Introduction

Absence epilepsy is the most common pediatric epilepsy syndrome and absence seizures are part of many forms of pediatric and adult epilepsies. Typical absence seizures are characterized as generalized seizures that consist of multiple, brief (up to 20 seconds) impairments of consciousness that have an abrupt onset and offset [1]. Absences are unique among seizure types because of their pharmacologic treatments and characteristic bilaterally synchronous 3 Hz spike wave discharges on electroencephalography (EEG). A typical absence seizure is manifested behaviorally as a “staring spell” and can be accompanied by atonic postures such as drooping of the head and/or automatisms such as lip smacking. The majority of children affected by absence seizures will become seizure-free as they enter adulthood [2–7]. Even though studies have concluded that these seizures cause no long-term cellular damage, absence seizures have increasingly been shown to interfere with social and intellectual development during childhood [8••, 9••, 10–14].

This review will describe the various clinical syndromes associated with absence seizures. We will also discuss the evidence supporting various anti-epileptic drug treatments available for these disorders.

Clinical syndromes

Childhood absence epilepsy

Childhood Absence Epilepsy (CAE) is a pediatric epilepsy syndrome occurring in 10 %‒17 % of all childhood onset epilepsy, making it the most common pediatric epilepsy syndrome [15, 16]. The incidence of childhood absence epilepsy in the United States is 1.9 to 8 per 100,000 usually occurring in children between the ages of 4 years and adolescence, with girls affected more than boys [17]. The International League Against Epilepsy defines CAE as having very frequent (multiple per day) absences in children of school age (peak manifestation of 6‒7 years) and an EEG with bilateral, synchronous, and symmetrical spike wave discharges at 3 Hz [18]. In 2005, this was modified to include age criteria with onset of seizures between 4 and 10 years, with a peak between 5 and 7 years [19]. It has since become clear that there is a rare subset of patients with onset of absence seizures under the age of 4 years, a proportion of whom have glucose transporter type 1 deficiency [20].

Reported remission rates for CAE have ranged from 21 %3‒74 % [2, 21, 3–5, 22–24, 6, 25, 26, 7, 27–30]. Prospective cohort studies have reported seizure free rates of 57 %‒74 % [2–6, 25]. In addition, patients with CAE have been reported to have increased rates of adverse behavioral, psychiatric, language, and cognitive comorbidities (including attention problems, anxiety, depression, social isolation and low self-esteem) [14, 31, 13]. The 2010 Childhood Absence Epilepsy study reported that 35 % of subjects had pretreatment attention deficits that did not abate even after seizure freedom was attained [9••, 32].

Although labeled a “benign” syndrome, the clinical course of CAE is variable, it is associated with significant comorbidities, and remission rates are lower than in other classic “benign” idiopathic epilepsies such as Benign Rolandic Epilepsy [33].

Juvenile absence epilepsy

Juvenile absence epilepsy (JAE) is a distinct clinical syndrome from CAE, although there is some considerable overlap. Patients with JAE experience absences as the main seizure type and as the name implies, onset begins between 10 and 17 years of age [34]. Absences in JAE tend to be associated with a less severe impairment of consciousness and they lack a pyknoleptic pattern (ie, only one or a few absences daily) [35]. In addition, generalized tonic clonic seizures are much more common in JAE and have been reported to eventually occur in almost 80 % of patients [36].

The prognosis of JAE has not been well studied. There is some evidence that rates of seizure freedom are greater for those patients with only absences than those with absences plus generalized tonic clonic seizures [37]. JAE is also thought to persist into adulthood at higher rates than CAE.

Jeavons syndrome

Eyelid myoclonia with absences (EMA) is classified as the International League Against Epilepsy as absence seizures with special features [38]. EMA can occur with idiopathic, cryptogenic, or symptomatic epilepsies. These are characterized by prominent eyelid jerking with upward eye deviation that is often triggered by eye closure. The ictal EEG findings consist of 3‒6 Hz generalized polyspike and wave complexes with occasional occipital paroxysmal bursts preceding the generalized discharges [39]. The idiopathic form of EMA is referred to as Jeavons syndrome with seizures triggered by eye closure and all patients are photosensitive [40].

The long term prognosis for Jeavons syndrome has not been studied. There is some evidence that it is a life-long disorder which is resistant to medical treatment [41].

Treatment

Childhood absence epilepsy

A total of eight randomized control trials (RCTs) for the treatment of CAE have been reported (Table 1). One of these was a class I RCT and the remaining seven are classified as class III RCTs because of multiple methodological limitations and provide insufficient evidence to inform clinical practice [42]. Valproic acid was the most commonly studied antiepileptic drug (AED) (n = 5) followed by ethosuximide (n = 4), lamotrigine (n = 3), leveitracetam (n = 1), and gabapentin (n = 1).

Table 1 RCT evaluating the treatment efficacy in absence epilepsy
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The one class I RCT was a 446 patient, 32 center double-blind, randomized, superiority trial that compared the efficacy and tolerability of ethosuximide, valproic acid, and lamotrigine [9••]. At the week 16‒20 visit, subjects on ethosuximide (53 %) and valproic acid (58 %) had significantly higher freedom from failure rates than lamotrigine (29 %, P < 0.001). Subjects taking ethosuximide had significantly less attention dysfunction compared with subjects on valproic acid (33 % vs 49 %, P = 0.03) so these findings imply that ethosuximide is the optimal initial monotherapy for CAE [9••]. However, this optimal monotherapy still failed in 55 % of the subjects at 12 months (16 % because of continued seizures, 25 % because of intolerable side effects, 19 % withdrew from study) [9••]. At 12-month follow-up, only 37 % of the subjects achieved freedom from treatment failure on the first AED. Subjects on ethosuximide (45 %) and valproic acid (44 %) had significantly higher freedom from failure rates than lamotrigine (21 %). Intolerable adverse events were higher in the valproic acid group (0.037) [8••].

The usefulness of levetiracetam could not be determined based on the class III placebo-controlled trial because the study did not show statistically significant difference between the placebo and levetiracetam. [43•]. In addition, gabapentin has been established as ineffective for absence seizures and there are class IV reports demonstrating that carbamazepine, oxcarbazepine, phenobarbital, phenytoin, tiagabine, and vigabatrin may worsen or precipitate absence seizures [44–47].

Nonpharmacolog treatments for refractory absence seizures have also been investigated. Vagus nerve stimulation in nine patients was reported to have a mean reduction in daily seizure frequency of 53 % and a 50 % responder rate of 55 % [48•]. The ketogenic and modified Atkins diets have also been reported to have a >50 % seizure reduction in 82 % of patients which was not correlated with age, number of previous anticonvulsants, or gender [49].

Table 2 lists case series that evaluated the efficacy of various AEDs. Because these studies were not randomized, the level of evidence supported by these studies is limited. Several case series reporting outcomes with lamotrigine treatment suggested wide variability in degree of seizure control [50–52]. Another case study evaluating the effects of levetiracetam showed efficacy for seizure freedom [53]. A study evaluating the effects of topiramate was terminated due to the lack of efficacy [54].

Table 2 Other studies evaluating the treatment efficacy in absence epilepsy
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Juvenile absence epilepsy

No RCTs have been conducted for treatment of JAE. Expert opinion surveys in the US and Europe found valproic acid and lamotrigine to be the most common initial treatments [55, 56]. Second line treatments with limited evidence of modest efficacy have included ethosuximide, amantadine, and the ketogenic diet [43•, 49].

Jeavons syndrome

Reports have indicated that Jeavons syndrome is resistant to pharmacologic treatment [41]. Avoidance of seizure precipitants can be important and non-pharmacologic treatments for photosensitive patients, such as wearing special glasses, can be of benefit [57]. A study evaluating the effect of add-on levetiracetam reported 80 % responder rate for number of days with seizure and number of generalized tonic clonic seizures, at 12 weeks evaluation [58]. Medications most commonly referenced for treatment of Jeavon’s syndrome have been valproic acid, ethosuximide, benzodiazepines, levetiracetam, and phenobarbital.

Conclusions

Based on the available evidence, older AEDs—ethosuximide and valproic acid—are more efficacious than newer AEDs. Because of reduced side effects, ethosuximide remains the first line treatment for childhood absence epilepsy. There is a lack of class I randomized studies as well as comparison studies for the treatment of other absence epilepsies. In addition, despite advances in the understanding of the pathophysiology and treatment of absence seizures during the past decade, there is still much to learn. The criteria for syndrome classification of CAE, JAE, and Jeavon’s syndrome remain unclear and may be best based on a yet unknown biomarker. The ongoing Childhood Absence Epilepsy study aims to address many of these issues for CAE [8••], but questions related to JAE and Jeavon’s syndrome remain unanswered.