Clinical manifestations

Presentation and course

Myoclonic absence seizures are characterized by typical absences associated with rhythmic bilateral clonic jerking, mainly of the upper body, with a tonic component. The upper limbs fling open (tonic phase) and, as they jerk, elevate progressively. The body may also deviate slightly and with each rhythmic jerk bends toward the floor. The ictal EEG shows bilateral generalized spike-wave discharges at 3 Hz (20).

Clonic (rhythmic) and myoclonic (arrhythmic, singular) symptoms are particularly frequent at the onset of typical absence seizures but may also occur at any other stage of the seizure randomly, continuously, or repetitively (09; 81; 71; 72; 20). The most common symptoms are clonic or myoclonic jerking of the eyelids, eyebrows, and eyeballs, including random or repetitive eye closures and horizontal or vertical nystagmus-like ocular movements.

A few other episodes recorded lasted from 11 to 14 seconds, with similar electroclinical expression. Her seizures were finally controlled on ethosuximide and lamotrigine. After 4 years of good electroclinical response, lamotrigine was phased out. Eight months later, her EEG during hyperventilation showed some irregular spike-wave discharges, and during intermittent photic stimulation at 10 flashes/second, a generalized spike-wave discharge was evoked, but no concomitant clinical events were noted. About 6 months later, she started having similar absence seizures, and lamortigine was added to ethosuximide again. The past history was noncontributory except for 10 febrile seizures before she was 5 years old. Neurologic assessment was normal. Family history revealed that her father had three febrile seizures in infancy.

Fast eyelid flickering is probably the most common ictal clinical manifestation and may occur during brief generalized discharges without discernible impairment of consciousness. This should not be confused with eyelid myoclonia and absences on eye closure, the cardinal symptom of what was previously called Jeavons syndrome where the majority of cases are photosensitive (18; 22; 21; 25). Perioral myoclonias at the corner of the mouth and jerking of the jaw are less common. Clonic or myoclonic jerks of the head, body, and limbs are less frequent than of the face and may be mild or violent, singular, continuous, or repetitive. In some patients with absence seizures, single myoclonic jerks of the head and, less often, the limbs may occur during the progression of ictus.

A 5-year-old boy was presented because of frequent episodes of loss of contact concomitant with horizontal head jerky movements. EEG showed generalized spike-wave ictal discharge similar to childhood absence epilepsy preceded by high amplitude delta-theta waves in centroposterior regions. The discharge immediately starts with rhythmic horizontal head jerking. The boy’s eyes remained open with a vague look and no response. His head turned to the right side while jerking. He recovered after about 12 seconds.

However, not any typical absence seizures with the above myoclonic and clonic motor manifestations are classified as myoclonic absence seizures, which are mainly of two types according to the muscles involved: (a) the classical type manifests with rhythmic jerks of shoulders, arms, and legs with a concomitant tonic contraction during absence seizures and constitutes the defining symptoms of epilepsy with myoclonic absences; and, (b) myoclonic absences manifest with rhythmic jerks of perioral or eyebrow muscles during absence seizures, and they are the defining symptom of facial myoclonia with absences.

Classical type of myoclonic absences. Classical myoclonic absences manifest with rhythmic jerks of the shoulders, arms, and legs with a concomitant tonic contraction during absence seizures and constitutes the defining symptoms of epilepsy with myoclonic absences (86; 90; 08; 07; 42; 81; 20). The myoclonic absence seizures consist of impairment of consciousness, which is usually severe.

An 11-year-old boy suffered from epilepsy with myoclonic absences of idiopathic (unknown) cause since the age of 12 months when he was noticed to have jerks of the upper part of his body (head, upper limbs) mostly induced by noise. These episodes, observed a few times per week, were described as earthquake-like. At the age of 6-years-old, he was reported to have about 10 episodes daily of vague looks concomitant with rhythmic jerking of the head and upper limbs. The episodes had not responded to high doses of sodium valproate, lamotrigine, clobazam, or levetiracetam. When ethosuximide was introduced to his treatment instead of lamotrigine, absence episodes responded, but he had for the first time three generalized tonic-clonic seizures during which his head and eyes turned left and mouth twisted; clonic-myoclonic movements of upper limbs occurred for few minutes, and he did not respond for about 45 minutes.

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

A boy presented with a variability of typical myoclonic absence seizure while standing. Synchronous with the generalized spike-wave discharge, the upper part of his body, upper limbs, and right leg rhythmically jerk with concomitant unsteadiness, but he didn’t fall.

The duration of the absences varies from a few seconds to 60 seconds with a high daily frequency of occurrence. They are precipitated by hyperventilation and occur mainly on awakening. Photosensitivity is uncommon (14%). Myoclonic absences precipitated by eye-closure or eye-opening in non-photosensitive patients have been described (74; 86). Other types of seizures also occur in two thirds of the patients (74; 86; 31; 72). These are infrequent generalized tonic-clonic seizures, “absences” or “falling attacks,” and atonic seizures that may precede or follow the onset of myoclonic absences. Absence status is rare. Absences with persistent localized neck myoclonia have been described (55). Complex gestural automatisms can rarely occur during myoclonic absence seizures (66).

Myoclonic absences are a rare seizure type (probably 0.5% in selected cases of epilepsy) with a male preponderance (70%) and a mean age of onset at 7 years (07), starting as early as 4 years (31) and 6 months (90). Neurologic examination is usually normal, but half (45%) have impaired cognitive functioning prior to the onset of absences. A family history of epilepsy is found in a fifth of the cases. Etiological factors are found in one third of patients, and these are mainly chromosomal abnormalities (31; 32), prematurity, and perinatal damage (07).

See also MedLink Neurology article: Epilepsy with myoclonic absences.

Second type of myoclonic absences. The second type of myoclonic absences manifests with facial rhythmic jerks of perioral or eyebrow muscles during absence seizures, and they are the defining symptom of facial (perioral) myoclonia with absences (73; 26; 18; 22; 50; 04; 02; 19; 20; 29; 93). The characteristic feature is perioral myoclonia, which, as studied on video-EEG, consists of rhythmic contractions of the orbicularis oris muscle (causing protrusion of the lips), contractions of the depressor anguli oris (resulting in twitching of the corners of the mouth), or, rarely, more widespread involvement to include the muscles of mastication (producing jaw jerking). Another motor manifestation during the absence is eyebrow or eyelid myoclonus, which is synchronous but less prominent than the perioral myoclonus (73; 69; 29). Because not only perioral muscles are involved, the term facial instead of perioral myoclonia with absence should be preferred (26; 19; 20). Impairment of consciousness varies from severe to mild, and most patients are usually aware of the perioral myoclonia. Duration is usually brief, lasting a mean of 4 seconds (range 2 to 20 seconds). Absences of facial myoclonia may occur many times per day, one to two times per week, or they may be rare. Patients with facial myoclonia with absences may present from early childhood to early adolescence, usually following a GTCS, or less commonly with absences or absence status epilepticus. All patients suffer generalized tonic-clonic seizures, which often start before or soon after the onset of clinically apparent absences. Exceptionally, GTCS may start many years after the onset of absences. GTCS are usually infrequent (ranging from once in a lifetime to 12 per year) and are often heralded by clusters of absences or absence status. Absence status epilepticus is very common (57%) and frequently ends with GTCS.

A 15-month-old boy was presented with a 2-month history of frequent episodes of sudden loss of consciousness associated with perioral and eyebrow rhythmic jerks. The discharge was associated with impairment of consciousness and concomitant eyebrow and perioral rhythmic jerky movements. The electroclinical event lasted up to 19 seconds. The absence seizures are similar to those of childhood absence epilepsy. He responded on an appropriate daily dose of sodium valproate.

A 22-month-old boy was presented with a history of daily brief episodes of staring associated with rhythmic eyebrow and head jerking. Video-EEG showed three repeated generalized spike-wave discharges, each associated with a brief typical absence seizure with concomitant rhythmic eyebrow and head jerking. During video-EEG, frequent generalized spike-wave discharges were recorded--some associated with clinical events. He was given and responded to sodium valproate. Up to the age of 20 years old when he was last seen, a few attempts to withdraw treatment were associated with relapses, two with generalized tonic-clonic seizure during sleep. The cognitive development was assessed as borderline low. His older sister also had idiopathic generalized epilepsy.

An 8-year-old girl started having episodes with eyelid blinking, not responding to verbal commands, and de novo mouth movement. She was experiencing 10 to 15 episodes daily. Basic sleep-awake video-EEG did not show abnormalities. During hyperventilation, the generalized spike-wave discharge evoked was associated with the following seizure: eyelid flutter, no response to verbal commands, and concomitant de novo mouth movements. Some high-amplitude, 3 Hz slow waves heralded or followed the generalized discharges. A few other episodes recorded lasted from 11 to 14 seconds with similar electroclinical expression. Her seizures were finally controlled on ethosuximide and lamotrigine. After 4 years of good electroclinical response, lamotrigine was phased-out. Eight months later, her EEG, during hyperventilation showed some irregular spike-wave discharges, and during intermittent photic stimulation at 10 flashes per second, a generalized spike-wave discharge was evoked, but there were no concomitant clinical events. About 6 months later, she started having similar absence seizures, and lamortigine was added to ethosuximide again. The past history was non-contributory except for 10 febrile seizures when we was younger than 5 years old. Neurologic assessment was normal. Family history revealed her father had three febrile seizures in infancy.

There are three characteristic idiopathic generalized syndromes wherein absence and myoclonic seizures predominate in the phenotype, namely: epilepsy with myoclonic absences, eyelid myoclonia and absences precipitated on voluntary or on-command eye closure in the presence of light (22; 21; 25), and facial myoclonia with absences (19; 20).

Prognosis and complications

Epilepsy with myoclonic absences is often resistant to treatment; 50% of patients (probably with structural causes) continue having seizures in adult life, with a high incidence of generalized tonic-clonic and atonic types. Rarely, patients may develop features of other types of epilepsy such as Lennox-Gastaut syndrome or juvenile myoclonic epilepsy. Of those who were normal prior to the onset of absences, 50% develop cognitive and behavioral impairment. Mental retardation is present only in patients with poor seizure control (90). Frequent GTCS is a predictor of bad prognosis (07). The fact that 45% have impaired cognitive functioning prior to the onset of absences and 70% final may indicate in addition to the degree of genetic expression and underlying pathology the negative effect seizures and EEG discharges have on cognition and evolution.

See also MedLink Neurology article: Epilepsy with myoclonic absences.

Death in the rare occasion of generalized tonic-clonic status epilepticus may occur (96). Absence status epilepticus continues in adult life for half of the patients.

Clinical vignette

Clinical vignette 1. A 7.5-year-old boy suffered from idiopathic (unknown) episodes of myoclonic absences. The absences started about 2 months prior to being seen and consisted of vague looks and occasional dropping of items from his hands. In the previous week, the frequency had increased to five to seven episodes daily.

During hyperventilation in another episode, a single eyelid jerk and a single upper limb myoclonic jerk were part of the described myoclonic absence seizure. Perinatal and past history were noncontributory. Neurologic examination, neuroimaging, and relevant investigations were normal. The electroclinical events responded to sodium valproate, and he had remained free of seizures and EEG discharges for 3 years when last seen.

Clinical vignette 2. An 8-year-old boy was brought for examination because of some jerking of his upper limbs, close to his chest. The jerks had first appeared 4 months prior to examination at frequency of three to four per week but had progressed to one to two per day. The parents also noticed some “vague looks.”

Neurologic assessment revealed hyperkinesis, stuttering, poor attention span, immature behavior, and clumsiness. There were no lateralized focal findings. MRI was normal. Cognitive assessment determined the patient performed at the level of 4 to 5 years old, and he was reported to have severe educational problems. Past and family history were noncontributory. He was given sodium valproate up to 30mg/kg and remained free of seizures for 2.5 years when his treatment was withdrawn. He relapsed with up to 10 myoclonic absence seizures per day. Valproate was reintroduced at a daily dose of 24mg/kg. Four years later, he was free of seizures, and the daily dose was reduced to 11mg/kg; but 18 months later (age 16 years old), he did not take treatment for 5 days, and he relapsed again. Subsequently, he decided to comply with treatment and manage his weight gain, due to sodium valproate, with alternative measures.

Clinical vignette 3. An 11-year-old boy suffered from epilepsy with myoclonic absences of idiopathic (unknown) cause since the age of 12 months when he was noticed to have jerks of the upper part of his body (head, upper limbs) mostly induced by noise. These episodes, observed a few times per week, were described as earthquake-like. At the age of 6-years-old, he was reported to have about 10 episodes daily of vague looks concomitant with rhythmic jerking of the head and upper limbs. The episodes had not responded to high doses of sodium valproate, lamotrigine, clobazam, or levetiracetam. When ethosuximide was introduced to his treatment instead of lamotrigine, absence episodes responded, but he had for the first time three generalized tonic-clonic seizures during which his head and eyes turned left and mouth twisted; clonic-myoclonic movements of upper limbs occurred for few minutes, and he did not respond for about 45 minutes.

Clinical vignette 4. A 6-year-old girl suffered from myoclonic absences of idiopathic (unknown) cause since the age 5.9 years. Her head would bend forward, eyes were open with a vague look concomitant with upper limb and right leg jerking, and unsteadiness; occasionally she would fall. If an episode happened while she was doing homework, when she recovered she would be surprised to find all her work disorganized. If she held things she dropped them. She had daily episodes.

She responded to sodium valproate 30mg/kg. Five years later, valproate was reduced to 17 mg/kg, and treatment was discontinued a year later. From the start, she was discovered to have moderate to severe educational difficulties that made her discontinue secondary level education and was receiving special care. She had remained free of seizures with normal follow-up EEG for 9 years off treatment when she was last seen.

Biological basis

Localization

Myoclonic absences are generalized epileptic seizures with mainly 3 to 6 Hz generalized multiple spike-and-slow wave discharges of higher amplitude in the anterior regions (14).

Etiology and pathogenesis

The etiology of myoclonic absences is unknown. A seemingly homogenous electroclinical phenotype may reflect a variable degree of genetic complex/polygenic heterogeneity with a family history positive for epilepsy in approximately 25% of the cases. Additional etiological factors have been found such as prematurity, perinatal hypoxia, congenital hemiplegia, partial trisomy of the long arm of chromosome 14 (08), trisomy 12p syndrome (32), mutation in the SLC2A1 gene (46), and de novo variants in SETD1B gene-related disorders (49).

Pathophysiology

The underlying pathophysiology of myoclonic absences is not known but may have similarities with the pathophysiology of typical absences seizures. It appears that the basic pathophysiological mechanisms involved in the generation of spike and wave discharges in the thalamic relay neurons is actually dependent on inhibitory inputs from neurons of the nucleus reticularis thalami that engage different hyperexcitable cortical areas. The degree of cortical involvement may be related proportionally to the instability of the T-type Ca²+ channel in the thalamus and the ionized not protein-bound calcium effects the excitability of muscle cells and neurons. Neither the cortex nor the thalamus alone can sustain these discharges, indicating that both structures are involved in their generation. Meeren and colleagues described a consistent focus within the perioral region of the somatosensory cortex in epileptic rats with absence seizures (63). Assessment of their electroclinical characteristics supports the cortical focus theory of absence seizures. During the first cycles of the seizure the cortex drives the thalamus whereas thereafter cortex and thalamus drive each other, thus, amplifying and maintaining the rhythmic discharge (63). Simultaneous EEG/fMRI measurements document cortical deactivation and thalamic activation. Cortical deactivation is related to slow waves and disturbances of consciousness of varying degrees. Motor symptoms correspond to the spike component of the 3 Hz spike-and-wave-discharges. Thalamic activation can be interpreted as a response to overcome cortical deactivation and to restore normal cortical functions (89).

Ikeda and colleagues studied myoclonic absences with ictal single photon-emission computed tomography in two patients (53). They performed ictal and interictal (99 m)Tc-ethyl cysteinate dimer SPECT. They then generated images of subtraction ictal SPECT coregistered to MRI from the interictal and ictal data to evaluate topographic changes in cerebral blood flow during myoclonic absences as compared to the interictal state. In one patient the cerebral blood flow increased in the perirolandic areas, thalamus, caudate nucleus, and precuneus, and decreased in the middle frontal gyrus and bilateral orbitofrontal regions. In the other patients, cerebral blood flow increased in the thalamus, putamen, and globus pallidus but was decreased in the precuneus. These results indicate that in addition to the thalamus and basal ganglia, the perirolandic cortical motor area is involved in myoclonic absences. The authors hypothesized that in myoclonic absences the blood perfusion in the perirolandic cortical motor area might have changed under the influence of the cortico-thalamic network oscillation features (53).

de Saint Martin and colleagues reported a young girl with rolandic seizures that started at the age of 3 years 6 months (28). In addition, between the age of 5 and 6 years, the girl had (1) increased seizure frequency; (2) brief perioral and palpebral myoclonic jerks, concomitant with the spike component of interictal spike-waves, and (3) persistent but fluctuating oromotor deficits (drooling, dysarthria, dysphagia). The EEG showed a marked increase in abundance and amplitude of wake and sleep interictal abnormalities, which became bilateral. Awake FDG-PET revealed a bilateral increase of glucose metabolism in opercular regions. A complete and definitive EEG and clinical remission occurred at age 5 years 11 months and persisted through last interview at age 7 years 9 months. The authors concluded that epileptiform dysfunctions within rolandic areas may induce "interictal" positive or negative oromotor symptoms, independent of classic seizures.

Epidemiology

The classical type of myoclonic absences is a rare seizure type (probably 0.5% in selected cases of epilepsy) with a male preponderance (70%) and a mean age of onset at 7 years (07), starting as early as 4 years (31) and 6 months (90) or even earlier from the age of 1 year (54).

Perioral myoclonia with absences is also very rare, probably less than 1% of typical absence seizures in children, but because it fails to remit it is higher in adults with absences (9.3%). Girls are affected far more frequently than boys (72). In children, based on 13 cases with facial myoclonia, 46.5% had perioral, 38.5% eyebrow, and 15% perioral combined with eyebrow myoclonia with absences. The male to female ratio was 1.6:1 (26).

Prevention

The prevention is based on early correct diagnosis, using appropriate antiseizure medication at an optimum daily dose taking into consideration the risk/benefit ratio. Reducing underlying causes, preventing triggering risk factors, assuring compliance, and avoiding sodium channel blocker antiepileptic drugs will help to prevent seizures from happening. Early diagnosis and treatment of comorbidities will also add to a better quality of life.

Differential diagnosis

Confusing conditions

Myoclonic absences are usually typical, and the diagnosis is mainly based on a detailed history, careful clinical observations, and video-EEG studies with polygraphic recording (EMG of various shoulder and arm muscles) of the electroclinical episodes (74; 09; 71; 20; 07). Clinically, the rhythmic myoclonic movements can be overlooked due to tonic contraction of the arm, or the intensity of the myoclonias can be reduced due to treatment. When the motor manifestations are asymmetric, focal motor seizures are erroneously diagnosed.

Myoclonic absences differ from typical absence seizures of childhood absence epilepsy because myoclonic jerks are generally not seen in childhood absence epilepsy. If they are present, they are subtle. The lack of atonic component also distinguishes myoclonic absences from myoclonic atonic seizures.

The differential diagnosis of epilepsy with myoclonic absences from other syndromes with absences is easy because of the characteristic type of myoclonic absences. The difficulty is between idiopathic and symptomatic and probably symptomatic (structural, unknown) cases that manifest with the same seizure type (myoclonic absences). Symptomatic cases often have an abnormal neurologic state, abnormal background EEG, and abnormal brain MRI and some may necessitate meticulous biochemical assessment. A minority may continue to be unknown. Chromosomal abnormalities are common. Additionally, absences with rhythmic myoclonic jerking but less than 2.5 Hz generalized spike-wave discharges and other characteristics of atypical absences may occur in epileptic encephalopathies (36; 07; 23; 24), and these may account for some of the cases with chromosomal abnormalities (31).

GLUT1 deficiency is a metabolic disorder due to defective transport of glucose across the blood-brain barrier. It should be suspected when absence seizures are associated with at least one among the following: irregular ictal EEG discharges, mild intellectual disability, migraine, microcephaly, drug resistance, and worsening during fasting (77); also, if it coexists with complex movement disorders characterized by ataxia, dystonia, and chorea, which could be paroxysmal or continuous, and may be influenced by fasting, fever, or infection. However, many patients with Glut1-deficiency syndrome remain undiagnosed or misdiagnosed on account of the disorder’s varied phenotype (95).

Facial (perioral or eyebrow) myoclonia with absences is frequently misdiagnosed as focal motor seizures. Also, patients with focal motor seizures are unlikely to suffer from nonconvulsive status epilepticus, which is observed in facial myoclonia with absences. The main differential diagnosis of facial myoclonia with absences is from other syndromes of idiopathic generalized epilepsy with absences. Video-EEG invariably reveals the electroclinical characteristics of facial (perioral or eyebrow) myoclonia that sometimes may be subtle, particularly in treated patients. Useful clinical indicators in favor of facial myoclonia with absences and against the syndrome of childhood absence epilepsy are: (1) onset of generalized tonic-clonic seizures before or at the same age as typical absences, (2) relatively brief duration of absences with facial myoclonia, and (3) frequent occurrence of absence status epilepticus. Perioral myoclonia may rarely occur in absence seizures of other idiopathic generalized epilepsies (50).

Long-lasting atypical status epilepticus associated with an impairment of attention and continuous polymorphous jerks mixed with other complex abnormal movements in infants suffering from a nonprogressive encephalopathy were described by Caraballo and colleagues (10). One subset of the clinical manifestations includes absences, subcontinuous jerks (at times rhythmic or arrhythmic), and mainly positive brief myoclonic absences. A second subset is characterized by absence status and mainly negative, continuous, rhythmic myoclonus and dyskinetic movements. And a third subset shows continuous spike activity in rolandic regions as well as bilateral rhythmic myoclonias followed by inhibitory phenomenon. These cases with nonprogressive encephalopathies have to be differentiated from other forms, including neuronal ceroid-lipofuscinosis.

Associated and underlying disorders

Myoclonic absences are seen in the syndromes of epilepsy with myoclonic absences (recognized by the ILAE commission) as well as facial (perioral or eyebrow) myoclonia with absences and eyelid myoclonia and absences induced immediately after voluntary or on-command eye closure in the presence of light.

Epilepsy with myoclonic absences. Briefly, epilepsy with myoclonic absences is a rare syndrome of idiopathic generalized epilepsy that demands scrupulous exclusion of other forms of structural cases manifesting with the same seizure (myoclonic absences). Myoclonic absences are the defining symptom with rhythmic myoclonic jerks mainly of the shoulders, arms, and legs. GTCS or atonic fits occur in two thirds of patients predicting an unfavorable prognosis. These are cases of structural epilepsy or cases with other types of seizures or may indicate a wider genetic expression (20). Absence status epilepticus is rare (72; 07; 96).

The ILAE diagnostic scheme considers only the idiopathic form, which probably represents less than a third of the whole spectrum of epileptic disorders manifesting with myoclonic absences (34). Prevalence is very low (less than 0.5% to 1%) among selected patients with epileptic disorders.

Age at onset is between 5 months and 13 years (median 7 years), and males (70%) predominate.

Neurologic and mental state. One third of patients are normal (idiopathic form). The others are of structural cause, mainly with learning difficulties prior to seizures.

Etiology. The etiology of epilepsy with myoclonic absences is unknown but presumed to be genetic. In a seemingly homogenous electroclinical phenotype there appears to be the expression of a variable genetic heterogeneity (complex or polygenic) (20). One quarter of patients has a family history of epilepsy. Two siblings with epilepsy with myoclonic absences have been reported (13).

Myoclonic absences (the seizures, not the syndrome) are due to idiopathic, genetic, structural or cryptogenic causes, including chromosomal abnormalities. Elia and associates investigated etiology in 14 patients with epilepsy with myoclonic absences (31; 32). Five were cryptogenic. Two had myoclonic absences associated with other seizure types due to neuronal migration abnormality or a metabolic disorder. Seven, with or without other seizure types, had chromosomopathies (two trisomy 12p, four Angelman syndrome, and one with inv dup (15)). One of these cases with trisomy 12p syndrome was also detailed.

Of interest are the few cases of myoclonic absences occurring in glucose transporter type 1 (GLUT1) deficiency syndrome with mutations in the SLC2A1 gene (46). This syndrome often manifests with a variety of absence seizures that are usually of early onset (83; 64; 75; 82; 77; 67).

Bahi-Buisson and colleagues described a family with a dominantly inherited mutation in glutamate dehydrogenase (GDH), with the mother, brother, and both sisters having myoclonic absence seizures, but only the mother and one sister had the complete hyperinsulinism/hyperammonemia pattern (01). For the two sisters with myoclonic absences, epilepsy started during the second year of life whereas in the brother, it started at 6 years. All three children showed the same EEG pattern characterized by photosensitive, generalized, and irregular spike-wave discharges and runs of multiple spikes. The mother's EEG recordings were normal without photosensitivity. Magnetic resonance imaging and spectroscopy were normal (01).

Klitten and colleagues described a patient with epilepsy with myoclonic absences and learning disability who was found to have a de novo balanced translocation: t(6; 22)(p21.32; q11.21) (57). The breakpoint at 6p21.32 was found to truncate the N-methyl-d-aspartate (NMDA)-receptor associated gene SYNGAP1. The breakpoint at 22q11.21 was within a highly variable region without known protein-coding genes. Mutations of SYNGAP1 are associated with nonsyndromal intellectual disability, and two thirds of the patients have generalized epilepsy (57).

Myoclonic absences rarely can occur in SCN8A infantile developmental and epileptic encephalopathy (41). Generalized epilepsy seizures with an important subset of myoclonic absences are also reported in SYNGAP1 and SETD1B-related intellectual disability and autism spectrum disorder (49; 52). Seizures are frequent and drug-resistant in 50% of cases. Adding cannabidiol in three cases with SYNGAP1 drug-resistant cases showed reported improvement from 80% to 95% (58). Larger studies are needed for confirmation and the obvious impact on quality of life.

Rarely, myoclonic absences may occur in children with Dravet syndrome. In 2017, Myers and Scheffer reported a 20-year-old man with Dravet syndrome for whom, by 5 years of age, photosensitive myoclonic absence seizures had become his dominant seizure type, implicating the role of SCN1A mutations (65). This rare seizure type may be underreported in Dravet syndrome as the myoclonic features may be subtle and can be missed if thorough history taking and video recordings are not available (65). An infant diagnosed with Dravet syndrome with focal cortical myoclonus on conventional EEG when he was 6 months old has been reported, which may broaden the types of seizures of Dravet syndrome and may provide some diagnostic clues for Dravet syndrome (61).

See article on Epilepsy with myoclonic absences.

Facial myoclonia with absences. Facial myoclonia with absences, as such, has not been recognized either as a seizure type or as a syndrome by the ILAE; however, absences with facial (perioral or eyebrow) myoclonia is a discrete seizure type unequivocally documented with video-EEG recordings. Furthermore, there is often a nonfortuitous clustering of other clinical and EEG features, indicating that these absences may constitute the main symptom of an interesting syndrome “facial myoclonia with absences” within the idiopathic generalized epilepsies.

Prevalence is small, occurring in less than 1% of children (9.3% in adults) with typical absences. Age at onset is at 2 to 13 years (median 10 years). Females predominate (about 80%).

Neurologic and mental state. Normal.

Etiology. Facial myoclonia with absences is probably genetically determined. Half of patients have first-degree relatives and mainly siblings with idiopathic generalized epilepsy and absences.

Clinical manifestations. Typical absence seizures with perioral or eyebrow myoclonia are the defining symptom. Facial myoclonia consists of rhythmic protrusion of the lips, twitching of the corners of the mouth, or jaw or eyebrow jerking. Impairment of consciousness varies from severe to mild. The absences last 2 to 9 seconds (median 4 seconds), with varying frequency from many times per day to one to two per week or less frequently.

The majority of patients suffer from GTCS, starting before, soon after, or, exceptionally, many years after the absences. GTCS are usually infrequent and are often heralded by clusters of absences or absence status epilepticus.

Absence status epilepticus is very common (57%) and frequently ends with GTCS.

In children the term facial instead of perioral myoclonia with absences is preferably used for the reason that some cases present with perioral, others with eyebrow, or perioral and eyebrow. Based on a population of 13 children, 46% presented with perioral, 38% with eyebrow, and 15% with perioral/eyebrow myoclonias with absences. The age of onset varied from 1 to 13 years (mean 5±3 years). All children were assessed with sleep-awake video EEG recording following sleep deprivation. The duration of the recorded generalized spike-wave discharges varied from 0.25 to 20 seconds and 15% showed a positive response to intermittent photic or pattern stimulation. The response to sodium valproate was 85%. No absence status epilepticus was recorded in this population of children. Those cases with GTCS in their phenotype had a less favorable outcome (26). Absence and myoclonic seizures, the predominant type of seizures in the phenotype, characterize the syndrome epilepsy with myoclonic absences (formerly known as Tassinari syndrome) and also two syndromes in development, eyelid myoclonia and absences (formerly known as Jeavons syndrome) and facial myoclonia with absences (22; 20; 21).

Early-onset absence epilepsy. Nasser and colleagues described the electroclinical features of nine children with normal development and typical absence seizures starting before the age of 4 years (67). Eight patients had rhythmic myoclonic jerks involving the muscles of the upper face (eyebrows and eyelids) or neck, present from the onset to the end of the typical absence discharge. The myoclonia were synchronous with spike-wave complexes. One patient with GLUT-1 deficiency was refractory to antiepileptic polytherapy. The other eight became seizure-free; five with one antiepileptic drug and three with a combination of two drugs. The authors suggested that the motor symptoms during the absence seizures may represent a distinctive age-related feature of early-onset absence epilepsy (67).

In the author’s experience based on a study of 19 children (F: M =1.7:1) with early-onset absence seizures (< 3 years, mean 2.7±0.7 years), two groups were identified: nonmyoclonic (37%) and myoclonic type (63%). In the nonmyoclonic group, there are cases with spanioleptic and pyknoleptic absence seizures. The spanioleptic are reminiscent of juvenile absence epilepsy whereas the pyknoleptic are either childhood absence-like or an early expression of what later evolves to juvenile myoclonic epilepsy with or without positive response to intermittent photic stimulation. Early predictors are marked clonic-myoclonic component and the brief generalized spike/poly-spike wave discharges. In the nonmyoclonic group, the cases that are mostly associated with cognitive and educational problems are the CAE-like, followed by the JAE-like. Those who evolved to juvenile myoclonic epilepsy do well.

The absence seizures in the myoclonic group are mostly pyknoleptic. Spanioleptic absence seizures in this category may be a false impression as many absence seizures are inconspicuous and not easily recognized if not recorded by video-EEG and the transient events during brief generalized discharges are not meticulously studied. Some cases can be identified as myoclonic epilepsy of infancy or childhood. Others are reminiscent of epilepsy with myoclonic absences or facial (perioral) myoclonia with absences or myoclonic atonic epilepsy. One category, which can be early identified, is eyelid myoclonia and absences evoked on eye closure (formerly known as Jeavons syndrome).

Almost 75% of the cases respond to monotherapy with sodium valproate in nonresponders. Ethosuximide, levetiracetam, and lamotrigine can be combined with valproate. Relapses are frequent in the myoclonic group (70%) as compared to the nonmyoclonic (20%) even after long duration of successful treatment, mean 4.3 ± 0.8 years and 6.6±3 years, respectively. Brief generalized spike-wave discharges, photosensitivity, and GTCS are the most unfavorable relapse risk factors.

Early-onset absence epilepsy includes a variety of epileptic syndromes. All children are developmentally normal at onset, but the majority develop cognitive and educational problems with advancing age in spite of an early and successful treatment. Their phenotypic heterogeneity reflects genetic differences that most likely predetermine evolution. It is also probable that environmental variables, duration of symptoms, and response to treatment contribute to the outcome (12; 17).

See article on Typical absences.

Diagnostic workup

The EEG, preferably sleep-awake video-EEG after sleep deprivation, particularly in children, is the single most important diagnostic procedure in diagnosing myoclonic absence seizures. These are often induced by hyperventilation though not as easily as other typical absence seizures of childhood and juvenile absence epilepsy. Ideally, these patients should have video polygraphic-EEG recordings in an untreated state as this may reveal features favoring a specific epileptic syndrome and may, therefore, determine long-term prognosis and management. If this is not possible, the clinical manifestations of the seizures should be documented with camcorders by the parents or the treating physicians. Breath-counting during hyperventilation (wherein the patient is asked to count his or her deep breaths) is an important, often neglected, method to detect impairment of consciousness during the discharge (43; 72). In infants, without the aid of a paper windmill to blow, it is impossible to encourage a continuous and effective hyperventilation. Also, counting during hyperventilation is less successful in young children because the pattern of breathing is interrupted and effective hyperventilation is rarely achieved (19). In infancy and early childhood video-EEG recordings need meticulous assessment in order to identify inconspicuous and brief clinical events.

In epilepsy with myoclonic absences, the interictal EEG shows normal background activity with generalized irregular spike-wave activity (in one third of the cases) that is sometimes intermingled with polyspikes; rarely, focal or multifocal spike-waves or spikes occur (07). The ictal EEG comprises rhythmic generalized and bilateral synchronous and symmetric 3 Hz spike-wave activity as can be seen in typical absences. Occasionally, these classic discharges may be intermingled with polyspikes. The polygraphic recordings reveal bilateral and rhythmic myoclonias with a strict and constant relation with the spike wave of the discharge; the latency between EEG spikes and EMG myoclonic activity varies between 15 and 40 milliseconds in proximal muscles. Later into the seizure, the myoclonias are associated with progressive tonic contraction of the affected muscles (85; 07).

In perioral myoclonia with absences, the interictal EEG also shows normal background activity with frequent, less than 1-second generalized discharges of 3 to 7 Hz spike or multiple spike waves that are usually asymmetrical. Focal abnormalities are common, including single spikes, spike-wave complexes, or slow waves. Ictal EEG shows brief (mean 4 seconds; range 2 to 9 seconds) generalized discharges of 3 to 4 Hz spikes or multiple spike waves with frequent irregularities in terms of the number of spikes, fluctuations in spike amplitude, and fragmentations. Perioral myoclonia may occur during generalized EEG discharges of polyspikes and waves without evidence of absence (27).

In children with myoclonic absences, genetic studies should be considered if no etiology is found after a detailed clinical examination and MRI, particularly in patients with associated neurodevelopmental disorders or a structural or functional brain disorder is known to be associated with a genetic basis. Genetic testing should be also a primary investigation for cases presenting in infancy and early childhood.

The myoclonic absence phenotype might be a common clinical expression of several etiologies rather than a discrete entity.

Management

First-line antiepileptic drugs in typical absences are sodium valproate or ethosuximide, which are of equal efficacy, controlling absences in approximately 75% of patients; lamotrigine is less effective, with nearly half of the patients becoming seizure-free (68; 76; 45; 92). Clonazepam, levetiracetam, sulthiame, and zonisamide are also used as add-on treatments (80). Sodium channel blocker antiseizure drugs should be avoided.

Myoclonic absences are usually resistant to monotherapy. Therefore, a combination of high doses of valproate, often combined with lamotrigine or ethosuximide, levetiracetam (35), or clonazepam are recommended (07). A favorable response to add-on treatment with rufinamide in three cases with drug-resistant myoclonic absences has been reported (48). Perampanel has also demonstrated efficacy and safety in generalized tonic-clonic seizures (06) and in myoclonic seizures (30) among patients with idiopathic generalized epilepsy and does not seem to exacerbate absence seizures.

To choose the correct antiepileptic medications at an appropriate daily dose taking into consideration the risk-benefit ratio and recognizing comorbidities for early intervention contributes to better management. Sodium valproate has been proved to be most successful for this type of seizure either as monotherapy or combined with other appropriate antiepileptic drugs. In this respect, taking into consideration the dose-related teratogenicity it should be avoided as a first choice in adolescent females. Special care should be given to those females on valproate who intend to become pregnant or are pregnant, where the daily dose of valproate should be based on a careful risk-benefit decision (88). Levetiracetam is increasingly prescribed for these patient populations despite a scarcity of evidence of clinical effectiveness or cost-effectiveness. In the SANAD II study, levetiracetam compared to valproate was found to be neither clinically effective nor cost-effective (62). For girls and women of child-bearing potential, these results inform discussions about the benefit and harm of avoiding valproate. There is an urgent need for the development of up-to-date, globally applicable recommendations (87).

In a single-center retrospective study of 131 cases with typical absence seizures, eighteen cases (13.7%) were classified as difficult to treat. Absence seizures were more often difficult to treat in patients with myoclonic absence seizures and absence seizures with eyelid myoclonia (40.0%), compared with patients with typical absence seizures (11.4%) (47). Additional factors contributing to difficult-to-treat absence seizures were positive family history of epilepsy, higher seizure frequency prior to treatment, and longer time between seizure onset and treatment onset (47).

Carter and colleagues reviewed medical records between 2017 and 2022 to identify electroclinical variability and response to treatment of patients with myoclonic absences (11). Of the 10 patients identified, four had an atonic component and two out of three of those that were drug-resistant underwent corpus callosotomy. One was seizure-free 8 months after surgery and the other had greater than 50% seizure reduction over a 5-month period. A larger study is needed to evaluate the efficacy of this treatment.

Flamini and colleagues investigate the effectiveness of add-on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic-clonic, atonic, focal to bilateral tonic-clonic), nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic absence), and epileptic spasms (39). Among patients with treatment resistant epilepsy, add-on CBD was associated with a reduction in the frequency of convulsive seizure types, nonconvulsive seizure types, and epileptic spasms. At least 50% reduction was reported in greater than or equal to 49% of patients across all evaluated seizure types and at nearly all intervals for up to 144 weeks of treatment.

Absence status epilepticus of perioral myoclonia with absences, for which most patients are aware, should be terminated with self-administered benzodiazepines and mainly buccal or nasal spray midazolam.

Contraindicated drugs. The treatment of myoclonic absences is demanding because many antiepileptic drugs are either ineffective or exaggerate absences and myoclonic jerks (78; 72; 93; 13). An antiepileptic drug is contraindicated not only when it exaggerates seizures but also when it is ineffective in controlling the seizures that it is supposed to treat. It may cause unnecessary adverse reactions and deprives the patient of the therapeutic effect that could be provided by another antiepileptic drug. Carbamazepine, phenytoin, oxcarbazepine, phenobarbital, gabapentin, pregabalin, vigabatrin, and tiagabine are contraindicated in the treatment of myoclonic absences, irrespective of cause and severity. This is based on clinical and experimental evidence. In particular, the GABA agonists vigabatrin and tiagabine are used to induce, not to treat, absence seizures and absence status epilepticus (72). Lacosamide, a novel antiseizure medication, is believed to exert its anticonvulsant action through selective enhancement of slow inactivation of voltage-gated sodium channels. Lacosamide has been demonstrated to be efficacious as an adjunctive therapy for primary generalized tonic-clonic seizures (91) but may have the potential to worsen or to induce fresh myoclonic seizures (05). In this respect, lacosamide should be used with caution in idiopathic generalized epilepsies.

Recognizing GLUT1 deficiency syndrome as a rare cause of myoclonic absences is important because a ketogenic diet is effective in improving epileptic seizures and may also reduce some neurologic symptoms (40; 56). Most antiepileptic drugs are contraindicated either because they are ineffective or because they exaggerate seizures. Phenobarbital, but also chloral hydrate and diazepam, may further impair GLUT1 and should not be used in these patients.

Outcomes

The evolution of epilepsy with myoclonic absences, the prototype of myoclonic absences, is variable. Almost 45% have intellectual disability from start, 75% final, and half persist beyond adolescence. This variability of clinical phenotype may be an expression of the genetic heterogeneity, in addition to the effect it may have on cognition, the seizures, the interictal-ictal EEG activity, and even more, in some cases, the underlying pathology. Early diagnosis and early appropriate treatment, taking into consideration the risk-benefit ratio and treating early coexisting comorbidities, significantly contribute to better outcome and quality of life.