Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Juvenile absence epilepsy is a genetically determined generalized epilepsy syndrome with a peak onset at 9 to 13 years of age. It manifests with severe and frequent absence seizures. The majority of patients also have generalized tonic-clonic seizures, and a few also have sporadic myoclonic jerks. EEG shows classical generalized 3 Hz spike-and-slow-wave discharges. Response to appropriate pharmacological treatment is usually excellent, but relapses are common on drug withdrawal. Appropriate antiseizure treatments include sodium valproate, ethosuximide, lamotrigine, and possibly levetiracetam. Other antiseizure medications, such as carbamazepine, eslicarbazepine, lacosamide, oxcarbazepine, phenytoin, tiagabine, and vigabatrin, are contraindicated. In this article, the author details clinical, electroencephalographic, genetic, and management aspects of juvenile absence epilepsy and emphasizes how its differential diagnosis compares with other focal and generalized epileptic syndromes.
• Juvenile absence epilepsy is a genetically determined generalized epilepsy characterized by (a) typical absence seizures occurring frequently with significant impairment of consciousness and (b) generalized tonic-clonic seizures. Myoclonic jerks may also occur; these are mild and with no particular circadian distribution.
• The differential diagnosis includes other syndromes manifesting with absence seizures, such as childhood absence epilepsy, juvenile myoclonic epilepsy, generalized epilepsy with phantom absences, and absence seizures associated with glucose transporter 1 (GLUT-1) deficiency syndrome.
• Most of the available evidence is inconclusive regarding the evolution and prognosis of juvenile absence epilepsy. The prevailing view is that most patients with juvenile absence epilepsy usually respond well to appropriate pharmacological treatment, but this may need to be lifelong.
The first description of juvenile absence epilepsy was probably by Janz and Christian in 1957, when they categorized patients with non-pyknoleptic absences (36). Doose and associates found that peak age at onset in children with absence seizures congregated into 3 groups: children 4 to 8 years of age with childhood absence epilepsy (female preponderance); children younger than 4 years of age; and children 10 to 12 years of age (no sex differences) and with cycloleptic (in cycling clusters) or spanioleptic (spanios=rare) absences and frequently generalized tonic-clonic seizures (15).
The Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) proposed in 1981 that typical absences of “idiopathic” generalized epilepsies be differentiated from atypical absences of symptomatic generalized epilepsies (10). However, all epilepsies with typical absence seizures remained for a long time clustered in the group of "petit mal" and were considered a form of "centrencephalic epilepsy." In 1989, the ILAE Commission proposed to distinguish 3 syndromes of “idiopathic” generalized epilepsy: childhood absence epilepsy, juvenile absence epilepsy, and juvenile myoclonic epilepsy (11). Subsequently, the ILAE Task Force proposed that juvenile absence epilepsy be classified as a syndrome of adolescence (20; 06) under the category of “genetic generalized epilepsies” along with childhood absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone (57).
• The main seizure types include absence seizures, which may occur multiple times per day, as well as generalized tonic-clonic seizures. Myoclonic jerks may occur as well.
• Typical age of onset is 9 to 13 years of age.
• Absence status epilepticus may occur.
Frequent typical absences are the characteristic and defining seizures of juvenile absence epilepsy. The usual frequency of absences is approximately 1 to 10 per day, but this may be much higher for some patients (46; 48). They are similar to those of childhood absence epilepsy, although they may be milder. The hallmark of the absence is abrupt, brief impairment of consciousness with total or partial unresponsiveness. Duration of the absences varies from 4 to 30 seconds but it is usually long (approximately 16 seconds) (20). Mild or inconspicuous impairment of consciousness, such as of phantom absences, is not typical of juvenile absence epilepsy. The ongoing voluntary activity usually stops at onset but may be partly restored during the ictus. Automatisms are frequent, usually occurring 6 to 10 seconds after the onset of the EEG discharge. In juvenile absence epilepsy, mild myoclonic movements of the eyelids may occur during the absence. However, more severe and sustained myoclonic jerks of facial muscles may indicate other generalized epilepsies with absences. Severe eyelid or perioral myoclonus, rhythmic limb-jerking, and single or arrhythmic myoclonic jerks of the head, trunk, or limbs during the absence ictus are not typical of juvenile absence epilepsy. Absence status epilepticus is truly generalized nonconvulsive (without any type of motor manifestation) and may occur in up to one fifth of patients.
Generalized tonic-clonic seizures occur in up to 80% of patients, often after awakening, although nocturnal or diurnal generalized tonic-clonic seizures may also be experienced (15; 70; 46; 49; 41). Generalized tonic-clonic seizures are usually infrequent, but in some cases may become severe and intractable.
Myoclonic jerks occurring in 15% to 25% of patients are infrequent, mild, and of random distribution (11; 48).
Rarely, patients with juvenile absence epilepsy may present with an uncommon evolution of generalized to focal seizures followed by secondary generalization (double generalization phenomenon) (56). Patients with juvenile absence epilepsy rarely report visual hallucinations (27).
Seizure-precipitating and facilitating factors. Absence seizures are typically precipitated by hyperventilation in patients with juvenile absence epilepsy. Mental and psychological arousal may also precipitate typical absences. Conversely, sleep deprivation, fatigue, alcohol, excitement, and lights alone or usually in combination are the main facilitating factors for generalized tonic-clonic seizures. Some authors reported that 8% to 56% of juvenile absence epilepsy patients suffered from photosensitivity clinically or on EEG (42).
Age and sex at onset. Age at onset is primarily 9 to 13 years (70% of the patients), but the range is from 5 to 20 years (46; 48; 03). Myoclonic jerks and generalized tonic-clonic seizures usually begin 1 to 10 years after the onset of absences. Rarely, generalized tonic-clonic seizures may precede the onset of absences. Both sexes are equally affected.
Most of the available evidence is inconclusive regarding evolution and prognosis of juvenile absence epilepsy (48; 58). The prevailing view is that juvenile absence epilepsy often responds well to appropriate pharmacological treatment. The seizures may resolve in 15% to 40% of patients but life-long treatment is necessary in many patients (14; 03). Patients who have had generalized tonic-clonic seizures may be less likely to remit compared to those who have had only absence seizures (14; 44).
Cognitive abnormalities and academic problems may be present early at onset of juvenile absence epilepsy (33). Specifically, difficulties with attention, language function, and visuo-spatial skills have all been reported (52). Individuals with juvenile absence epilepsy are more likely to have below average performance on academic tasks as well as behavior problems (44).
An 11-year-old child was referred for frequent (1 to 10 per day), brief periods of unresponsiveness lasting for 10 to 20 seconds. This was described by witnesses as “the eyes glaze or stare, and he is not with it.” There were frequent perioral and limb automatisms, which varied in each absence. An EEG confirmed the diagnosis of “absences”. These responded only when sodium valproate was combined with ethosuximide. Medication was slowly withdrawn after 3 seizure-free years, but a generalized tonic-clonic seizure occurred half an hour after waking from a short sleep compounded by the excitement of a planned trip. A new video-EEG revealed absences typical of juvenile absence epilepsy. The patient reported occasional mild jerks of the hands, mainly at night. Retrospective evaluation of the first EEG revealed that the ictal EEG manifestations consisted of long, 15- to 22-second, generalized discharges of multiple spike-and-waves at 3.5 Hz, favoring juvenile absence epilepsy.
Reviewed at 37 years of age, the patient was a solicitor and had occasional absences, particularly when excited, despite adequate doses of sodium valproate and ethosuximide. He endorsed occasional mild jerks occurring randomly during the day. Two generalized tonic-clonic seizures had occurred at the age of 18 and 19 years after excessive and unaccustomed alcohol drinking and sleep deprivation in the first and missing medication doses in the second.
• Juvenile absence epilepsy is thought to have a genetic basis, although the mode of transmission is not well established.
• Several genetic abnormalities have been identified.
• Structural changes in the brain have been identified in some patients.
The exact etiology of juvenile absence epilepsy is not well established. A genetic association is thought to be likely, with a complex pattern of inheritance; several genes have been linked to this syndrome. A family history is occasionally present; typically, family members have a related genetic generalized epilepsy.
The mode of transmission, genes involved, and relation to other forms of genetic generalized epilepsy has not been fully established; a single Mendelian mode appears to be unlikely.
Genetics. There is an increased incidence of epileptic disorders in families of patients with juvenile absence epilepsy, and there are reports of monozygotic twins with juvenile absence epilepsy (46). Concordance studies in generalized epilepsies have shown that there are independent genetic effects on the type of genetic generalized epilepsy syndrome and the seizure type (69; 39).
Various genetic abnormalities have been identified in patients with juvenile absence epilepsy. Abnormalities have been linked to chromosome 8 (18), 21 (54), 3q26 (55), 18 (17), and probably 5 (17). Specific gene alterations have been reported in EFHC1, CACNA1A, CACNB4, GRIK1, GABRG2, GABRA1, and CLCN2 (54; 28; 62). An association was also found between the G allele of rs7588807 located in the INHA gene and juvenile absence epilepsy (71). Gene expression analysis in untreated patients with childhood and juvenile absence epilepsy demonstrates an inconsistent pattern (68).
Pathology. Autopsy (43) and MRI studies (16) found microdysgenesis and other cerebral structural changes in patients with juvenile absence epilepsy. Specifically, frontal lesions including atypical appearing focal cortical dysplasias and nodular heterotopias have been reported in patients with juvenile absence epilepsy (21). Tondelli and colleagues reported grey matter volume and surface area reduction in the bilateral frontal regions, anterior cingulate, and right mesial-temporal lobe in patients with juvenile absence epilepsy compared to healthy controls. Correlation analysis with disease duration showed that longer disease was correlated with reduced surface area in right pre- and postcentral gyrus. A possible effect of valproate treatment on brain structures was excluded (64).
Another study demonstrated decreased fractional anisotropy and increased mean diffusivity and radial diffusivity values in the genu and the body of the corpus callosum and right anterior corona radiata, as well as decreased axial diffusivity in the left posterior thalamic radiation, inferior cerebellar peduncle, right cerebral peduncle, and right corticospinal tract. There were no significant differences in cortical thickness or deep gray matter structure volumes between patients and controls (12).
Pathophysiology. Variants in the T-type calcium channel gene CACNA1H that alter channel properties have been found in subjects with phenotypes including childhood absence, juvenile absence, juvenile myoclonic and myoclonic astatic epilepsies, as well as febrile seizures and temporal lobe epilepsy (31). The proposition is that these variants contribute to an individual's seizure susceptibility but are not sufficient to cause epilepsy on their own (31).
In a magnetoencephalography study of 5 patients with juvenile absence epilepsy, the dynamic statistical parametric mapping of the cortical source distribution of generalized spike-and-slow-wave showed strong medial prefrontal activation in all patients, with activation in the posterior cingulate and precuneus in 3 of 5 patients simultaneously or slightly after medial prefrontal activation (53). Furthermore, dynamic statistical parametric mapping showed that the initial activation of a generalized spike-and-wave discharge appears in the focal cortical regions. The authors concluded that cortical regions that constitute a default mode network are strongly involved in the generalized spike-and-wave process in some patients with juvenile absence epilepsy, and focal cortical activation appears at the onset of a generalized spike-and-wave discharge.
An Australian fMRI study of 8 patients with juvenile absence epilepsy demonstrated overall fewer and weaker functional connectivity measures compared with healthy controls. Reduced functional connectivity was noted between the medial prefrontal cortex and the occipital cortex whereas there was increased connectivity between the medial prefrontal cortex and thalamus, cerebellum, and hippocampus (50).
Exact prevalence of juvenile absence epilepsy is uncertain because of variable criteria. In adults older than 20 years, its prevalence may be around 2% to 3% of all epilepsies and around 8% to 10% or more of genetic generalized epilepsies (49; 47; 03).
In the classical monograph of Janz, 116 patients were considered to have juvenile absence epilepsy as opposed to 505 with childhood absence epilepsy and 280 with juvenile myoclonic epilepsy (34). In the study by Wolf and Inoue, in adults with continuing absences, “non-pyknoleptic” absences (juvenile absence epilepsy) were nearly as frequent as “pyknoleptic” absences (70). In a survey of 7332 patients from 14 epilepsy centers in Lombardy, 1494 (17.4%) had “idiopathic” generalized epilepsy, and 160 of these were diagnosed as having juvenile absence epilepsy (47). In another study with strict classification criteria, the prevalence of juvenile absence epilepsy in adults was 13.3% among patients with absences and 10.2% among patients with genetic generalized epilepsy. Juvenile myoclonic epilepsy with absences was 2.3 times more common than juvenile absence epilepsy (49). An Iranian study found a slightly higher prevalence of juvenile absence epilepsy, accounting for 18% of genetic generalized epilepsies and more than half of epilepsies with absences (03).
The diagnosis of juvenile absence epilepsy may be difficult, even by specialists, and may be misdiagnosed as inattention or daydreaming. In practical terms, a patient suspected of typical absences should be asked to hyperventilate for 3 minutes, possibly with video recording for documentation of the clinical features (48).
Focal epilepsies. The differential diagnosis of juvenile absence epilepsy from focal seizures with impaired cognition can sometimes be difficult on a purely clinical basis. Automatisms may be common in both. Absence seizures tend to be shorter (less than 30 seconds) and occur daily or multiple times per day. Focal seizures may be longer and occur less frequently. EEG will often show generalized spike-wave discharges at a frequency of 3 to 4 Hz both ictally and interictally in absence epilepsy, and focal abnormalities are rare. Focal epilepsy may have a normal interictal EEG or there may be focal abnormalities. Absence seizures from frontal lobe origin may have concomitant, more or less regular, bilateral spike-wave discharges (22). Focal motor components, asymmetrical ictal discharges, or interictal frontal foci in the EEG may help in their differentiation.
Other generalized epilepsies with absence seizures. The differentiation of juvenile absence epilepsy from other generalized epilepsies with absences may be difficult without video-EEG comparisons (48).
Childhood absence epilepsy. Severe impairment of consciousness and high daily frequency are the main characteristics of childhood absence epilepsy, but these may also be features of juvenile absence epilepsy. Onset of juvenile absence epilepsy is later (peak at 12 to 13 years), and absences are not as frequent or as severe as in childhood absence epilepsy (19). However, age at onset alone is not an absolute criterion for differentiation between childhood absence epilepsy and juvenile absence epilepsy. There is an overlap with juvenile absence epilepsy starting earlier and childhood absence epilepsy starting at later than 10 years of age (35). Further, patients with juvenile absence epilepsy may also have frequent daily absence seizures (46). Generalized tonic-clonic seizures are common in juvenile absence epilepsy, and one third of these patients may also have mild and random myoclonic jerks. EEG features may also be similar, though polyspikes (more than 3 to 4) favor juvenile absence epilepsy.
Juvenile myoclonic epilepsy. Absence seizures occur in one third of juvenile myoclonic epilepsy patients but these are usually mild, often inconspicuous, and have different EEG patterns. The main seizure type of juvenile myoclonic epilepsy is myoclonic jerks on awakening.
Epilepsy with myoclonic absences, eyelid myoclonia with absences, perioral myoclonia with absences. These types of absence seizures are characterized by their predominant ictal myoclonic manifestations that do not consistently feature in juvenile absence epilepsy (48). Eyelid myoclonia or perioral myoclonia with absences have been proposed as epileptic syndromes different from juvenile absence epilepsy (48), but this view is not universally accepted.
Generalized epilepsy with phantom absences. Generalized epilepsy with phantom absences is characterized by a triad of: (1) phantom absences; (2) generalized tonic clonic seizures of late onset; and (3) absence status epilepticus, which occurs in 50% of patients (41). Phantom absences are typical absence seizures with the mildest form of impairment of consciousness. They are so mild that they are inconspicuous to the patient and imperceptible to the observer. On video-EEG, they manifest with interruption, delays or errors of counting, and occasionally with eyelid blinking. Generalized tonic-clonic seizures are usually the first overt clinical manifestation. They are of late onset (adult life), infrequent, and without consistent circadian distribution or specific precipitating factors. About 50% of patients suffer solely from absence status epilepticus of many hours’ duration or prior to generalized tonic-clonic seizures. This is also of mild or moderate severity that sometimes is difficult to recognize as pathological.
Absence seizures associated with glucose transporter-1 (GLUT1) deficiency syndrome. Of clinical importance is the diagnosis of absence seizures associated with GLUT1 deficiency syndrome. Seizures begin between the age of 1 and 4 months in 90% of cases. The frequency and severity of seizures varies among affected individuals. Typical or atypical absences, mainly of early onset, are the most prominent seizure types. Typical absences may imitate various syndromes of genetic generalized epilepsy with absences such as epilepsy with myoclonic absences, childhood absence epilepsy, or juvenile absence epilepsy (60). The ketogenic diet is highly effective in controlling the seizures (40). An early diagnosis and early start of a ketogenic diet may prevent deterioration. Phenobarbital is contraindicated.
Molecular genetic testing for SLC2A, which is the only gene known to be associated with GLUT1 deficiency, is now clinically available. Families with members manifesting various types of genetic generalized epilepsy with absences (early-onset absence seizures, childhood or juvenile absence epilepsy, juvenile myoclonic epilepsy) should be tested for SLC2A1 gene mutations (60).
The EEG, preferably video-EEG, is the single most important procedure in diagnosing juvenile absence epilepsy (41).
The interictal EEG frequently shows spike- or polyspike-wave discharges over an otherwise normal EEG background. These discharges occur at a frequency of 3 to 4 Hz, sometimes up to 4 to 5 Hz at the onset of the burst; they are slightly faster and often more fragmented and disorganized compared to those seen in childhood absence epilepsy (05; 19). There may be a frontal predominance. Focal epileptiform abnormalities and abortive asymmetrical bursts of spikes or polyspikes are common (61; 37). Rhythmic delta activity over the temporal regions may be seen in a subset of patients (Gelisse at el 2011).
The characteristic ictal EEG during typical absence seizures consists of bilaterally synchronous and symmetrical discharge of rhythmic spike-and-slow wave complexes. These occur at a frequency of 3.5 to 4 Hz, sometimes with a frontal predominance. The frequency at the initial phase of the discharge is usually fast (3 to 5 Hz) with a gradual and smooth decline in frequency from the initial to the terminal phase. These discharges may be more fragmented than in childhood absence epilepsy and they occur in longer runs (05).
In comparison with other syndromes of generalized epilepsy, the density of epileptiform discharges (total duration of epileptiform discharges per hour) and the duration of EEG paroxysms are the highest in juvenile absence epilepsy followed by juvenile myoclonic epilepsy, childhood absence epilepsy, and generalized epilepsy with tonic-clonic seizures only (59).
Brain imaging is typically normal. Cognitive, academic, and/or behavioral problems may become apparent with neuropsychological testing.
• Valproate is often considered the first-line treatment for juvenile absence epilepsy as it is beneficial in controlling both absence and generalized tonic-clonic seizures; however, there is a risk of teratogenicity and medication interaction.
• Other medications such as ethosuximide for absences and lamotrigine or possibly levetiracetam may also be beneficial.
• Certain medications, including carbamazepine, oxcarbazepine, eslicarbazepine, vigabatrin, and tiagabine may worsen seizure in this condition.
The main antiseizure medications used in this condition are sodium valproate, lamotrigine, ethosuximide, and possibly levetiracetam (66; 48; 25). Clonazepam, clobazam, and acetazolamide are sometimes considered as second-line drugs; they share a similar risk of tolerance and adverse effects.
Ethosuximide and valproate are equally effective as monotherapy in controlling the absences of more than 80% of patients with typical absence seizures. Valporate also controls generalized tonic-clonic seizures and so is often the treatment of choice in juvenile absence epilepsy. Approximately 82% of patients will become seizure-free with these drugs (70). Valproate is highly associated with teratogenic effects and is often avoided in patients of childbearing potential. The teratogenic effect is dose-dependent. Although “safe” doses have not been well established, recommendations have been made in Europe not to exceed a daily dose of 600 to 700 mg per day (63; 09) and in North America not to exceed 750 mg per day (30).
Lamotrigine may be successfully used either as an addition to valproate in uncontrolled patients because of a beneficial pharmacodynamic interaction (48), or as monotherapy, controlling approximately 50% of patients with absence seizures (23; 32). It is likely less effective than valproate and ethosuximide in controlling absence seizures (Glauser et el 2013; 38). In some instances, lamotrigine may worsen myoclonus (13).
Though initially licensed for focal epilepsies, levetiracetam has demonstrated efficacy in primarily generalized tonic-clonic seizures (07), myoclonic jerks (45), absence seizures (66), and photosensitivity and has a relatively safe adverse drug reaction profile in both men and women. However, its efficacy in absence epilepsy is questionable and an aggravating effect was retrospectively found in an unspecified number of children with absence epilepsy from 3 pediatric neurology departments in France (04).
Perampanel has been reported to be effective in generalized tonic clonic, myoclonic, and absence seizures of generalized epilepsies, including juvenile absence epilepsy (67). Add-on zonisamide was found beneficial in a report of an observational post-marketing study of 13 patients with pharmacoresistant juvenile absence epilepsy (65). Zonisamide was particularly more efficacious in absences than in generalized tonic clonic seizures.
Vigabatrin and tiagabine are pro-absence drugs that may precipitate absences and absence status epilepticus. Other antiseizure medications such as carbamazepine, oxcarbazepine, eslicarbazepine, phenytoin, lacosamide, phenobarbital, and gabapentin either may be ineffective or may exacerbate absence seizures (48; 01).
Vagus nerve stimulation has been beneficial in 3 patients with medically refractory juvenile absence epilepsy (02).
Ketogenic and modified Atkins diets may be beneficial in patients with drug-resistant juvenile absence epilepsy (26).
Patients should be warned about precipitating factors of generalized tonic-clonic seizures. Treatment may be life-long because attempts to withdraw medication often lead to relapses even after many years free of seizures (48; 51; 29). It may be difficult to regain seizure control after relapse (29).
The seizures in juvenile absence epilepsy frequently respond well to treatment. As many as 80% of patients may become seizure free with medications (70). Factors associated with suboptimal control include absences with clonic components, more than 10 generalized tonic-clonic seizures, generalized tonic-clonic seizures during sleep and at random, history of absence status epilepticus, developmental delay, spike-wave bursts of more than 5 seconds, asymmetry of spike-waves, persistence of absences beyond 25 years of age, and persistence of absences for more than 12 years (70).
Although the condition may eventually resolve in some, life-long treatment will be necessary for many patients (03). Patients who have had generalized tonic-clonic seizures may be less likely to remit compared to those who have had only absence seizures (14; 44).
Patients with juvenile absence epilepsy who continue to have active epilepsy into adulthood are at risk for a number of significant adverse social outcomes that require ongoing advice and counseling (08).
Although no information is available that is specific to this syndrome and pregnancy, information is available on epilepsy and pregnancy. Several antiseizure medications including sodium valproate have potentially teratogenic effects.
Jules C Beal MD
Dr. Beal of Weill Cornell Medicine and New York-Presbyterian Queens Hospital received honorariums from LivaNova as a member of advisory committees.See Profile
Solomon L Moshé MD
Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Childhood Degenerative & Metabolic Disorders
Jun. 10, 2021
Epilepsy & Seizures
Jun. 01, 2021
Epilepsy & Seizures
May. 04, 2021
Epilepsy & Seizures
Although absences are considered a paradigm of primarily generalized seizures, they may occasionally be of focal onset (focal onset generalized absence
Apr. 26, 2021
Epilepsy & Seizures
Apr. 26, 2021
Epilepsy & Seizures
Inhibitory motor seizures are ictal motor epileptic events of central paresis usually unilateral mono- or hemiparesis while consciousness is intact.
Apr. 26, 2021
Epilepsy & Seizures
Initial evaluation The initial diagnosis of seizure is based on the history. If first-line treatment fails, the diagnosis is (or should be) questioned
Apr. 23, 2021
Epilepsy & Seizures
Apr. 12, 2021