Childhood absence epilepsy (CAE) is an age-dependent, idiopathic form of generalised epilepsy characterised by multiple absence seizures per day, as well as bilateral, symmetrical, and synchronous discharges of 3-Hz generalised spike and waves (GSW) in the electroencephalogram. CAE makes for 2% to 10% of all paediatric epilepsies and 8-15% of school-aged childhood epilepsies1). Seizures occur many times daily and consist of brief staring spells, sometimes with rhythmic eye blinking or motor automatisms, lasting seconds, with immediate return to the baseline level of awareness and activity. Children with CAE develop normally, although attentional deficiencies or other subtle behavioural or cognitive abnormalities may be present at onset.
Investigations
Fig. 1: A typical absence seizure on electroencephalogram, characterized by 3 Hz generalized spike wave discharges, with abrupt onset and offset, lasting several second
On electroencephalography (EEG), seizures are characterized by a highly recognizable pattern of generalized (bilateral, symmetric and synchronous) 3 Hz spike and wave discharges. See figure 1
Consider the possibility of Glucose transporter 1 deficiency syndrome in a child who has absence seizures that started before the age of 4 years or who has absence seizures along with an abnormal neurologic exam or significant developmental delays.
Treatment
Three antiepileptic medications, namely ethosuximide (ETX), valproic acid (VPA), and Lamotrigine (LTG), have traditionally been the primary choices for treating childhood absence epilepsy (CAE). The 2010 Childhood Absence Epilepsy research presented conclusive evidence, classified as class I, supporting the use of ETX as the most effective initial treatment for CAE[1]. See algorithm figure 2.
Summary of medications used for childhood absence epilepsy
Name
Initial dose
Maintenance dose
Maximum dose
Ethosuximide
10–15 mg/kg/day
20–30 mg/kg/day
40 mg/kg/day up to 2 g/day
Valproate
10–15 mg/kg/day
20–30 mg/kg/day
60 mg/kg/day up to 3 g/day
Lamotrigine
For patients not taking valproate or other enzyme inducers: 0.3 mg/kg/day
For patients not taking valproate or other enzyme inducers: 4.5–7.5 mg/kg/day
For patients not taking valproate or other enzyme inducers: 300 mg/day
For patients taking valproate: 0.15 mg/kg/day
For patients taking valproate: 1–5 mg/kg/day
For patients taking valproate: 200 mg/day
For patients taking enzyme inducers and NOT valproate: 0.6 mg/kg/day
For patients taking enzyme inducers and NOT valproate: 5–15 mg/kg/day
For patients taking enzyme inducers and NOT valproate: 400 mg/day
Clobazam
<30 kg: 5 mg/day
<30 kg: 10–20 mg/day
<30 kg: 40 mg/day
>30 kg: 10 mg/day
>30 kg: 40 mg/day
>30 kg: 60–80 mg/day
Levetiracetam
20–30 mg/kg/day
40 mg/kg/day
60–90 mg/kg/day up to 3 g/day
Topiramate
1–3 mg/kg/day
5–9 mg/kg/day
15 mg/kg/day up to 1600 mg/day
Zonisamide
1–2 mg/kg/day
5–8 mg/kg/day
Tab. 1: Summary of medications used for childhood absence epilepsy
Fig. 2: Treatment Algorithm for Childhood Absence Epilepsy
Because VPA slows down the metabolism of LTG by blocking liver enzymes, titration of LTG starts at an even lower dose, moves more slowly, and hits a lower target in a person who is also taking VPA than in a person who is not taking any other medication.
There are important cognitive, behavioural, and psychological problems associated with CAE that need to be identified early and dealt with. Anxiety and attention deficit hyperactivity disorder (ADHD) are significantly associated with CAE[2].
Treatment resistant CAE
If first- and second-line drugs don't work, clobazam might be worth a try. However, there isn't much literature on its use in treatment-resistant CAE
The ketogenic diet has also been used successfully in children with treatment-resistant CAE[3]
There is mixed evidence about how well levetiracetam works for children absence epilepsy. Some reports say it works pretty well[4][5], while another report says it makes absence seizures worse[6].
Differentiating between CAE and JAE
Age at onset of CAE is considered to be 2 to 13 years of age and for Juvenile Absence Epilepsy (JAE) to be 8 to 20 years of age; there is five years of overlap[7][7].
Patients with JAE more often have GTCS and more frequently experience seizure-related injuries compared with patients with CAE
Valproate can be considered as the drug of choice in men and lamotrigine as the first drug of choice in women with JAE. See table 1
CAE has a good prognosis (most patients will become seizure-free off ASMs[8], whereas in JAE many patients have poor seizure control and the syndrome may last a long time[9].
Feature
CAE
JAE
Age at onset
Usual
4–10 years
9-13 yrs
Range
2–13; caution if diagnosing at <4yrs of age
8–20 years; exceptional cases may present in adulthood
Development
Typically normal, but may have learning difficulties or ADHD
Typically normal, but may have learning difficulties or ADHD
Absences
Frequency
At least daily to multiple per day but may be underrecognized by family
less than daily
Duration
Typical duration = 3–20 s
Typical duration = 5–30 s
Impaired awareness
Severe loss of awareness
Less complete impairment of awareness
Other seizure types
Febrile
Occasional
Occasional
Generalized tonic-clonic seizures
Rarely precede or occur during period of frequent absences but may occur later with evolution to other IGE syndrome
May precede and commonly occur during the period of frequent absences
Myoclonic
Prominent myoclonus exclusionary
Prominent myoclonus exclusionary
EEG background
OIRDA in 21%
Normal
Interictal epileptiform
discharge
Awake
2.5–4-Hz generalized spike-wave
3–5.5-Hz generalized spike-wave
Asleep
Polyspike and wave may be seen in drowsiness and sleep only
Irregular generalized spike-wave
Uncommon
More common than CAE
Photoparoxysmal response
Rare
IPS triggers generalized spike-wave in 15%–21% but does
not induce seizures
Rare IPS triggers generalized spike-wave in 25% but does not induce seizures
Hyperventilation induction
87%
87%
ICTAL EEG
Regular 3-Hz (range = 2.5–4 Hz) generalized spikewave; 21% may have absences starting at 2.5-Hz spike-wave, and 43% may have absences starting at 4 Hz; if no generalized spike-wave is seen with hyperventilation for 3 min in an untreated patient, CAE can be excluded Disorganized dischargesa less frequent
Regular 3–5.5-Hz generalized spike-wave If no generalized spike-wave is seen with hyperventilation for 3 min in an untreated patient, JAE can be excluded Disorganized dischargesa 8 times more frequent than CAE
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CAE, childhood absence epilepsy; EEG, electroencephalogram; IGE, idiopathic generalized epilepsy; IPS, intermittent photic stimulation; JAE, juvenile absence epilepsy; OIRDA, occipital intermittent rhythmic delta activity. a Disorganized discharges are defined as either brief (
Tab. 2: CAE and JAE. Updated diagnostic criteria for IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017-2021) and international external experts outside our Task Force
Pathophysiology
Absence seizures result from disruptions in thalamocortical rhythms via T-type calcium channel dysfunction.
The CACNA1H missense variant (rs61734410/P640L), though not a CAE disease-causing variant, has been reported to be more often associated with ETX non-response in the CAE trial, supported by in vitro neurophysiologic studies[10].
4.aFattore C, Boniver C, Capovilla G, Cerminara C, Citterio A, Coppola G, Costa P, Darra F, Vecchi M, Perucca E. A multicenter, randomized, placebo-controlled trial of levetiracetam in children and adolescents with newly diagnosed absence epilepsy.Epilepsia. 2011 Apr;52(4):802-9. doi: 10.1111/j.1528-1167.2010.02976.x. Epub 2011 Feb 14. [PMID: 21320119] [DOI: 10.1111/j.1528-1167.2010.02976.x]
5.aVerrotti A, Cerminara C, Domizio S, Mohn A, Franzoni E, Coppola G, Zamponi N, Parisi P, Iannetti P, Curatolo P. Levetiracetam in absence epilepsy.Dev Med Child Neurol. 2008 Nov;50(11):850-3. doi: 10.1111/j.1469-8749.2008.03099.x. Epub 2008 Sep 19. [PMID: 18808424] [DOI: 10.1111/j.1469-8749.2008.03099.x]
6.aAuvin S, Chhun S, Berquin P, Ponchel E, Delanoë C, Chiron C. Aggravation of absence seizure related to levetiracetam.Eur J Paediatr Neurol. 2011 Nov;15(6):508-11. doi: 10.1016/j.ejpn.2011.05.007. Epub 2011 Jun 15. [PMID: 21680209] [DOI: 10.1016/j.ejpn.2011.05.007]
7.a,
bHirsch E, French J, Scheffer IE, Bogacz A, Alsaadi T, Sperling MR, Abdulla F, Zuberi SM, Trinka E, Specchio N, Somerville E, Samia P, Riney K, Nabbout R, Jain S, Wilmshurst JM, Auvin S, Wiebe S, Perucca E, Moshé SL, Tinuper P, Wirrell EC. ILAE definition of the Idiopathic Generalized Epilepsy Syndromes: Position statement by the ILAE Task Force on Nosology and Definitions.Epilepsia. 2022 Jun;63(6):1475-1499. doi: 10.1111/epi.17236. Epub 2022 May 3. [PMID: 35503716] [DOI: 10.1111/epi.17236]
8.aMorse E, Giblin K, Chung MH, Dohle C, Berg AT, Blumenfeld H. Historical trend toward improved long-term outcome in childhood absence epilepsy.Epilepsy Res. 2019 May;152:7-10. doi: 10.1016/j.eplepsyres.2019.02.013. Epub 2019 Feb 25. [PMID: 30856420] [PMCID: 6573015] [DOI: 10.1016/j.eplepsyres.2019.02.013]
9.aDanhofer P, Brázdil M, Ošlejšková H, Kuba R. Long-term seizure outcome in patients with juvenile absence epilepsy; a retrospective study in a tertiary referral center.Seizure. 2014 Jun;23(6):443-7. doi: 10.1016/j.seizure.2014.03.002. Epub 2014 Mar 12. [PMID: 24684814] [DOI: 10.1016/j.seizure.2014.03.002]
10.aGlauser TA, Holland K, O'Brien VP, Keddache M, Martin LJ, Clark PO, Cnaan A, Dlugos D, Hirtz DG, Shinnar S, Grabowski G, Childhood Absence Epilepsy Study Group. Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy.Ann Neurol. 2017 Mar;81(3):444-453. doi: 10.1002/ana.24886. [PMID: 28165634] [PMCID: 6171340] [DOI: 10.1002/ana.24886]
Discussion