following severe postictal confusion lasting half a day after a generalized tonic-clonic seizures (25). She was found to have dysmorphic facial features (ie, a broad nasal tip and a high arched palate), mild dysfunction of fine motor skills, and moderate intellectual disability. The detailed investigations revealed mild cerebellar hypoplasia and 2q13 microdeletion, and the video-EEG showed 3 Hz generalized spike-and-wave discharges with impaired consciousness and rhythmic jerks in the left upper limb, which were sometimes induced by hyperventilation with normal interictal EEG (25). She was diagnosed as 2q13 microdeletion syndrome, the first reported case with epilepsy with myoclonic absences.

According to the recommendations of the International League Against Epilepsy, epilepsy with myoclonic absences is considered polygenic, with only specific cases reporting pathogenic variants (27).

The pathophysiological mechanisms of absence seizures have been studied in various animal models with generalized spike and wave discharges.

In one publication it was demonstrated that absence seizures in the WAG/Rij rat, an established rodent model of absence epilepsy, were highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH (26). Moreover, hyperventilation consistently activated neurons within intralaminar nuclei of the thalamus, a structure implicated in seizure generation. It was shown that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.

Epidemiology

Epilepsy with myoclonic absences is a rare epilepsy syndrome accounting for 0.5% to 1% of all epilepsies observed in a selected population at the Centre Saint Paul of Marseille (29; 31; 28; 04; 05). The true incidence of myoclonic absences is probably higher. The age of onset varies from 11 months to 12.6 years (mean 7 years). Some early-onset cases have been reported (01; 09; 32). In contrast to childhood absence epilepsy wherein there is a female preponderance (70%), in epilepsy with myoclonic absences, almost 69% of cases are male (M: F=2.2:1) (10).

Differential diagnosis

The diagnosis of epilepsy with myoclonic absences can be differentiated from other syndromes with typical absences with a detailed history, careful clinical observation, and video-EEG studies with polygraphic recording (EMG of various shoulder and arm muscles) of the electro-clinical episodes (10). The characteristic co-existence of absence and myoclonic seizures distinguishes epilepsy with myoclonic absences from other epilepsy syndromes with typical absence seizures, such as childhood absence epilepsy and juvenile absence epilepsy.

The clinical and EEG features of the syndrome epilepsy with myoclonic absences will also distinguish it from both eyelid myoclonia with and without absences and facial myoclonia with absences, both of which belong to the same group of idiopathic (genetic) epilepsy syndromes in which absence and myoclonic seizures are the predominant seizure type in the phenotypic expression (10; 11). The myoclonic component of these two syndromes mainly involves eyelid or facial twitching that is less intense than in epilepsy with myoclonic absences (28; 29; 10). The main clinical and EEG features that facilitate the differential diagnosis are shown in Table 1.

Table 1. Syndromes in Which Concomitant Typical Absences and Myoclonic Seizures Predominate in the Phenotype: Main Similarities and Dissimilarities

Differentiating myoclonic absences from idiopathic and symptomatic or unknown cases may be difficult. Symptomatic cases often have concomitant cognitive or neurologic dysfunction, abnormal background EEG, persistent focal discharges over one region, and brain MRI findings that may show diffuse atrophy or structural abnormality. Chromosomal analysis for trisomy 12p and 14q (12; 13; 05) or even de novo variants in SETD1B gene or other genes (see etiology) should also be considered (21).

Diagnostic workup

The diagnosis of epilepsy with myoclonic absences is based mainly on clinical knowledge of the syndrome and the direct observation of seizures during prolonged video-EEG or sleep-awake polygraphic video-EEG recordings after sleep deprivation (10). EEG is the only test needed. Background EEG is normal for age. Ictal EEG shows spike-wave discharges at 3 Hz that are bilateral, rhythmic, symmetrical, and synchronous accompanied by absences and myoclonias. The onset and termination of the discharge are abrupt except in a few cases in which the discharge terminates with slow delta waves prominent in the frontal regions (10). Polyspikes intermixed with typical discharge are seen in some other seizures. Drowsiness and hyperventilation facilitate discharges and the accompanied typical clinical features. Photosensitivity is seen in 17% of patients (10). Myoclonic absences may be seen during stage 1 of sleep and clusters of myoclonias during stages 2 and 3 (04).

In addition to clinical evaluation, an MRI and chromosomal analysis for trisomy 12p and 14q should be considered in symptomatic cases. MRI is considered for those cases with unfavorable evolution, particularly those with focal seizures or focal discharges consistently over one region.

Therefore, the diagnosis of myoclonic absence rests on the polygraphic recordings (EEG and EMG), which show spike-wave discharges at 3 Hz (similar to that observed in typical absences of childhood absence epilepsy) accompanied by severe, diffuse, and rhythmic myoclonias recorded on EMG (05).

Management

Valproate alone or combined with ethosuximide, with appropriate daily doses and plasma levels, is the most successful treatment (10). In difficult-to-treat cases, other combinations with valproate or ethosuximide are benzodiazepines (clonazepam, clobazam), levetiracetam, topiramate, zonisamide; ketogenic diet, vagus nerve stimulation, and cannabidiol may also be options. The cumulative evidence of such combinations is limited (10). In a reported case of epilepsy with myoclonic absences resistant to multiple commonly used antiepileptic drugs, low-dose phenobarbital unexpectedly achieved complete remission of epilepsy (23). Early electroclinical control may avoid cognitive deterioration and secure better cognitive development. Sodium channel-blocking antiseizure drugs, such as carbamazepine, oxcarbazepine, and eslicarbazepine, may provoke absence seizures or myoclonic status epilepticus and should be avoided.

In a study of 10 patients with epilepsy with myoclonic absences, 40% had an atonic component, 20% presented with myoclonic absence status epilepticus, and 60% had incomplete control of seizures (06). Of patients with an atonic component, 75% did not achieve seizure freedom with medication alone. Two patients with epilepsy with myoclonic absences and atonia underwent corpus callosotomy; one patient was seizure-free 8 months after surgery, and the other had greater than 50% seizure reduction over a 5-month period (06). The authors of the study stressed that the efficacy of this treatment should be further evaluated in a larger study.

In a single-center retrospective study of 131 children with typical absence seizures, myoclonic absence and absence seizures with eyelid myoclonia were analyzed to find associations between these characteristics and difficult to treat absence seizures. Epilepsy was classified as difficult to treat absence seizures in 18 (13.7%) patients. Absence seizures were more difficult to treat in patients with myoclonic absence seizures and in absence seizures with eyelid myoclonia (40.0%), compared with patients with typical absence seizures (11.4%) (20). Additional factors identified a positive family history of epilepsy, a higher seizure frequency prior to antiseizure treatment, and longer time between seizure onset and treatment onset.

Outcomes

Myoclonic absences resolve in one third of cases after an average of 5 years and persist or evolve in other types of epilepsy, such as Lennox-Gastaut syndrome. In fact, there are two forms: a pure form in which myoclonic absences are the sole or predominant type of seizures and another form in which myoclonic absences are associated with other seizure types, particularly generalized tonic-clonic. The later form has a very poor prognosis (05). Impaired cognitive functioning prior to the onset of absences is an indication of symptomatic etiology. In almost 50% of cases, children who are normal prior to the onset absences develop cognitive and behavioral impairment, indicating the deteriorating effect of the EEG discharges and seizures on cognition. Therefore, the earlier the diagnosis and control of seizures and EEG discharges, the better the prognosis regarding cognition (10).

In epilepsy with myoclonic absences, as in any type of epilepsy, in addition to early diagnosis and treatment a comprehensive neuropsychological assessment for concomitant cognitive and other comorbidities should be routinely applied, and appropriate early intervention and treatment should be introduced for better prognosis and quality of life. Further, when the word “epilepsy” is disclosed at critical stages of development, as a rule, it leads to poor self-esteem, lack of self-confidence, social withdrawal, and poorer subsequent quality of life, even in cases of self-limited epilepsies (07).

Special considerations

Pregnancy

Although no information is available that is specific to this syndrome and pregnancy, information is available on epilepsy and pregnancy.