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Current disclosures: In the early 90's and until 1994 I had limited paid presentations ~20 for Welcome, Marion Merrel Dow, Sanofi, Ciba-Geigy probably in that order. In between 1992-1994 I had a project grant from Marion Merrell Dow to support a clinical and research fellow. From 15th February 2004 (after my NHS retirement) I have a consultancy with UCB Pharma.

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Current thumbnail: Childhood absence epilepsy is the prototype idiopathic generalized epilepsy syndrome of typical absence seizures. It is a genetically determined, age related and affects otherwise normal children. It manifests with severe and frequent absence seizures of around 10 seconds for many times per day. EEG shows classical generalized 3Hz spike and slow wave discharges. If properly diagnosed, treatment is highly effective and prognosis is excellent.

In this update, C P Panayiotopoulos MD PhD FRCP, Consultant Emeritus, Department of Clinical Neurophysiology and Epilepsies, St. Thomas’ hospital, London details recent developments in the pathophysiology, genetics and pharmacological treatment of childhood absence epilepsies.

Historical Note and Nomenclature
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 anti-epileptic 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 made important progress by accurately defining and differentiating typical absences of primary (idiopathic) generalized epilepsies versus atypical absences of secondary (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 International League Against Epilepsy recognized the heterogeneity of epilepsies with absence seizures and proposed to distinguish three 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; Panayiotopoulos 1997; 2005).

Nomenclature and inclusion and exclusion criteria. Childhood absence epilepsy (pyknolepsy) was defined by the 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 definition suffers from the drawbacks of retrospective studies based on any child diagnosed as having "petit mal," that is any type of epilepsy with onset of absences in childhood. 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. This is a proposal for a more strict definition of childhood absence epilepsy (Hirsch et al 1994; Loiseau et al 1995a; 1995b; Panayiotopoulos 1997; Loiseau et al 2002; Panayiotopoulos 2005). Table 1 shows inclusion and exclusion criteria for childhood absence epilepsy, which do not differ significantly from those of the Commission (Commission 1989):

• Age at onset in childhood
• Frequent (several to many per day) absences presumably with severe impairment of consciousness
• Ictal EEG with bilateral, synchronous, symmetrical spike-waves, usually 3 Hz, on a normal background activity (that presumably excludes fragmented, asymmetrical and asynchronous spike-wave discharges of 3 to 5 Hz intra-discharge variations)
• Generalized tonic-clonic seizures are accepted only if they develop later in adolescence.

In addition, by accepting epilepsy with myoclonic absences as a separate syndrome, the Commission has excluded these typical absence seizures from childhood absence epilepsy (Commission 1989). It is along this line that we considered eyelid myoclonia (which is predominantly myoclonic and less of an absence) also as an exclusion criterion. That perioral myoclonia or single violent jerks during the ictus of an absence seizure is an exclusion criterion may be debatable; however, their presence indicates worse prognosis (Panayiotopoulos 1997). The same applies for multiple spikes (more than 3 spikes per wave) that also indicate a bad prognosis and coexistent myoclonic jerks or GTCS (Panayiotopoulos et al 1989b; Fong et al 1998; Fakhoury and Abou-Khalil 1999).

Further, by accepting typical absence seizures consistently provoked by specific stimuli, the Commission indicates that these may be a separate group from childhood absence epilepsy as we also propose (Commission 1989).

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 years to 7 years.
2. Normal neurologic state and development.
3. Brief (4 seconds 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 seconds to 20 seconds.

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

1. Other than typical absence seizures such as GTCS, or myoclonic jerks prior to or during the active stage of absences.
2. 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.
3. Mild or no impairment of consciousness during the 3-Hz to 4-Hz discharges.
4. Brief EEG 3-Hz to 4-Hz spike-wave paroxysms of less than 4 seconds, multiple spikes (more than 3) or ictal discharge fragmentations.
5. Visual (photic) and other sensory precipitation of clinical seizures.

Clinical Manifestations
Childhood absence epilepsy is characterized by severe and frequent (many per day) typical absence seizures (Table 1). Any other type of seizure at this stage is likely incompatible with this diagnosis.

Typical absence seizures of childhood absence epilepsy. Absence seizures in childhood absence epilepsy are characterized by abrupt onset and termination of marked impairment of consciousness with or without other signs. Duration is around 10 seconds (range 4 to 20 seconds, exceptionally longer) and there are many per day.

The hallmark of the absence attack is a sudden onset and interruption of ongoing activities, often with a blank stare. Lennox and Lennox state: “If warning occurs, the diagnosis of petit mal may be questioned” (Lennox and Lennox 1960). The attack ends as abruptly as it has commenced. The child resumes his or her on-going activity as if nothing had happened and is usually unaware of the seizure.

Severe impairment of consciousness is the essential feature of the absence seizure in childhood absence epilepsy. There is complete loss of awareness and responsiveness and cessation of on-going activities. The child stops talking, eating, and walking. There may be a vacant look, staring straight ahead or drifting upwards. Untreated absences with mild impairment of consciousness may be an exclusion criterion (Panayiotopoulos 1997; 2005).

Regarding other associated ictal clinical features automatisms are common in childhood absence epilepsy though of no prognostic significance. Mild tonic or clonic symptoms often occur, particularly in the first second of the absence seizure. However, marked eyelid or perioral or limb and trunk myoclonic jerks, particularly if they continue in the course of the absence seizure, may be exclusion criteria. Atonic falls do not occur (Loiseau 1992).
Absences are usually frequent throughout the day:

If attacks do not recur daily, the diagnosis may be questioned...They begin in driblets, the parents noting short episodes of immobility or eye-rolling but passing it off as day-dream or an emotional display...In time, however, the blackout periods increase in frequency or in duration and cannot be disregarded any longer...At this moment, they range from 10 to 200 per day (Lennox and Lennox 1960).

Precipitating factors of typical absence seizures in childhood absence epilepsy. Typical absence seizures occur spontaneously but are particularly influenced by various factors such as anger, sorrow, fear, surprise, embarrassment, lack of interest, release of attention, meal-time for some children, school-time for others, nyctohemeral factors (evening or awakening), and metabolic factors (hypoglycemia, hyperventilation). Of all these, the main precipitating factor is hyperventilation. It is the easiest way to provoke absence seizures; a diagnosis of childhood absence epilepsy should be seriously questioned in an untreated child who does not have an attack on hyperventilation (Loiseau 1992; Wirrell et al 1996b). In a series from Strasbourg, hyperventilation provoked typical absence seizures in 100% of untreated patients with childhood absence epilepsy (Hirsch et al 1994). Typical absence seizures that are consistently elicited by specific stimuli such as light or patterns do not belong to childhood absence epilepsy (Commission 1989; Hirsch et al 1994; Loiseau et al 1995a; 1995b; Panayiotopoulos 1997; Loiseau et al 2002; Panayiotopoulos 2005).
Other types of seizures. Generally, other types of epileptic seizures are not part of childhood absence epilepsy. In particular, generalized tonic-clonic seizures or myoclonic jerks do not occur in childhood absence epilepsy preceding or concomitant with the stage of active absence seizures (Commission 1989; Hirsch et al 1994; Loiseau et al 1995a; 1995b; Panayiotopoulos 1997; Loiseau et al 2002; Panayiotopoulos 2005). GTCS as a presenting seizure is incompatible with childhood absence epilepsy. However, infrequent GTCS may occur in adolescence or adult life (Commission 1989; Loiseau et al 1995a; 1995b; 2002). Though absence status may occur in 5% to 16% of cases, with typical absence seizures starting before the age of 10 years (Dieterich et al 1985), this is probably incompatible with childhood absence epilepsy (Panayiotopoulos 1997; Agathonikou et al 1998; Panayiotopoulos et al 2001; Panayiotopoulos 2005).

Age and sex at onset. The onset of childhood absence epilepsy is classically considered between 4 years to 10 years with a peak at 5 years to 7 years, although some authors have suggested a much wider range reflecting differences in definition criteria (Bergamini et al 1965; Loiseau et al 1995a; Panayiotopoulos 1997; Loiseau et al 2002; Panayiotopoulos 2005). Lowest and highest age at onset compatible with childhood absence epilepsy is uncertain. Onset earlier than 4 years is a rare possibility (Darra et al 1996; Sgro et al 1996). Onset after the age of 10 years may be exceptional (Loiseau et al 1995a; Panayiotopoulos 1997; Loiseau et al 2002; Panayiotopoulos 2005).

Childhood absence epilepsy is clearly more frequent in girls than in boys. Sixty percent to 70% of affected children are girls (Lennox and Lennox 1960; Bergamini et al 1965; Loiseau 1992).

Clinical Vignette
A 10-year-old intelligent girl had uncontrollable typical absences since age 5 years. Absences were severe of 8 seconds to 15 seconds duration and as frequent as tens or hundreds per day. Despite adequate doses of syrup of sodium valproate, ethosuximide, and lamotrigine, alone or usually in combination, she continued having frequent absences. When she was first seen at age 8 years, she was on syrup sodium valproate 600 mg and lamotrigine 150 mg. On video-EEG 7 clinical absences lasting from 8 to 15 seconds were recorded. Clinically, there was severe impairment of consciousness, often with automatisms associated with high amplitude 3-Hz generalized spike-and-slow wave discharges. All absences stopped within a week after replacing syrup with tablets of sodium valproate 800 mg and reducing lamotrigine. Two years later she remains seizure-free on tablets of sodium valproate 600 mg and lamotrigine 50 mg. An attempt to withdraw lamotrigine resulted in relapses. The following is her personal account of her experience:

I was 5 years when mummy and daddy noticed that I started to stare and not pay attention to them when they spoke to me...They took me to a doctor...I had blood tests and an EEG...I was told that I had epilepsy...I had to start taking medicine...I had more spells...at school some children made fun of me...Some friends would help me by calling my name during the spells; that seemed to help me stop...I saw more doctors...more tests...changed my medication, but I never seemed to get any better...By the time I was 8 years old the spells had got a lot worse...I seemed to be having spells all the time...Once I had one in the swimming pool, and my dad had to pull me out; it made me scared...The medicine was making my hands shaky, and I could not write clearly or concentrate at school...Last year I was taken to see a new doctor who changed my syrup to tablets and asked me to take less of the other medication...A week later my spells stopped...I have not had any spells since...I am finding school much more fun now, and I do not feel tired any more...I am allowed to play in the swimming pool without people having to keep watching me...I am happy now that my problem is gone away...We are going to have a big party when I stop taking medicine.

Etiology
Childhood absence epilepsy is a genetic disorder of an unknown mode of transmission.

Pathogenesis and Pathophysiology
Childhood absence epilepsy is idiopathic generalized epilepsy, which is genetically determined with a 15% to 44% positive family history of epilepsy. In two independent series, 17% of patients with childhood absence epilepsy had first-degree relatives with epilepsy manifesting with absence seizures, GTCS, or both (Loiseau et al 1995a; Callenbach et al 1998). In studies on twins, 84% of monozygotic twins had 3-Hz spike-waves; typical absence seizures developed in 75% of pairs and 16 times less often in dizygotic twins (Lennox and Lennox 1960). However, as concordance in monozygotic twins is not 100%, nongenetic factors are likely (Berkovic et al 1994; 1998). Bianchi and colleagues found that in 24 families with a childhood absence epilepsy proband, there was a high concordance (33.3%) for the same clinical form in first-degree relatives, whereas febrile convulsions (46.7%) and GTCS (30%) were more common in distant relatives (Bianchi 1978). Thus, a genetic abnormality is responsible for a predisposition and for the EEG trait, but childhood absence epilepsy, which is its clinical expression, is likely to be multifactorial.

Although childhood absence epilepsy is genetically determined, the precise mode of inheritance and the genes involved remain largely unidentified (Crunelli and Leresche 2002). Currently, various chromosomal loci have been identified in families with absences of childhood onset (not necessarily equated with childhood absence epilepsy). Linkage to chromosome 1 was found in families with absences starting in childhood and later developing myoclonic jerks and GTCS as in juvenile myoclonic epilepsy (Delgado-Escueta et al 1999; Medina et al 2005). Linkage analysis of a 5 generation family in which affected patients had childhood absences and generalized tonic-clonic seizures provided evidence for a locus on chromosome 8q24 (Fong et al 1998; Delgado-Escueta et al 1999). The candidate region for this locus, designated ECA 1, has been refined, but a gene remains to be identified. According to the criteria proposed in this chapter, neither of these groups is childhood absence epilepsy.

Furthermore, available evidence suggests that mutations in genes encoding GABA receptors (Feucht et al 1999; Marini et al 2003) or brain expressed voltage-dependent calcium channels (Chen et al 2003) may underlie childhood absence epilepsy or at least absences of childhood onset. Feucht and colleagues (Feucht et al 1999) found a significant association between a polymorphism in GABRB 3 in chromosome 15q11 and patients of 50 families with childhood absence epilepsy. Marini and colleagues (Marini et al 2003) found GABA-A receptor gamma2 subunit gene (GABRG2) mutations on chromosome 5 in a large family with childhood absence epilepsy and febrile seizures (including febrile seizures plus and other seizure phenotypes). This gene mutation segregated with febrile seizures and childhood absence epilepsy and also occurred in individuals with the other phenotypes. The clinical and molecular data suggested that the GABA-A receptor subunit mutation alone could account for the febrile seizure phenotype, but an interaction of this gene with another gene or genes was required for the childhood absence phenotype in this family. Linkage analysis for a putative second gene contributing to the childhood absence phenotype suggested possible loci on chromosome 10, chromosome 13, chromosome 14 and chromosome 15 (Marini et al 2003). Chen and colleagues (Chen et al 2003) found 68 variations, including 12 missense mutations, in the calcium channel CACNA1H gene in patients with childhood absence epilepsy. The identified missense mutations occurred in the highly conserved residues of the T-type calcium channel gene (Chen et al 2003). However, another study of 33 nuclear families, each with 2 or more individuals with childhood absence epilepsy, provided conclusive evidence that genes encoding GABA-A and GABA-B receptors, voltage-dependent calcium channels, and the ECA1 region on chromosome 8q do not account independently for the childhood absence trait in a majority of the families (Robinson et al 2002).

Functional imaging with positron emission tomography demonstrates normal cerebral glucose metabolism and benzodiazepine receptor density in absence epilepsies with diffuse hypermetabolism during 3-Hz spike-and-wave discharges (Ryvlin and Mauguiere 1998; Duncan 1999). There is no evidence of any interictal overall abnormality of opioid receptors, though typical absences have been found to displace 11C-diprenorphine from the association areas of the neocortex. In contrast, binding of 11C-flumazenil to central benzodiazepine receptor has been shown not to be affected by serial absences (Duncan 1999). Kapucu and colleagues (Kapucu et al 2003) evaluated of 23 patients of childhood absence epilepsy with 99mTc-hexamethylpropylenamine oxime brain single photon emission computed tomography. Interictally, 10 of them had relative hypoperfusion in the frontal lobes that could involve neighboring parietal and temporal regions. The activation study during absence seizures revealed that 13 of 23 patients had relative hyperperfusion in the same brain regions that were relatively hypoperfused in the baseline study. These hyperperfused regions occupied larger areas than baseline hypoperfused regions. All patients had global increased perfusion in the ictal study.

Autopsy and MRI studies found microdysgenesis and other cerebral structural changes in some patients with childhood absence epilepsy that may be inconceivable for this benign, age-dependent, and age-limited epileptic syndrome (Meencke and Janz 1985; Meencke 1995; Woermann et al 1998). Meencke reviewed autopsy findings in childhood absence epilepsy and confirmed his previous reports on microdysgenesis, with the frontal lobe more severely affected in 12 patients (Meencke and Janz 1985; Meencke 1995). Using quantitative MRI, Woermann and colleagues found that patients with idiopathic generalized epilepsy had significantly larger cortical grey matter volumes than control subjects (Woermann et al 1998). Abnormalities of the regional distribution of cerebral grey and subcortical matter were frequent in patients with idiopathic generalized epilepsy but not so frequent in patients with childhood absence epilepsy. However, all cases of Meencke had frequent absences from childhood to adulthood and GTCS, which would not conform with a strict diagnosis of the syndrome of childhood absence epilepsy (Meencke 1995). Similar may be the single patient with abnormal MRI of Woermann and colleagues (Woermann et al 1998).

The pathophysiological mechanisms of absence seizures have been studied in various animal models with generalized spike and wave discharges associated with behavioral arrest (Danober et al 1998; Futatsugi and Riviello 1998; Snead et al 1999; Crunelli and Leresche 2002; Manning et al 2003). It appears that generalized spike and wave discharges are generated and sustained by highly synchronized abnormal oscillatory rhythms in thalamocortical networks that mainly involve neocortical pyramidal cells, the reticular thalamic nucleus, and the relay nuclei of the thalamus. Neither the cortex nor the thalamus alone can sustain these discharges, indicating that both structures are involved in the discharges’ generation.

The involvement of thalamus as the generator of generalized spike and wave discharges is documented by the following: (1) stimulation of the medial thalamus induces cortical generalized spike and wave discharges without leading to self-sustained activity and (2) thalamic neurons can intrinsically generate action potentials in both a tonic and a burst-firing mode (Snead et al 1999; Blumenfeld 2003; Manning et al 2003). The relative importance of the cortex in the initiation and synchronization of generalized spike and wave discharges is mainly documented by the finding that following thalamectomy, instigation of generalized spike and wave discharges persists even though the thalamus is required to maintain rhythmicity once the discharges are established. More recently, in a rat model of absence, Meeren and colleagues (Meeren et al 2002) showed that during generalized spike and wave discharges, cortical and thalamic interactions lag behind an initial burst of activity in the peri-oral region of the primary somatosensory cortex during the first 500 ms of discharge activity. These findings suggest that, in this animal model, a cortical focus is the dominant factor in initiating the paroxysmal oscillation within the corticothalamic loops and that the large-scale synchronization is mediated by a fast intracortical spread of seizure activity (Meeren et al 2002).

Both inhibitory and excitatory neurotransmissions are involved in the genesis and control of absence seizures. This may be the result of an excessive cortical excitability due to an unbalance between inhibition and excitation, or it may be the result of excessive thalamic oscillations due to abnormal intrinsic neuronal properties under the control of inhibitory GABAergic mechanisms. It is likely that the generation of absences is due to a predominance of inhibitory activity, in contrast to generalized or focal convulsive seizures in which an excess of excitatory activity is present (Manning et al 2003).

The basic intrinsic neuronal mechanisms involve low-threshold (T-type) calcium currents elicited by activating the low threshold calcium channels. These channels are present in high densities in thalamic neurons and trigger regenerative burst firing that drive normal and pathologic thalamocortical rhythms, including the generalized spike and wave discharges of absence seizures. Ethosuximide exerts its anti-absence effect by either reducing thalamic low-threshold calcium currents probably through a direct channel-blocking action that is voltage dependent or through a potent inhibitory effect in the peri-oral region of the primary somatosensory cortex (Manning et al 2003).

Of neurotransmitters, GABA-B receptors play the most prominent role by eliciting the long-standing hyperpolarization required to drive low threshold calcium channels for the initiation of sustained burst firing. GABA-B agonists such as baclofen aggravate, and GABA-B antagonists suppress typical absences. GABAergic drugs (such as vigabatrin and tiagabine) are pro-absence substances; they interfere with the degradation and re-uptake of GABA (Panayiotopoulos 2001; Manning et al 2003). The only exception of GABAergic activation inhibiting absences is that, of the reticular thalamic nucleus, with exclusively GABA-A receptors; it functions as a pacemaker to synchronize thalamocortical oscillations. Enhanced activation of GABA-A receptors in this nucleus decreases the pacemaking capacity of these cells, therefore decreasing the likelihood of generating absence seizures.

Crunelli and Leresche (Crunelli and Leresche 2002) and Manning and colleagues (Manning et al 2003) have provided excellent reviews on the modern aspects and discoveries of the pathogenesis, pathophysiology, and pharmacology of childhood absence epilepsy.

Epidemiology
The annual incidence rate of childhood absence epilepsy in children less than 15 years of age has been estimated between 6.3/100,000 (Olsson 1988; Loiseau et al 1990) and 8.0/100,000 (Bianchi 1978). Recruitment bias explains that the frequency of childhood absence epilepsy in childhood epilepsies has been differently assessed, ranging from 2.3% to 37.7% of cases. In 2 recent prospective community-based studies, prevalence of childhood absence epilepsy was 10% (Callenbach et al 1998) and 12.3% (Berg et al 2000) for children younger than 16 years of age with epilepsy.

Prevention
No information was provided by the author.

Differential Diagnosis
The diagnosis of childhood absence epilepsy may be difficult, even by specialists, and may be misdiagnosed as attention disturbance or day-dreaming. In practical terms, a child suspected of typical absences should be asked to overbreathe for 3 minutes while counting his or her breaths. Hyperventilation will provoke an absence in nearly all untreated children with childhood absence epilepsy (Hirsch et al 1994; Wirrell et al 1996b). This procedure should preferably be video-taped for documentation of the clinical features (Loiseau et al 2002; Panayiotopoulos 2005).

Focal epilepsies. The differential diagnosis of childhood absence epilepsy from complex focal seizures is detailed in the chapter on typical absence seizures. Automatisms may be common in both. A main problem is typical absence seizures from frontal lobe origin that may also have concomitant more or less regular bilateral spike-wave discharges (Ferrie et al 1995). Focal motor components, asymmetrical ictal discharges, or interictal frontal foci in the EEG may help in their differentiation. MRI may demonstrate frontal abnormalities (Ferrie et al 1995) or subependymal grey matter heterotopia (Raymond and Fish 1996). Focal EEG abnormalities are frequent in childhood absence epilepsy (Lombroso 1997).

Other idiopathic generalized epilepsies with absence seizures. The differentiation of childhood absence epilepsy from other idiopathic generalized epilepsies with absences may be difficult without video-EEG comparisons (Panayiotopoulos 2005).

Juvenile absence epilepsy. Severe impairment of consciousness and high daily frequency is the main characteristic of childhood absence epilepsy, but this may also be a feature of mainly juvenile absence epilepsy. Onset of juvenile absence epilepsy is later (peak at 12 to 13 years), and absences are not as frequent as in childhood absence epilepsy. 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 later than 10 years of age (Janz et al 1994). Further, juvenile absence epilepsy may also have frequent daily absence seizures (Obeid 1994). GTCS are nearly unavoidable 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 (ie, Janz syndrome). Absence seizures occur in one-third of juvenile myoclonic epilepsy patients (Panayiotopoulos et al 1989a) but these are usually highly mild, often inconspicuous and have different EEG patterns. The main seizure type of juvenile myoclonic epilepsy is myoclonic jerks on awakening, and these do not occur in childhood absence epilepsy. The problem is when juvenile myoclonic epilepsy starts with absences prior to the onset of myoclonic jerks, but again there are a number of clinico-EEG differences such as milder impairment of consciousness, frequent polyspikes and fragmentations of the EEG discharges in juvenile myoclonic epilepsy (Panayiotopoulos et al 1989a; 1994). Some authors consider these cases as childhood absence epilepsy evolving or progressing to juvenile myoclonic epilepsy (Wirrell et al 1996a; Delgado-Escueta et al 1999). In our opinion, this is juvenile myoclonic epilepsy starting with absences in childhood. In the majority of these patients with juvenile myoclonic epilepsy starting with typical absence in childhood, video-EEG studies would clearly differentiate them from the typical absence seizures of childhood absence epilepsy (Panayiotopoulos et al 1989a; 1989b). However, there may be cases where their differentiation is difficult, and juvenile myoclonic epilepsy will not be diagnosed until many years after with the appearance of myoclonic jerks and GTCS. Prognostic consequence of such a misdiagnosis may be severe.

Epilepsy with myoclonic absences, eyelid myoclonia with absences, perioral myoclonia with absences. These types of absence seizures are betrayed by their predominant ictal myoclonic manifestations that do not feature in childhood absence epilepsy (Panayiotopoulos 2005). Epilepsy with myoclonic absences is already a recognized epileptic syndrome by The Commission on Classification and Terminology of the International League Against Epilepsy (Commission 1989; Engel 2001). We are of the opinion that eyelid myoclonia with absences and perioral myoclonia are epileptic syndromes different from childhood absence epilepsy, but this view is not universally accepted. For example, the ILAE Task Force recognizes them only as different seizure types and not as epileptic syndromes (Engel 2001). Children otherwise fitting with all other childhood absence epilepsy criteria have absence seizures with sustained myoclonic jerks (Hirsch et al 1994).
Absence epilepsy of early childhood. Doose and colleagues proposed a syndrome of absence epilepsy of early childhood (Doose et al 1965; Doose 1994); this is not recognized by the ILAE Task Force as an epileptic syndrome (Engel 2001). This is characterized by an onset before the age of 5 years, with possible occurrence, at the onset or later, of GTCS or myoclonic-astatic seizures, irregular 2- to 3-Hz spike-and-wave EEG discharges, and often an unfavorable prognosis. This may be a heterogeneous group of disorders (Doose 1994). Age at onset artificially covers various idiopathic generalized epilepsies with a polygenic inheritance. Absence epilepsies of early childhood include early onset childhood absence epilepsy and other absence epilepsies in which more important environmental factors explain the frequency of GTCS and a less favorable outcome.

Symptomatic absence seizures. In genetically predisposed individuals, brain damage may precipitate typical absence seizure occurrence, most often associated with neurologic signs or mental retardation. In most cases, the association is probably coincidental. However, cerebral pathology may modify the expression of genetic seizure susceptibility (Ferrie et al 1995). In these cases, the correct diagnosis is not childhood absence epilepsy, but a symptomatic absence epilepsy with a less favorable outcome.

Diagnostic Workup
Typical absences are easily induced by hyperventilation in nearly all untreated children with childhood absence epilepsy (Hirsch et al 1994; Wirrell et al 1996b).

The EEG, preferably video-EEG, is the single-most important diagnostic procedure in diagnosing childhood absence epilepsy. Ideally, all children with absence seizures should have video-EEG recordings in an untreated state. The EEG accompaniment of typical absence seizures is a bilaterally synchronous and symmetrical discharge of rhythmic spike-and-slow wave complexes (Commission 1989).|{diagram:tap1.bmp}{caption:Ictal EEG of classical typical absence seizure of childhood absence epilepsy}{label:Note the regular rhythm of the discharge, the constant spike-and-slow wave relation, the abrupt onset, and the abrupt termination.}||{diagram:tap2.bmp}{caption:Ictal EEG of typical absence seizure of childhood absence epilepsy}{label:Note the regular rhythm of the discharge, the constant spike-and-slow wave relation, and the abrupt onset. The opening phase is often variable and unreliable. The child remains unresponsive from the onset of the initial to the onset of the terminal phase of the discharge. However, she is able to understand the technologist during the terminal phase when the ictal discharge is waning out.}| The ictal EEG shows generalized, spike- or double-spike (no more than 3 spikes are allowed) and slow-wave complexes at 3 Hz (no less than 2.7 Hz and no more than 4 Hz) at the initial phase of the discharge with gradual and smooth decline in frequency from the initial to the terminal phase. The discharge is regular, with well-formed spikes, which retain a constant relation with the slow-waves. The duration is usually around 10 to 12 seconds (no less than 4 seconds and exceptionally more than 20 seconds). The opening phase of the discharge (1 to 2 seconds of onset) may be faster, irregular and asynchronous, and unreliable for such measurements. Fragmentation of the ictal discharges (ie, transient discontinuation of the rhythmic spike-wave and multiple spike-and-slow wave discharges) are considered as exclusion criteria for childhood absence epilepsy (Panayiotopoulos et al 1989b; Hirsch et al 1994).

Interictal EEG. Background EEG is normal (Commission 1989). However, some patients exhibit a rather particular posterior delta rhythm. This usually occurs in long runs of 3 Hz sinusoidal high activity, either symmetrical or more often asymmetrical in the occipital and occipito-parietal areas. It is blocked by eye-opening and enhanced by hyperventilation. Asymmetrical posterior slow waves, usually with a right predominance, are physiological in children.

Interictal paroxysmal activity, consisting of single or brief discharges of bilateral spike-wave may occur particularly during nonREM sleep with important morphologic changes. Transient asymmetries of ictal or interictal spike-wave discharges are frequent mainly in treated patients. Transient focal epileptiform abnormalities such as centrotemporal sharp waves (Hedstrom and Olsson 1991) or persistent focal abnormalities (Lombroso 1997) occur in childhood absence epilepsy.

Response to intermittent photic stimulation is not mentioned by the Commission (Commission 1989). Clinical photosensitivity is proposed as an exclusion criterion (Hedstrom and Olsson 1991; Hirsch et al 1994; Panayiotopoulos 1997; 2005) though this is well accepted by other authors (Wolf and Goosses 1986). Mild EEG photosensitivity may occur (Hirsch et al 1994).

Prognosis and complications
Most of the available evidence is inconclusive regarding evolution and prognosis of childhood absence epilepsy (Panayiotopoulos 2005). This is because classification criteria are markedly different in the relevant reports or of insufficiently short follow-up periods. Most authors include in childhood absence epilepsy any child with absences before the age of 10 years, which may not be childhood absence epilepsy (Bouma et al 1996; Panayiotopoulos 1997; 2005). Retrospective studies in adults may lack accurate initial data. Patients must be followed beyond 18 or 20 years of age (Loiseau et al 1983; 1995b; Loiseau and Duche 1995).

Childhood absence epilepsy, if properly defined, may have an excellent prognosis. In 1924 at a time when no anti-absence drug existed, Adie concluded that even if absence seizures in pyknolepsy persisted for a long time, they ultimately ceased, never to return (Adie 1924). This is consistent with recent findings that absences of childhood absence epilepsy, even if they may persist several years, finally disappear with age in more than 90% of cases (Loiseau et al 1983; 1995a; 1995b). In a Swedish population-based study, a 91% remission rate was found when patients with absence epilepsy had only absences (Hedstrom and Olsson 1991). In adults, absences of idiopathic generalized epilepsy generally tend to be infrequent and milder, and they may occur with precipitating factors (Gastaut et al 1986; Panayiotopoulos 1997), though in some of them absences may be extremely severe (Panayiotopoulos 1997; Agathonikou et al 1998; Panayiotopoulos 2005).

However, cessation of absence seizures may not mean remission. This again depends on diagnostic inclusion and exclusion criteria. Considering absences with onset in childhood as childhood absence epilepsy, prognosis is uncertain and has great variations (Loiseau 1992; Loiseau et al 1995a; Bouma et al 1996; Panayiotopoulos 1997; 2002). GTCS may appear, mainly between 8 and 15 years (Dieterich et al 1985) or sometimes even later, between 20 to 30 years of age (Gastaut et al 1986), and patients may develop juvenile myoclonic epilepsy (Wirrell et al 1996a; Delgado-Escueta et al 1999). Absence seizures in these patients may persist, improve, or disappear. With an early institution of effective therapy, GTCS occurred in 30% of cases, whereas occurrence was 68% after incorrect therapy (Bergamini et al 1965).

When stricter criteria are applied for childhood absence epilepsy, GTCS are infrequent and easily controlled by medication (Loiseau et al 1983; Loiseau and Duche 1995; Loiseau et al 1995a; 2005). Loiseau and colleagues studied 53 patients older than 20 years at last follow-up. Inclusion criteria were age at onset (3 to 10 years) of daily and EEG-recorded typical absences as a presenting sign of normal children who were seen within the first year of onset or treatment and with no history of preceding seizures other than febrile convulsions (Loiseau and Duche 1995; Loiseau et al 1995a). EEG with multiple or irregular spike-waves or photosensitivity were excluded. Absences persisted in 5 (less than 10%) and in 2 of them as the only type of seizure. GTCS occurred in 14 patients (26%), but in 11 of them GTCS were isolated or rare. GTCS were more common among patients with onset of absences from 9 to 10 years and without posterior delta rhythms. Control of absences with treatment varied; it was achieved in 12 patients within weeks, but in most cases they persisted for years. The later the onset of typical absence seizures, the higher is the risk of convulsive seizures. GCTS developed in 16% of patients with onset of typical absence seizures before 9 years of age; this raised to 44% for those with onset of typical absence seizures between 9 and 10 years. (Loiseau et al 1995a). In another approach, Agathonikou and colleagues studied 39 adults with idiopathic generalized epilepsy and typical absence seizures starting before 10 years of age (Agathonikou et al 1997). All were older than 18 years (31.5 ± 10.5; range 18 to 56) and all had EEG-recorded (15 with video-EEG) typical absences. Typical absences had onset at 6.2 ± 1.9 years (range 2 to 9) and still persisted in 28 (71.8%). GTCS occurred in 87.2% (onset 13 ± 7.2 years; range 2 to 36). Myoclonic jerks occurred in 38.5% (onset 2.6 ± 4.1 years; range 7 to 18). Sex (women, 82%) and photosensitivity (56.4%) were markedly predominating factors. Only one of them fulfilled strict criteria of childhood absence epilepsy and was well controlled on medication. Of the others, 8 were classified as eyelid myoclonia with absences, 5 as juvenile absence epilepsy, 4 as perioral myoclonia with absences, 3 as juvenile myoclonic epilepsy, 3 as absences with single myoclonic jerk, 3 as predominantly photosensitive idiopathic generalized epilepsy with typical absence. Twelve patients had unclassified idiopathic generalized epilepsy (8 with photosensitivity).

Attention disturbance in children with typical absence seizures has been noted for a long time. In childhood absence epilepsy, typical absence seizures are frequent, and EEG shows brief discharges of bilateral spike-wave without apparent clinical impairment. Neuropsychological studies have documented cognitive dysfunctioning (reaction time tasks and sustained attention tests) during these discharges. Mirsky and colleagues described it as follows: “The transitory bursts of spike-wave activity represent the tip of an iceberg. Below the surface, there may be a more or less continuously active pathophysiological process, which is reflected, in impaired performance on tests of attention and in alterations in event-related brain potentials” (Mirsky et al 1995). Therefore, scholastic difficulties are not surprising. Behavior disorder may be due to typical absence seizures as well as parents' attitude and medication. Social adaptation is poor in one third of patients having had childhood absence epilepsy, even when in remission (Loiseau et al 1983; Dieterich et al 1985; Wirrell 2003).

Management
Because of numerous disturbing absence seizures, drug therapy is necessary for childhood absence epilepsy. At present, the main anti-absence agents are ethosuximide, sodium valproate and lamotrigine (Panayiotopoulos 2001; Posner 2003; Panayiotopoulos 2005). Clonazepam, clobazam, and acetazolamide are only second-line drugs; they share a similar risk of tolerance and adverse effects.

Ethosuximide or valproate as first-choice drugs in absence epilepsies has long been a debated issue. They are equally effective as monotherapy in controlling the absences of more than 80% of children with childhood absence epilepsy. Many clinicians today prefer sodium valproate because this drug, as opposed to ethosuximide, also controls GTCS but this may no be of concern in the pure forms of childhood absence epilepsy.

Hepatotoxicity of valproate practically does not exist in this age-group and in idiopathic generalized epilepsies. When valproate does not control typical absence seizures, ethosuximide is the drug of second choice. Lamotrigine is likely to get an increasing status in the therapy of absence epilepsies, either as added to valproate in uncontrolled patients because of a beneficial pharmacodynamic interaction (Panayiotopoulos 2001; 2005), or as monotherapy controlling approximately 50% of patients (Frank et al 1999; Coppola et al 2004). If monotherapy fails, the combination of valproate plus ethosuximide is recommended because of an additive efficacy and a nonadditive toxicity. Acetazolamide and benzodiazepines may also be tried in the few remaining cases of failure with the above 3 drugs. Of the newest drugs levetiracetam appears to be the most promising (Panayiotopoulos 2001; Cavitt and Privitera 2004; Fattouch et al 2004; Panayiotopoulos 2005); topiramate has a weak effect (Cross 2002). Carbamazepine, vigabatrin, and tiagabine are contraindicated, as there is clinical and experimental evidence that they exaggerate absences.

In a relatively recent study of children with childhood and juvenile absence epilepsy, initial drug treatment was successful in 52 (60%) of 86 patients (Wirrell et al 2001). Success tended to be greater for sodium valproate than for other drugs (p = 0.07), and lower if generalized tonic-clonic or myoclonic seizures coexisted (p < 0.004 and p < 0.03). Terminal remission was more likely if the initial drug was successful than if it had failed (69% vs. 41%; p < 0.02). Subjects whose initial drug treatment had failed were more likely to suffer from juvenile myoclonic epilepsy and to develop intractable epilepsy.

Gradual withdrawal of medication is recommended in patients who are seizure-free for 1 to 2 years and have a normalized EEG. EEG confirmation of the seizure-free state is needed during this withdrawal period (Loiseau 1992).

Pregnancy
Not applicable.

Anesthesia
No information was provided by the author.

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ILAE.
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Abbreviations
EEG:electroencephalography
GTCS:generalized tonic clonic seizures
MRI:magnetic resonance imaging

ICD Code
ICD Code: 345.0

Synonyms
Petit mal
Pyknolepsy

Major keyword descriptors
abnormal thalamo-cortical circuitry
absence epilepsy
atypical absences of secondary (symptomatic) generalized epilepsies
centrencephalic epilepsy
cryptogenic generalized epilepsy
hyperventilation
idiopathic generalized epilepsy
interictal EEG
juvenile absence epilepsy
juvenile myoclonic epilepsy
microdysgenesis
photosensitivity
spike-and-slow waves
tonic-clonic seizures
typical absence seizures
video-EEG

Minor keyword descriptors
absence
drug therapy
epilepsy
impairment of consciousness
seizures

Age of Presentation
02-05 years
06-12 years

Age of typical Presentation
02-05 years
06-12 years

Population group(s) Preferentially Affected
none selectively affected

Occupation group(s) Preferentially Affected
none selectively affected

Sex
female>male, >2:1
female>male, >1:1

Family History
family history may be obtained

Heredity
heredity typical
heredity may be a factor

Glossary
Proposed definition of childhood absence epilepsy

Childhood absence epilepsy is a disease or syndrome of frequent (many per day), brief (more than 4 s), typical absence seizures, which occur, in otherwise normal children. Age of onset is between 4 and 10 years of age, with a peak at 5 to 7 years. Remission usually occurs before the age of 12 years but infrequent GTCS may develop in adolescence.

Clinically, there is abrupt and severe impairment (loss) of consciousness, with cessation of voluntary activity that is not restored during the ictus. The eyes spontaneously open, overbreathing, speech and other voluntary activity stop within the first 3 sec from the onset of the discharge. Automatisms are frequent but have no significance in the diagnosis. The eyes stare or move slowly, random eyelid blinking (usually not sustained) may occur.

Persistent eyelid myoclonia, perioral myoclonia, rhythmic massive limb jerking, single or arrhythmic myoclonic jerks of the head, trunk or limbs are probably not compatible with childhood absence epilepsy. However, milder myoclonic elements particularly at the onset of the seizure discharge may be a feature of childhood absence epilepsy. Generalized tonic-clonic seizures and other types of seizures like myoclonic jerks should not be featured in childhood absence. Visual (photic) and other sensory precipitation is most likely against a diagnosis of childhood absence epilepsy. Mild or no impairment of consciousness is not compatible with childhood absence epilepsy.

The EEG in childhood absence epilepsy has a normal background, with frequent rhythmic posterior delta activity. Ictal discharges consist of generalized high-amplitude spike and double (maximum occasional three spikes are allowed) spike- and slow-wave complexes. They are rhythmic at around 3 to 4 Hz (>2.5 Hz) with a gradual and regular (0.5 Hz to 1 Hz) slowdown from the initial to the terminal phase of the discharge. The initial phase of the discharge (1 to 2 sec from the onset) is usually fast and unreliable for these measurements. There are no marked variations in the relation of spike to the slow wave, no fluctuations in the intradischarge frequency and certainly no fragmentations of the ictal discharges.

Illustration captions
Title:
Legend:
Fig 1. Ictal EEG of classical typical absence seizure of childhood absence epilepsy

Note the regular rhythm of the discharge, the constant spike and slow wave relation, the abrupt onset, and the abrupt termination. Also, compare with the clinical manifestations of the same patient {video clip 2}.
Note to the editors: This is the same figure as fig 1 in the topic: Typical absence seizures by C P Panayiotopoulos

Fig 2. Ictal EEG of typical absence seizure of childhood absence epilepsy

Note the regular rhythm of the discharge, the constant spike and slow wave relation, and the abrupt onset. The opening phase is often variable and unreliable. The child remains unresponsive from the onset of the initial to the onset of the terminal phase of the discharge. However, she is able to understand the technologist during the terminal phase when the ictal discharge is waning out.

Note to the editors: This is the same figure as fig 2 in the topic: Typical absence seizures by C P Panayiotopoulos

Video-Clip 1. Typical seizure of childhood absence epilepsy (1). Clinical Vignette.

This 9-year-old girl's seizure starts and ends abruptly. She stops counting and opens her eyes within 2 seconds of onset of the discharge. She is unresponsive. Note the marked automatisms and the lack of staring in her eyes. Seizures were controlled only when syrup was substituted by tablets of sodium valproate.

Note to the editors: This is the same video clip as of video clip 1 in the topic: Typical absence seizures by C P Panayiotopoulos

Video-Clip 2. Typical seizure of childhood absence epilepsy (2)
This 8-year-old boy suddenly stops counting and opens his eyes within 2 seconds of the onset of the discharge. Note the initial brief eyelid flickering followed by eyes and head deviating upwards and to the right. He is unresponsive.

Note to the editors: This is the same video clip as of video clip 2 in the topic: Typical absence seizures by C P Panayiotopoulos

Permuted topic, Synonyms, Variants
Childhood absence epilepsy
absence epilepsy, Childhood

Related Topics
Absence status epilepticus
Benign childhood epilepsy with centrotemporal spikes
Benign myoclonic epilepsy in infancy
Early onset benign childhood seizures with occipital spikes (Panayiotopoulos syndrome)
Epilepsy
Epilepsy with myoclonic absences
Eyelid myoclonia with and without absences
Typical absence seizures

Differential Diagnosis
attention disturbance
day-dreaming
focal epilepsies
juvenile absence epilepsy
juvenile myoclonic epilepsy
Janz syndrome
epilepsy with myoclonic absences
eyelid myoclonia with absences
perioral myoclonia with absences
early onset childhood absences epilepsy
brain damage
mental retardation
symptomatic absence epilepsy

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