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BMJ Clin Evid. 2008; 2008: 0317.
Published online 2008 January 10.
PMCID: PMC2907950

Absence seizures in children

Ewa Posner, Consultant Paediatrician

Abstract

Introduction

About 10% of seizures in children with epilepsy are typical absence seizures. Absence seizures have a significant impact on quality of life.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for typical absence seizures in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2007 (Clinical evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: clonazepam; ethosuximide; gabapentin; lamotrigine; and valproate.

Key Points

Absence seizures are characterised by sudden, brief, frequent periods of unconsciousness, which may be accompanied by automatic movements. They may occur alone, or may coexist with other types of seizures in a child with other epileptic syndromes.

  • Absence seizures have a typical spike and wave pattern on the EEG. Atypical absence seizures have different EEG changes and clinical manifestations, and have a different natural history and response to treatment.
  • Absence seizures can be differentiated from complex partial seizures by their abrupt ending and lack of a postictal phase.
  • About 10% of seizures in children with epilepsy are typical absence seizures, with genetic factors considered to be the main cause. Where they are the only manifestation of epilepsy, they generally resolve spontaneously by the age of 12 years.

Lamotrigine increases the likelihood of being seizure free compared with placebo, but it can cause serious skin reactions.

There is consensus that ethosuximide and sodium valproate are beneficial in childhood absence seizures, although we don't know this for sure.

  • Ethosuximide is associated with aplastic anaemia, skin reactions, and renal and hepatic impairment.
  • Valproate is associated with behavioural and cognitive abnormalities, liver necrosis, and pancreatitis.

We don't know whether clonazepam or gabapentin reduce the frequency of absence seizures.

About this condition

Definition

Absence seizures are sudden, frequent episodes of unconsciousness lasting a few seconds, and are often accompanied by simple automatisms or clonic, atonic, or autonomic components. Typical absence seizures display a characteristic EEG showing regular symmetrical generalised spike and wave complexes with a frequency of 3 Hz, and usually occur in children with normal development and intelligence. Typical absence seizures are often confused with complex partial seizures — especially in cases of prolonged seizure with automatisms. However, the abrupt ending of typical absence seizures, without a postictcal phase, is the most useful clinical feature in distinguishing the two types. Typical absence seizures should not be confused with atypical absence seizures — which differ markedly in EEG findings and ictal behaviour, and usually present with other seizure types in a child with a background of learning disability and severe epilepsy. Typical absence seizures may be the sole seizure type experienced by a child. If this is the case, and the child is of normal development and has no structural lesions, the child is said to have childhood absence epilepsy. Alternatively, typical absence seizures may coexist in children with other epileptic syndromes — such as juvenile myoclonic epilepsy or juvenile absence epilepsy, in which other seizure types are also present. This differentiation into typical versus atypical seizures is important, as the natural history and response to treatment vary between the two groups. Interventions for atypical absence seizures or for absence seizures secondary to structural lesions are not included in this review.

Incidence/ Prevalence

About 10% of seizures in children with epilepsy are typical absence seizures. Annual incidence has been estimated at 0.7 to 4.6/100,000 people in the general population, and 6 to 8/100,000 in children aged 0 to 15 years. Prevalence is 5 to 50/100,000 people in the general population. Similar figures were found in the USA (Connecticut) and in Europe-based (Scandinavia, France) population studies. Age of onset ranges from 3 to 13 years, with a peak at 6 to 7 years.

Aetiology/ Risk factors

The cause of childhood absence epilepsy is presumed to be genetic. Seizures can be triggered by hyperventilation in susceptible children. Some anticonvulsants, such as phenytoin, carbamazepine, and vigabatrin are associated with an increased risk of absence seizures.

Prognosis

In childhood absence epilepsy, in which typical absence seizures are the only type of seizures suffered by the child, seizures generally cease spontaneously by 12 years of age or sooner. Less than 10% of children develop infrequent generalised tonic clonic seizures, and it is rare for them to continue having absence seizures. In other epileptic syndromes (in which absence seizures may coexist with other types of seizure) prognosis is varied, depending on the syndrome. Absence seizures have a significant impact on quality of life. The episode of unconsciousness may occur at any time, and usually without warning. Affected children need to take precautions to prevent injury during absences, and should refrain from activities that would put them at risk if seizures occurred (e.g., climbing heights, swimming unsupervised, or cycling on busy roads). Often, school staff members are the first to notice the recurrent episodes of absence seizures, and treatment is generally initiated because of the adverse impact on learning.

Aims of intervention

Cessation or decrease in the frequency of seizures, with minimum adverse effects of treatment.

Outcomes

Seizure frequency often measured as normalisation of the EEG; adverse effects of treatment. We found no RCTs assessing quality of life.

Methods

Clinical Evidence search October 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to October 2007, Embase 1980 to October 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 3. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the Review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, open or blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was a minimum follow-up length of 6 weeks. We also did a cohort harms search for Gabapentin. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table
GRADE Evaluation of interventions for Absence seizures in children.

Glossary

Epileptic syndrome
The term used in the classification of childhood seizure disorders. It relates to a recognisable clinical and EEG pattern.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

References

1. Panayiotopoulos CP. Treatment of typical absence seizures and related epileptic syndromes. Paediatr Drugs 2001;3:379–403. [PubMed]
2. Jallon P and Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia 2005;46(suppl 9):10–14. [PubMed]
3. Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev 2000;22:75–80. [PubMed]
4. Hom CS, Ater SB, Hurst DL. Carbamazepine-exacerbated epilepsy in children and adolescents. Pediatr Neurol 1986;2:340–345. [PubMed]
5. Parker AP, Agathonikou A, Robinson RO, et al. Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Dev Med Child Neurol 1998;40:517–519. [PubMed]
6. Panayiotopoulos CP, Agathonikou A, Sharoqi IA, et al. Vigabatrin aggravates absences and absence status. Neurology 1997;49:1467. [PubMed]
7. Panayiotopoulos CP. A clinical guide to epileptic syndromes and their treatment. Oxfordshire, UK: Bladon Medical Publishing, 2002:132.
8. Posner EB, Mohamed K, Marson AG. Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents (Cochrane Review). In: The Cochrane Library, Issue 3, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2005; primary sources Cochrane Epilepsy Group trials register, the Cochrane Central Register of Controlled Trials, Medline, Embase, and contact with various drug companies.
9. French JAK, Theodore WHB, Montouris GDN, et al. Appendix C: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy: Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. CONTINUUM Lifelong Learning in Neurology 2007;13:203–211. [PubMed]
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12. Duchowny M, Gilman J, Messenheimer J, et al. Long-term tolerability and efficacy of lamotrigine in pediatric patients with epilepsy. J Child Neurol 2002;17:278–285. [PubMed]
13. Besag FM, Wallace SJ, Dulac O, et al. Lamotrigine for the treatment of epilepsy in childhood. J Pediatr 1995;127:991–997. [PubMed]
14. Schlumberger E, Chavez F, Palacios L, et al. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia 1994;35:359–367. [PubMed]
15. Coppola G, Auricchio G, Federico R, et al. Lamotrigine versus valproic acid as first-line monotherapy in newly diagnosed typical absence seizures: an open-label, randomized, parallel-group study. Epilepsia 2004;45:1049–1053. [PubMed]
16. Callaghan N, O'Hare J, O'Driscoll D, et al. Comparative study of ethosuximide and sodium valproate in the treatment of typical absence seizures (petit mal). Dev Med Child Neurol 1982;24:830–836. [PubMed]
17. Sato S, White BG, Penry JK, et al. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 1982;32:157–163. [PubMed]
18. Martinovic Z. Comparison of ethosuximide with sodium valproate as monotherapies of absence seizures. In: Parsonage M, et al. Advances in epileptology: 14th Epilepsy International Symposium. New York: Raven Press, 1983:301–305.
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2008; 2008: 0317.
Published online 2008 January 10.

Ethosuximide

Summary

There is consensus that ethosuximide is beneficial in childhood absence seizures, although we don't know this for sure.

Ethosuximide is associated with aplastic anaemia, skin reactions, and renal and hepatic impairment.

Benefits and harms

Ethosuximide versus placebo:

We found three systematic reviews (search date 2005, search date 2002, search date not reported) which found no RCTs.

Ethosuximide versus valproate:

See option on valproate.

Ethosuximide versus other anticonvulsants:

We found three systematic reviews (search date 2005, search date 2002, search date not reported) which found no RCTs.

Comment

Common adverse effects associated with ethosuximide include gastrointestinal disturbances, anorexia, weight loss, drowsiness, photophobia, headache, and behaviour and psychotic disturbances. Rare adverse effects include aplastic anaemia, serious skin reactions, and renal and hepatic impairment.

Substantive changes

Ethosuximide Two systematic reviews added , neither of which identified any additional RCTs. Categorisation unchanged (Trade-off between benefits and harms).

2008; 2008: 0317.
Published online 2008 January 10.

Lamotrigine

Summary

Lamotrigine increases the likelihood of being seizure free compared with placebo, but it can cause serious skin reactions.

Benefits and harms

Lamotrigine versus placebo:

We found three systematic reviews (search date 2005, search date 2002, search date not reported) which found no RCTs in unselected children or adolescents with typical absence seizures, but found one RCT in children and adolescents in whom lamotrigine had previously been shown to be clinically effective. We found one open-label continuation study including children from this RCT which looked at long-term tolerability of lamotrigine, and we found two open-label add-on studies that additionally reported on adverse effects of lamotrigine.

Seizure frequency

Lamotrigine compared with placebo Lamotrigine may reduce seizure rates after 4 weeks compared with placebo in children and adolescents with absence seizures (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Seizure frequency

RCT
29 children and adolescents aged 3 to 15 years with newly diagnosed typical absence seizures, in whom lamotrigine was clinically effective
In review
Proportion of children free from seizures 4 weeks
64% with lamotrigine
21% with placebo

P = 0.03
Effect size not calculatedlamotrigine

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
29 children and adolescents aged 3 to 15 years with newly diagnosed typical absence seizures, in whom lamotrigine was clinically effective number of people and description
In review
Adverse effects
with lamotrigine
with placebo
252 children; 43 (17%) with absence seizures Adverse effects average 96.7 weeks
with lamotrigine

The most common adverse effects with lamotrigine were dizziness (23/252 [9%]), somnolence (20/252 [8%]), nausea (16/252 [6%]), vomiting (13/252 [5%]), and headache (13/252 [5%])
A high proportion of children (125/252 [50%]) discontinued, mostly because of inadequate response or for administrative reasons

Open-label add-on study
117 children aged 0 to 17 years with various drug-resistant epilepsies
Participants receiving treatment for absence seizures at the time of enrolment, and continued treatment during the study
Adverse effects
25/117 (21%) with lamotrigine
Primarily skin rash in 12 children (10 also receiving valproic acid). Ataxia, drowsiness, headache, and vomiting at 1 to 18 days after initiation of lamotrigine also reported.
No correlation with lamotrigine blood levels found

Open-label add-on study
285 children aged less than 13 years with refractory epilepsies and at least two seizure types
Participants receiving treatment for absence seizures at the time of enrolment, and continued treatment during the study
Withdrawal caused by rash
21/285 (7%) with lamotrigine
Rash was the most common adverse effect leading to discontinuation of lamotrigine, total withdrawal rate 36/285 (13%)

Lamotrigine versus valproate:

We found no systematic reviews but found one RCT.

Seizure frequency

Lamotrigine compared with valproate Lamotrigine may be less effective than valproate at reducing seizures in children with absence seizures (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Seizure frequency

RCT
38 drug-naïve children with typical absence seizures Proportion of children free from seizures 1 month
1/19 (5%) with lamotrigine
10/19 (53%) with valproate

P = 0.004
Effect size not calculatedvalproate

RCT
38 drug-naïve children with typical absence seizures Proportion of children free from seizures 3 months
7/19 (37%) with lamotrigine
12/19 (63%) with valproate

P = 0.19
Not significant

RCT
38 drug-naïve children with typical absence seizures Proportion of children free from seizures 12 months
10/19 (53%) with lamotrigine
13/19 (68%) with valproate

P = 0.51
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours

RCT
38 drug-naïve children with typical absence seizures Adverse effects (including headache, weight gain, and diplopia)
2/19 (11%) with lamotrigine
6/19 (32%) with valproate
Generally mild and transient, no withdrawals due to adverse effects

P value not reported

Lamotrigine versus other anticonvulsants:

We found three systematic reviews (search date 2005, search date 2002, search date not reported) which found no RCTs.

Further information on studies

The RCT comparing lamotrigine versus placebo randomised a group of children who responded to treatment with lamotrigine in an open-label trial (potentially introducing selection bias).

Comment

None.

Substantive changes

Lamotrigine Two systematic reviews added , neither of which identified any additional RCTs. Categorisation unchanged (Trade-off between benefits and harms).

2008; 2008: 0317.
Published online 2008 January 10.

Valproate

Summary

There is consensus that sodium valproate is beneficial in childhood absence seizures, although we don't know this for sure.

Valproate is associated with behavioural and cognitive abnormalities, liver necrosis, and pancreatitis.

Benefits and harms

Valproate versus placebo:

We found three systematic reviews (search date 2005, search date 2002, search date not reported) which found no RCTs.

Valproate versus ethosuximide:

We found three systematic reviews (search date 2005, search date 2002, search date not reported) , which found three small RCTs. Results from the RCTs could not be pooled because each assessed different outcomes.

Seizure frequency

Valproate compared with ethosuximide Valproate may be as effective as ethosuximide at reducing seizure rate after 4 weeks to 4 years in children with absence seizures (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Seizure frequency

RCT
28 children and adolescents who had not previously received any anticonvulsant treatment (treatment naïve) aged 4 to 15 years with typical absence seizures
In review
Over 50% decrease in seizure frequency (assessed by 6-hour telemetry at two intervals 6 months apart, and by parent and teacher reports of seizure frequency) 6 months
12/14 (86%) with sodium valproate
11/13 (85%) with ethosuximide

RR 1.01
95% CI 0.74 to 1.39
Not significant

RCT
Crossover design
16 children and adolescents aged 3 to 18 years with absence seizures, including children with other seizure types, treatment-naïve children
In review
Subgroup analysis
Response to treatment (no generalised spike wave discharges on 12 hour telemetered EEG) 6 weeks
6/7 (86%) with valproic acid
4/9 (44%) with ethosuximide

RR 1.93
95% CI 0.88 to 4.25
Not significant

RCT
Crossover design
29 children and adolescents aged 3 to 18 years with absence seizures, including children with other seizure types, children refractory to anticonvulsant treatment
In review
Subgroup analysis
Response to treatment (no generalised spike wave discharges on 12 hour telemetered EEG) 6 weeks
3/15 (20%) with valproic acid
4/14 (29%) with ethosuximide

RR 0.70
95% CI 0.19 to 2.59
Not significant

RCT
20 children aged 5 to 8 years with recent (within 6 months) onset of absence seizures Complete remission of seizures (seizure frequency assessed using EEG recordings and parent-completed record cards)
7/10 (70%) with sodium valproate
8/10 (80%) with ethosuximide

RR 0.88
95% CI 0.53 to 1.46
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
28 children and adolescents who had not previously received any anticonvulsant treatment (treatment naïve) aged 4 to 15 years with typical absence seizures
In review
Adverse effects
with sodium valproate
with ethosuximide

RCT
Crossover design
16 children and adolescents aged 3 to 18 years with absence seizures, including children with other seizure types, treatment-naïve children
In review
Subgroup analysis
Adverse effects
with valproic acid
with ethosuximide

RCT
Crossover design
29 children and adolescents aged 3 to 18 years with absence seizures, including children with other seizure types, children refractory to anticonvulsant treatment
In review
Subgroup analysis
Adverse events
with valproic acid
with ethosuximide

Valproate versus lamotrigine:

See option on lamotrigine.

Valproate versus other anticonvulsants:

We found three systematic reviews (search date 2005, search date 2002, search date not reported), which found no RCTs.

Further information on studies

Comment

Common adverse effects associated with valproate include dyspepsia, weight gain, tremor, transient hair loss, and haematological abnormalities. Rare adverse effects include behavioural and cognitive abnormalities, potentially fatal liver necrosis, and pancreatitis.

Substantive changes

No new evidence

2008; 2008: 0317.
Published online 2008 January 10.

Clonazepam

Summary

We don't know whether clonazepam reduces the frequency of absence seizures.

Benefits and harms

Clonazepam versus placebo, or other anti-epileptic drugs:

We found no RCTs about the effects of clonazepam.

Comment

Observational data suggest that clonazepam may be effective for the treatment of typical absence seizures in children, but may also cause adverse effects including drowsiness and ataxia, hyperactivity, personality change, and weight gain.

Clinical guide:

Clonazepam is used only occasionally for the treatment of typical absence seizures in children; it is not recommended as a first-line drug.

Substantive changes

No new evidence

2008; 2008: 0317.
Published online 2008 January 10.

Gabapentin

Summary

We don't know whether gabapentin reduces the frequency of absence seizures.

Benefits and harms

Gabapentin versus placebo:

We found two systematic reviews which identified one RCT.

Seizure frequency

Gabapentin compared with placebo Gabapentin may be no more effective at 2 weeks than placebo at reducing seizure rates in children with absence seizures (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Seizure frequency

RCT
33 children aged 4 to 16 years with absence seizures
In review
Seizure frequency (measured with quantified EEG) 2 weeks
with gabapentin
with placebo

Reported as not significant
The trial may have lacked power to detect clinically important effects
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
33 children aged 4 to 16 years with absence seizures
In review
Adverse effects
with gabapentin
with placebo

No data from the following reference on this outcome.

Further information on studies

The RCT was of short duration and used relatively small doses of gabapentin. The target dosage range was 15 to 20 mg/kg daily, although the current maintenance dose used in children with other types of epilepsy is 30 mg/kg daily.

Comment

None.

Substantive changes

Gabapentin Two systematic reviews added , neither of which identified any additional RCTs. Categorisation unchanged (Trade-off between benefits and harms).


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