Childhood absence epilepsy

C P Panayiotopoulos MD PhD (Dr. Panayiotopoulos of St. Thomas' Hospital has no relevant financial relationships to disclose.)
Jerome Engel Jr MD PhD, editor. (Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.)
Originally released October 18, 1993; last updated June 12, 2017; expires June 12, 2020

This article includes discussion of childhood absence epilepsy, CAE, petit mal, and pyknolepsy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Childhood absence epilepsy is the prototype genetic generalized epilepsy syndrome of typical absence seizures. It is common and age related, and it affects otherwise normal children. It manifests with severe and frequent (pyknoleptic) absence seizures, around 10 seconds each, many times per day. EEG shows classical generalized 3 Hz spike-and-slow wave discharges. Prognosis of childhood absence epilepsy is excellent if properly diagnosed and treated. In this update, the author details developments in the pathophysiology, genetics, and pharmacological treatment of childhood absence epilepsy. The focus is on the current understanding of its clinical and EEG phenotype, epidemiology, and outcome along with the differential diagnosis associated with other idiopathic/genetic generalized epilepsies involving absence seizures. The author particularly emphasizes that most of the older and newer antiepileptic drugs are contraindicated for the treatment of childhood absence epilepsy.

Key points

 

• Childhood absence epilepsy is the most characteristic and classic example of a genetic generalized epilepsy characterized by typical absence seizures of high daily frequency and severe impairment of consciousness.

 

• Probably any other types of seizure in the active period of childhood absence epilepsy are incompatible with this diagnosis. Mild impairment of consciousness in untreated patients is an exclusion criterion.

 

• Differential diagnosis includes other types of syndromes manifesting with typical absence seizures; “epilepsy with absences seizures of childhood onset” is not synonymous with childhood absence epilepsy.

 

• Prognosis is usually excellent for patients diagnosed on strict inclusion and exclusion criteria for childhood absence epilepsy.

 

• Ethosuximide, sodium valproate, and lamotrigine are the most effective antiepileptic drugs.

Historical note and terminology

According to Temkin, Poupart was the first to describe absence seizures in 1705 (Temkin 1971). However, Tissot's description of petits accès or petits in 1770 is better known (Tissot 1770). They were called "absences" by Calmeil in 1824 (Calmeil 1824), "petit mal" by Esquirol in 1838 (Esquirol 1838), and "epilepsia mitior" by Reynolds in 1861 (Reynolds 1861). Gowers gave a most accurate description of the absence seizures “without conspicuous convulsions” (Gowers 1881). Friedman reported a long-term favorable prognosis but believed that these absences were not epileptic (Friedmann 1906). The frequency of typical absence seizures had also been conspicuous and Sauer coined the name “pyknolepsy” (from the Greek word pyknos, meaning closely packed, dense, or aggregated) (Sauer 1916). Hyperventilation as a test to introduce absences was first described by Brain in 1924 (Peterman 1945). In the same year, Adie reported on pyknolepsy, a form of epilepsy occurring in children with a good prognosis, and defined it as follows:

 

...a disease with an explosive onset between the ages of 4 and 12 years, of frequent short, very slight, monotonous minor epileptiform seizures of uniform severity, which recur almost daily for weeks, months, or years, are uninfluenced by antiepileptic remedies, do not impede normal and psychical development, and ultimately cease spontaneously never to return. At most, the eyeballs may roll upwards, the lids may flicker, and the arms may be raised by a feeble tonic spasm. Clonic movements, however slight, obvious vasomotor disturbances, palpitations, and lassitude or confusion after the attacks are equivocal symptoms strongly suggestive of oncoming grave epilepsy, and for the present they should be considered as foreign to the more favorable disease (Adie 1924).

Gibbs, Davis, and Lennox showed that petit mal absences were associated in EEG with a rhythmic 3 Hz discharge of regular spike-and-wave complexes (Gibbs et al 1935). The introduction of trimethadione revolutionized the treatment of absence seizures (Lennox 1945). Video-EEG analysis allowed a precise clinico-EEG correlation of typical absence seizures (Penry et al 1975).

The Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) made important progress by accurately defining and differentiating typical absences of idiopathic generalized epilepsies versus atypical absences of symptomatic generalized epilepsies (Commission 1981). However, all epilepsies with typical absence seizures remained for a long time clustered in the group of "petit mal" and considered as a form of "centrencephalic epilepsy."

In 1989 the Commission on Classification and Terminology of the ILAE recognized the heterogeneity of epilepsies with absence seizures and proposed to distinguish 3 syndromes of idiopathic generalized epilepsy (childhood absence epilepsy, juvenile absence epilepsy, and juvenile myoclonic epilepsy) (Commission 1989). Further, it also recognized typical absence seizures in "other idiopathic generalized epilepsies," in "idiopathic generalized epilepsies with specific provocation," and also in a syndrome of cryptogenic generalized epilepsy (epilepsy with myoclonic absences). Panayiotopoulos and colleagues described syndrome-related characterization of absence seizures with video-EEG analysis (Panayiotopoulos et al 1989b).

The ILAE Task Force in recognition of the diversity of typical absence seizures proposed 4 types that are probably of different pathophysiology and syndromic significance: (1) the classical typical absence seizure, (2) myoclonic absence seizures, (3) phantom typical absence seizures, and (4) eyelid myoclonia with absence (Engel 2006). The task force also recognizes childhood absence epilepsy as a separate epileptic syndrome within idiopathic generalized epilepsies (Engel 2001; Engel 2006). Other syndromes with predominant absence seizures identified by the ILAE Task Force are epilepsy with myoclonic absences, juvenile absence epilepsy, and juvenile myoclonic epilepsy.

All these types of seizures and electroclinical syndromes are mostly maintained in the more recent report of the ILAE Commission on Classification and Terminology (Berg et al 2010; Commission on Classification and Terminology of the International League Against Epilepsy 2014). However, the latest ILAE position paper for the operational classification of seizure types does not consider phantom absences though “it is recognized that awareness and responsiveness can be at least partially retained during some generalized seizures, for example, with brief absence seizures, including absence seizures with eyelid myoclonias or myoclonic seizures” (Fisher et al 2017a; Fisher et al 2017b).

Nomenclature and inclusion and exclusion criteria. Childhood absence epilepsy (pyknolepsy) was defined by the 1989 Commission as follows:

 

Pyknolepsy occurs in children of school age (peak manifestation age 6 to 7 years), with a strong genetic predisposition in otherwise normal children. It appears more frequently in girls than in boys. It is characterized by very frequent (several to many per day) absences. The EEG reveals bilateral, synchronous symmetrical spike-waves, usually 3 Hz, on a normal background activity. During adolescence, generalized tonic-clonic seizures often develop. Otherwise, absences may remit or, more rarely, persist as the only seizure type (Commission 1989).

However, this brief definition may be misinterpreted because of some ambiguity in its terminology as illustrated by the fact that many reports consider childhood absence epilepsy any type of epilepsy with onset of absences in childhood (Sadleir et al 2006). Therefore, epidemiology, genetics, age at onset, clinical manifestations, other types of seizures, long-term prognosis, and treatment do not accurately reflect the syndrome of childhood absence epilepsy. More strict definition of childhood absence epilepsy has been proposed (Loiseau et al 1995a; Loiseau et al 1995b; Hirsch et al 2008; Panayiotopoulos 2008). Table 1 shows inclusion and exclusion criteria for childhood absence epilepsy, which do not differ significantly from those of the Commission (Commission 1989):

(1) “Childhood absence epilepsy occurs in children of school age (peak manifestation age 6 to 7 years)”. A simplistic but unsatisfactory practice is to label as childhood absence epilepsy any child with onset of daily absences at 10 years or earlier (as early as 2 years of age) (Sadleir et al 2006; Sadleir et al 2008). The 10 years of age cut off is arbitrary and not a decisive “gold standard” to define what is and what is not childhood absence epilepsy. The arbitrary limit of 10 years is mainly based on the pioneering work of Doose and Janz who found that pyknoleptic absences usually start before 10 years of age, whereas non-pyknoleptic absences usually start after this age (Doose 1994; Janz et al 1994). Typical absence seizures of recognized syndromes, such as myoclonic absence or juvenile myoclonic epilepsy, may start before the age of 10 years. Further, “school age” does not include children younger than 3 to 4 years because absence seizures with onset at this age are heterogeneous; some may constitute discrete genetic entities; they are entirely different to those of childhood absence epilepsy (Doose 1994; Guerrini et al 2002; Audenaert et al 2003; Chaix et al 2003; Titomanlio et al 2007); and they are often of bad prognosis (Currier et al 1963; Livingston et al 1965; Dalby 1969). Childhood absence epilepsy starting before the age of 4 years and of good prognosis may be a very rare possibility that needs investigation (Darra et al 1996; Sgro et al 1996; Shahar et al 2007).

If diagnosis by age at onset is to be followed, the study population should be correctly defined as “epilepsy with childhood absence seizures” rather than childhood absence epilepsy, which is a subset of it.

(2) “Childhood absence epilepsy is characterized by very frequent (several to many per day) absences.” These absences are not only “several to many per day” but also severe according to the ILAE definition:

The hallmark of the absence attack is a sudden onset, interruption of ongoing activities, a blank stare, possibly a brief upward rotation of the eyes. If the patient is speaking, speech is slowed or interrupted; if walking, he stands transfixed; if eating, the food will stop on his way to the mouth. Usually the patient will be unresponsive when spoken to. In some, attacks are aborted when the patient is spoken to. The attack lasts from a few seconds to half a minute and evaporates as rapidly as it commenced (Commission 1981).

(3) In childhood absence epilepsy “the EEG reveals bilateral, synchronous symmetrical spike-waves, usually 3 Hz, on a normal background activity.” This terminology presumably excludes fragmented, asymmetrical, and asynchronous spike-wave discharges of 3 to 5 Hz intradischarge variations.

(4) In childhood absence epilepsy no other than absence types of seizures are accepted except that “during adolescence, generalized tonic-clonic seizures often develop. Otherwise, absences may remit or, more rarely, persist as the only seizure type.

In addition, the ILAE, by accepting epilepsy with myoclonic absences and juvenile myoclonic epilepsy as separate syndromes, probably exclude myoclonic absences and brief mild absences from childhood absence epilepsy (Commission 1989). It is by this logic that eyelid myoclonia with absences (which are primarily myoclonic) may also be an exclusion criterion. Further, by accepting reflex absence seizures as a distinct category, the ILAE indicates that these too may not be part of childhood absence epilepsy. That perioral myoclonia or single violent jerks occurring in the course (not at onset) of typical absence seizures is an exclusion criterion may be debatable; however, their presence indicates worse prognosis (Guilhoto et al 2003; Grosso et al 2005; Hirsch et al 2008). The same applies for multiple spikes and fragmented S-PWD that also indicate a bad prognosis, coexistent myoclonic jerks, or generalized tonic-clonic seizures (Panayiotopoulos et al 1989b; Fakhoury and Abou-Khalil 1999; Aydin-Ozemir et al 2014).

Table 1. Inclusion and Exclusion Criteria for Childhood Absence Epilepsy

Inclusion criteria:

 

(1) Age at onset between 4 and 10 years and a peak at 5 to 7 years.

 

(2) Normal neurologic state and development.

 

(3) Brief (4 to 20 seconds, exceptionally longer) and frequent (tens per day) absence seizures with abrupt and severe impairment (loss) of consciousness. Automatisms are frequent but have no significance in the diagnosis.

 

(4) EEG ictal discharges of generalized high-amplitude spike and double (maximum occasional three spikes are allowed) spike-and-slow wave complexes. They are rhythmic at around 3 Hz with a gradual and regular slowdown from the initial to the terminal phase of the discharge. Their duration varies from 4 to 20 seconds.

Exclusion criteria:
The following may be incompatible with childhood absence epilepsy:

 

(1) Early onset before the age of 3 years or late onset after 10 years.

 

(2) Other than typical absence seizures such as GTCS, or myoclonic jerks prior to or during the active stage of absences.

 

(3) Eyelid myoclonia, perioral myoclonia, rhythmic massive limb jerking, and single or arrhythmic myoclonic jerks of the head, trunk, or limbs. However, mild myoclonic elements of the eyes, eyebrows, and eyelids may be featured, particularly in the first 3 seconds of the absence seizure.

 

(4) Mild or no impairment of consciousness during the 3 to 4 Hz discharges.

 

(5) Brief EEG 3 to 4 Hz spike-wave paroxysms of less than 4 seconds, multiple spikes (more than three) or ictal discharge fragmentations.

 

(6) Visual (photic) and other sensory precipitation of clinical seizures.

The ILAE epilepsy manual classifies childhood absence epilepsy among epileptic syndromes of childhood; the classification is detailed below (Commission on Classification and Terminology of the International League Against Epilepsy 2014).

Childhood absence epilepsy. Childhood absence epilepsy is a genetic generalized epilepsy that should be considered in an otherwise normal child with multiple daily absence seizures associated with 2.5 to 3.5 Hz generalized spike-and-wave. Absence seizures are provoked by hyperventilation. Between 8 and 12 years of age, the distinction between the clinical syndromes of juvenile absence epilepsy and childhood absence epilepsy depends on the frequency of absence seizures.

A genetic generalized epilepsy is an epilepsy with generalized seizures associated with generalized epileptiform EEG patterns, such as generalized spike wave activity.

Clinical context. This syndrome is characterized by onset of frequent absence seizures between the ages of 2 to 12 years (peak 5 to 6 years of age). Both sexes are equally affected. Antecedent and birth history is normal. A previous history of febrile seizures may occur (seen in 15% to 20% of cases). Neurologic examination and head size are normal. Development and cognition are typically normal. Attention deficit hyperactivity disorder and learning difficulty may occur. Seizures are typically self-limiting. Self-limiting means having a high likelihood of seizures spontaneously remitting at a predictable age.

 

Caution. Onset of absence seizures less than 4 years, then consider glucose transporter disorders.

Mandatory epileptic seizures. Absence seizures in childhood absence epilepsy are typically frequent (multiple daily) and brief (average 10 seconds). Awareness and responsiveness are usually severely impaired, but the child may be more responsive towards the end of the seizure.

 

Caution. Absence seizures longer than 45 seconds or with postictal phase should not occur. Then consider focal dyscognitive seizures (eg, due to structural brain abnormality).

 

Caution. The presence of awareness during absence seizures. Then childhood absence epilepsy is unlikely, other syndromes with absences should be considered.

 

Caution. If onset or offset of absences is not abrupt, or absences occur less than daily. Then consider other syndromes with absences.

Mandatory epileptic seizures may have generalized convulsive seizures, which are seen occasionally, usually in adolescence, not in the early period after seizure onset.

 

Caution. Generalized convulsive seizures before adolescence? Then consider other epilepsy syndromes.

 

Exclusionary. Any other seizure type is not expected in this syndrome.

EEG background. The background is normal. Occipital intermittent rhythmic delta activity (OIRDA) may be seen in a third of children with childhood absence epilepsy, at a frequency of 2.5 to 4 Hz and may have a notched appearance.

 

Caution. Focal slowing seen consistently in 1 area consider structural brain abnormality.

 

Caution. Generalized slowing is not seen.

Interictal EEG. Generalized spike-and-wave, or fragments of generalized spike-and-wave, are seen in the interictal EEG. These are brief (usually less than 2 seconds) and occur most commonly seen in sleep.

 

Caution. Although focal spikes (as fragments of generalized spike-and-wave) can occur, if they consistently arise in 1 area, then consider structural brain abnormality.

Activation. EEG abnormality and absence seizures are provoked by hyperventilation. If hyperventilation is poorly performed, generalized spike-and-wave may not be triggered. Intermittent photic stimulation triggers generalized spike-and-wave in a small proportion of individuals.

EEG abnormality is enhanced by sleep deprivation and by sleep. Generalized spike-and-wave often becomes fragmented with sleep deprivation or in sleep. Fragmented generalized spike-and-wave can appear focal or multi-focal but usually is not consistently seen in 1 area. The morphology of the focal spike-and-wave typically appears similar to the generalized spike-and-wave.

 

Caution. Where hyperventilation is performed well for 3 minutes, and no generalized spike-and-wave is seen, childhood absence epilepsy is unlikely.

Ictal EEG. Regular 3 Hz generalized spike-and-wave occurs associated with absence seizures. Polyspike-and-wave can occur in the ictal EEG.

 

Caution. Slow spike-and-wave (less than 2.5 Hz) is exclusionary.

Imaging. Neuroimaging is normal. If the electroclinical diagnosis of childhood absence epilepsy is established, and there are no atypical features, neuroimaging is not required.

Genetics. It has a complex inheritance. In children who have absences that have onset before 4 years of age, 10% have GLUT1 deficiency (a mutation in SLC2A1). Other genes linked to this syndrome include GABRG2 and CACNA1A.

Family history of seizures/epilepsy. Up to 20% of patients may have a first-degree relative with seizures. When a family history is present, the affected family members typically have childhood absence epilepsy or a related genetic generalized epilepsies (eg, juvenile absence epilepsy, juvenile myoclonic epilepsy, or less commonly genetic epilepsy with febrile seizures plus).

A genetic generalized epilepsy is an epilepsy with generalized seizures associated with generalized epileptiform EEG patterns, such as generalized spike wave activity.

Differential diagnoses.

 

• Juvenile absence epilepsy: Consider if there are infrequent (eg, once daily) absence seizures in a child who is 8 years of age or older.

 

• Epilepsy with eyelid myoclonias: Consider if there is repetitive, rhythmic, fast greater than 4 Hz jerks of the eyelids, with upward deviation of the eyeballs, and with head extension; seizures are often very frequent and induced by eye closure and photic stimulation.

 

• Epilepsy with myoclonic absences: Consider if there are 3 Hz myoclonic jerks of upper limbs with tonic abduction.

Adapted from (Commission on Classification and Terminology of the International League Against Epilepsy 2014).

According to the new position paper of the ILAE Commission for Classification and Terminology, childhood absence epilepsy is an idiopathic or genetic self-limited epilepsy (Scheffer et al 2017).

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