Highlights
- •Several nosological entities present absence seizures according to different proposals of epileptic syndromes classification.
- •Although other antiepileptic drugs are effective, ESM is the choice for treatment of childhood absence epilepsy.
- •There is risk of academic failure and attentional deficits that persist despite seizure freedom in children with absence epilepsy.
- •In adults prognosis is influenced by rare clinical presentations such as perioral and eyelid myoclonic components that poses worse outcome.
- •Overall prognosis depend on age of onset, presence of other seizure types and response to initial treatment.
Abstract
Purpose
Although absence seizures do predominate in childhood they may occur at all ages and clinical presentation varies widely. Albeit considered a benign seizure type, chronic evolution with therapeutic refractoriness is possible in some patients with absences. The aim of this paper is to summarize the main syndromic presentation of absence seizures and its outcome regarding treatment and prognosis.
Method
We performed a review of literature with emphasis in historic and classical manuscripts about absence epilepsy.
Results
Absence was described in the beginning of last century as a seizure type with good evolution, but it is still difficult to preview a strict prognosis for an individual patient. Some positive early predictors were reported such as response to initial treatment and seizure onset in childhood. Genetic aspects are not yet well understood although some families have been reported with rare mutations in ion channel coding genes.
Conclusion
Absence seizures are present in different epilepsy syndromes and nosological classification is not always possible. Outcome depends on clinical variables such as age of onset, presence of other seizure types and initial response to treatment.
Keywords
1. Introduction
In this important 25th anniversary issue of Seizure — European Journal of Epilepsy it is of significance to remember one of the first clinical description of a seizure type, the absence, which was topic of publication in this periodical for 592 times. Absences and the related epileptic syndromes are still an area of controversy because of possible clinical presentation overlap that may poses difficulties in classification, prognosis and treatment. Absence seizures incidence varies from 0.7 to 4.6/100,000 in general population and 6 to 8/100,000 in children up to 15 years-old [
1
, 2
]. It is very meaningful to perform syndromic characterization in order to define therapeutic and prognostic implications in these cases.In the beginning of last century there was the first descriptions of absence seizures in German medical literature and in 1916 Sauer presented the term pyknolepsy, which is originated from Greek, πικνοζ (picnós), and means very frequent or grouped, to describe absence seizures with multiple daily recurrences [
3
, 4
, 5
]. In 1924 Adie described pyknolepsy, an epilepsy type with good remission in children, characterized by, “abrupt onset, between 4 and 12 years of age, with epileptic seizures of short duration, very frequent, which recurred almost daily, for weeks, months or years” [[6]
].In the first reports of EEG recording by Berger in 1933, there was an example of rhythmic spike-wave discharges, and two years later, Gibbs et al. described their main characteristics, such as rhythmicity at 3 Hz, at times accompanied by concomitant rhythmic clonic movements of the eyelids [
7
, 8
]. Gibbs et al., in 1936, reported that ictal spike-wave complexes (SWC) were faster in the beginning of seizures and had predominance in anterior regions [[9]
]. Finally, these authors differentiated this pattern from another, which they called “slow spike-wave complex” at 2 Hz. In this slower pattern, a diverse clinical presentation was associated that they called “petit mal variant” in which seizures affected awareness less prominently than in 3 Hz SWC seizure. Afterwards this clinical entity was entitled as the Lennox–Gastaut syndrome.2. Nosology
The International League Against Epilepsy (ILAE) in its publications about seizure classification since the first proposal leaded by Gastaut in 1970 considered absences within generalized seizure types which affected both cerebral hemispheres clinical and electrographically, and differentiated them from “atypical absences” [
[10]
]. The ILAE Commission of 1981 described typical absence seizure as “of sudden onset, interruption of ongoing activities, staring, possible upwards version of eyes with few seconds duration, associated to symmetrical 2–4 Hz, mainly 3 Hz, SWC, normal background activity” [[11]
]. At that time absences were subdivided according to its different clinical presentation based in the video-EEG study of Penry et al. from 1975 into: (1) with impairment of consciousness only; (2) with association of other clinical components such as clonic, atonic, tonic, autonomic, and with automatisms [[12]
]. Atypical absence seizures would have less abrupt onset and termination associated to slow irregular SWC, fast activity and slow background activity.Other proposals of classification of seizures and syndromes of ILAE and its members were also published along the years. The glossary published by Blume et al. in 2001 endorsed by ILAE in 2010 described absences seizures as dyscognitive seizures [
13
, 14
].Regarding the syndromic classification there were the first classical papers of ILAE from the 1980s in which epilepsies with typical absence seizures were considered as “primary” or “idiopathic” that were observed in people without neurological deficits and etiological factor and were divided into childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), and myoclonic absence epilepsy. It also considered other epileptic syndrome types that could present with absences, such as juvenile myoclonic epilepsy (JME) as well as others in which occurrence of absences was possible such as epilepsy with specific modes of seizure precipitation and generalized tonic-clonic seizures (GTCS) upon awakening [
[15]
].Myoclonic absence epilepsy, described by Tassinari et al. in 1969, was classified in cryptogenic (with probable but unknown etiology) or symptomatic (known etiology) epilepsy syndromes. In this, absences are accompanied by bilateral massive myoclonic jerks in cephalic region and upper limbs, at times associated to tonic muscle contraction and in EEG, bilateral 3 Hz SWC, similar to CAE. The prognosis is less favorable in this myoclonic syndrome with more refractoriness to treatment and possibility of intellectual disability [
[16]
].In 1977, Jeavons described absences with eyelid myoclonia immediately after eye closure and upwards eye deviation with onset in childhood and rare GTCS in adolescence. Ictal EEG reveals brief discharges (one to three seconds) of 3–6 Hz spike-wave or polispike-wave, mainly after eye closure, or during intermittent photic stimulation [
[17]
].In ILAE’s proposal of classification for epileptic syndromes from 2010, besides CAE and epilepsy with myoclonic absences, a group of idiopathic generalized epilepsies with variable phenotypes was set that includes JAE, JME and epilepsy with GTCS [
[14]
]. Absence syndromes were classified into childhood and juvenile types and absences with eyelid myoclonia were included. This proposal is still under discussion and it has been continuously revised. Several nosological entities present absence seizures according to this and other classifications.Although a syndromic diagnosis may not always be possible and more detailed classification systems might be necessary for specific epidemiological and genetic studies, it is considered by some authors that certain cases in which the described classification cannot be performed may constitute the concept of continuum suggested by Pazzaglia et al. in 1969 [
18
, 19
]. For these authors, there would be electroclinical variations of spike-wave patterns since a benign diffuse epilepsy, such as pyknolepsy, to malignant diffuse epilepsy as Lennox–Gastaut syndrome.Gloor et al. have considered that epilepsy would be a multifactorial condition, in which acquired factors could exacerbate the genetically determined neuronal excitability [
[20]
]. Berkovic et al. reinforced the concept of biological continuum between primary and secondary generalized epilepsy, with different proportions of genetic and acquired factors in intermediate cases [[21]
]. Different syndromes may probably have distinct genetic trait subgroups. According to individual seizure susceptibility and exposition to acquired factors, as well other epigenetic modulation, they could manifest as a continuum although they remain grouped in relatively specific entities of higher occurrence. These would permit categorization into syndromes and isolated cases, which would not fit into nosologic classifications [[19]
].3. Clinical presentation
The main clinical characteristics of epileptic syndromes with absence seizures regarding ILAE classification are described in Table 1 [
[15]
]. Although there are other proposal of nosological grouping, this description is frequently used for its practical application.Table 1Syndromes with typical absences described in the proposal for revised classification of epilepsies and epileptic syndromes of the commission on classification and terminology of the International League Against Epilepsy (1989)
[15]
.| Childhood absence epilepsy (pyknolepsy) |
|
| Juvenile absence epilepsy |
|
| Juvenile myoclonic epilepsy (“impulsive petit mal”) |
|
| Epilepsy with specific modes of seizure precipitation |
|
| Epilepsy with myoclonic absences |
|
Panayiotopoulos et al. proposed strict criteria for CAE and JAE that are shown in Table 2 [
[22]
]. This author discussed the electroclinical differences of typical absences in these as well as in other syndromes in adults such as eyelid myoclonia with absences, perioral myoclonia with absences, phantom absences with GTCS and absence epilepsy with single myoclonic jerks. All these syndromes have different prognosis and outcomes [[23]
]. Children with CAE have good outcome and antiepileptic drugs (AED) can be discontinued after some years of treatment. On the other hand, most patients with a defined diagnosis of JME and JAE must take AED throughout their lives. Other syndromes, such as eyelid myoclonia with absences and perioral myoclonia with absences, also carry a worse prognosis. For this reason, it would be very important to rigorously define the syndromic classification for every particular patient as an individual.Table 2Syndromes with typical absences described in Panayiotopoulos et al.’s proposal for absence epilepsies
16
, 17
, 22
, 23
.| Childhood absence epilepsy | |
|---|---|
| Clinical criteria | |
| Inclusion |
|
| Exclusion |
|
| EEG criteria | |
| Inclusion |
|
| Exclusion |
|
| Juvenile absence epilepsy | |
| Clinical criteria | |
| Inclusion |
|
| Exclusion |
|
| EEG criteria | |
| Inclusion |
|
| Exclusion |
|
| Myoclonic absence epilepsy | |
| (Based on Tassinari et al. [16] ) | |
| Clinical criteria | |
| |
| EEG criteria | |
| |
| Myoclonic absence epilepsy | |
| (Based on Jeavons [17] ) | |
| Clinical criteria | |
| |
| EEG criteria | |
| |
| Perioral myoclonia with absences | |
| Clinical criteria | |
| |
| EEG criteria | |
| |
| Syndrome of phantom absences and generalized tonic-clonic seizures | |
| Clinical criteria | |
| |
| EEG criteria | |
| |
Prognosis is also associated with syndromic classification that is usually age dependent. Wirrel et al. observed that terminal remission was more likely if initial AED was successful and those who persisted with absences were more prone to evolve to JME [
[24]
]. Trinka et al. described 163 patients with absences with onset at mean age of 10.9 years and followed for mean period of 25.8 years, and only 58% were in remission. These authors considered that CAE and JAE are closely related syndromes with large overlap of age of onset. Classification according to predominant pattern of absences (not pyknoleptic) at onset combined with later development of myoclonic or GTCS was useful in predicting less favorable long term seizure remission [[25]
].Shinnar et al. discussed early predictors of GTCS in CAE, such as failure of treatment response at week 16–20, older age at onset and shortest burst duration on baseline EEG, which may superpose the characteristics seen in patients with JAE [
[26]
]. Loiseau et al. considered that an accurate diagnosis is mandatory for establishing, when possible, a prognosis and management in a given patient [[27]
]. Remission rates of patients with CAE may be influenced by the classification criteria used for selection. Stricter diagnostic criteria allow the definition of a homogeneous group of patients with excellent prognosis [[28]
].4. Treatment
The syndromic approach is important for treatment evaluation. Wolf and Inoue considered that therapeutic response in patients with absence seizures is not uniform and is related to electroclinical presentation [
[29]
].One important randomized controlled trial (RTC) performed by Glauser et al. in 2010 considered for initial therapy ESM to be superior to VPA and LTG in a cohort of 446 children with CAE. After 16 weeks of treatment seizure free rate was not very high (53% ESM, 58% VPA, 29% LTG) as in 12 months follow-up, when only 37% had controlled the absences (45% ESM, 44% VPA, 21% LTG) [
30
, 31
]. Children with CAE had also risk of academic failure and high rates of attentional deficits that persisted despite seizure control [32
, 33
]. This study concluded that ESM was more efficacious than LTG and similar but with fewer cognitive side effects compared to VPA. These authors pointed to ESM as drug of choice for CAE, even with concerns for high risk of GTCS, as it is not considered effective against these. Nevertheless, the same group in a long-term evaluation of this cohort observed that risk of GTCS was much lower especially if the child responds to ESM initial therapy. The most important finding of this prospective study was the low incidence of GTCS in CAE [[26]
].Berg et al. discussed the potential disease modifying effect of ESM in CAE. When studying 68 children followed for 10 years a higher rate of remission was observed with ESM compared to VPA independent of atypical EEG patterns or other factors present in treatment selection [
[34]
].5. Genetic aspects
Lennox in 1951 observed that 66% of monozygotic twins showed concordance for the EEG pattern of 3 Hz SWC [
[35]
]. Metrakos and Metrakos, in 1961, studied families of 211 patients and proposed autossomic dominant mechanism of inheritance of 3 Hz SWC with maximum penetrance age dependent not related to seizure occurrence [[36]
]. Janz et al. [[37]
] observed in 31 families with more than one affected member that there was concordance for the presence or not of the pyknoleptic pattern, suggesting that there was different genetic subsyndromes. Multifactorial heritance was discussed by Doose et al. when describing 252 patients with absences with 3 Hz SWC [[38]
].Proposed genes include T-calcium channel gene CACNA1H, likely a susceptible gene in Chinese Han population and a contributory gene in Caucasians [
[39]
]. Although the mechanism underlying altered thalamic T-type currents remains unknown, future work can elucidate the role of both P/Q-type and T-type calcium channels in corticothalamic circuit dysfunction and absence epilepsy. Besides that, both human and experimental evidence strongly supports the view of brain region-specific changes in phasic and tonic GABAA inhibition in typical absence seizures [[40]
].6. Conclusions
Different absence syndromes are probable linked to genetically distinct trait subgroups. According to individual seizure susceptibility and exposition to acquired factors, they could manifest as a continuum, despite they remain grouped in relatively specific entities of higher occurrence. This fact would permit categorization into syndromes and isolated cases, which would not fit into nosological classifications. Whenever possible syndromic approach is fundamental in order to better evaluate and advise patients with absence seizures.
Conflict of interest statement
The author has no conflict of interest to disclose.
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Article info
Publication history
Published online: December 06, 2016
Accepted:
November 30,
2016
Received in revised form:
November 15,
2016
Received:
October 13,
2016
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