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Child health
AETIOLOGY/ The cause of childhood absence epilepsy is presumed to be genetic. Seizures can be triggered [3] RISK FACTORS by hyperventilation in susceptible children. Some anticonvulsants, such as phenytoin, carba[4] [5] [6] mazepine, 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 [7] 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 Cessation or decrease in the frequency of seizures, with minimum adverse effects of treatment. INTERVENTION OUTCOMES Seizure frequency measured as normalisation of the EEG; adverse effects of treatment with anticonvulsants. We found no studies assessing quality of life. BMJ 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 National Institute for Health and Clinical Excellence (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, p 7 ). What are the effects of treatments for typical absence seizures in children? ETHOSUXIMIDE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS
QUESTION OPTION
Seizures Compared with valproate Ethosuximide may be as effective as valproate at reducing seizure rate after 4 weeks to 4 years in children with absence seizures ( low-quality evidence ). Adverse effects Ethosuximide is associated with rare but serious adverse effects, including aplastic anaemia, skin reactions, and renal and hepatic impairment. Note We found no direct information about whether ethosuximide is better than no active treatment. There is, however, consensus that ethosuximide is beneficial. We found no clinically important results about the effects of ethosuximide compared with other anticonvulsants. For GRADE evaluation of absence seizures in children, see table, p 7 .
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Child health
Ethosuximide versus placebo: [8] [9] The reviews found no RCTs. Ethosuximide versus valproate: See benefits of valproate, p 4 .
[10]
Ethosuximide versus other anticonvulsants: [8] [9] [10] The reviews found no RCTs. Harms: 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 [1] hepatic impairment. Ethosuximide versus valproate: See harms of valproate, p 5 . Comment: OPTION None. LAMOTRIGINE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Seizures 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 ). Compared with valproate Lamotrigine may be less effective than valproate at reducing seizures in children with absence seizures ( low-quality evidence ). Adverse effects Lamotrigine is associated with serious skin reactions. Note We found no clinically important results about the effects of lamotrigine compared with other anticonvulsants. For GRADE evaluation of absence seizures in children, see table, p 7 . Benefits: We found three systematic reviews (search date 2005, search date 2002, search date not reported).
[8] [9] [10]
Lamotrigine versus placebo: [8] [9] [10] The reviews 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 [11] shown to be clinically effective. The RCT (29 children and adolescents aged 315 years with newly diagnosed typical absence seizures, in whom lamotrigine was clinically effective) compared [8] lamotrigine versus placebo for 4 weeks. Response was measured with 24-hour ambulatory EEG and a hyperventilation test during the EEG. The RCT found that lamotrigine significantly increased the proportion of children who remained seizure free for 4 weeks compared with placebo (AR for remaining seizure free: 64% with lamotrigine v 21% with placebo; P = 0.03). Lamotrigine versus valproate: We found no systematic review but found one RCT (38 drug-nave children with typical absence [12] seizures), which compared lamotrigine versus valproate. It found that lamotrigine was less effective than valproate at preventing seizures at 1, 3, and 12 months although this difference was only significant at 1 month (proportion of children free from seizures, at 1 month: 1/19 [5%] with lamotrigine v 10/19 [53%] with valproate; P = 0.004; at 3 months: 7/19 [37%] with lamotrigine v 12/19 [63%] with valproate; P = 0.19; at 12 months: 10/19 (53%) with lamotrigine v 13/19 (68%) [12] with valproate; P = 0.51). Lamotrigine versus other anticonvulsants: [7] [9] [10] The reviews identified no RCTs. Harms: Lamotrigine versus placebo: The RCT identified by the reviews reported abdominal pain, headache, nausea, anorexia, dizziness, [11] and hyperkinesia with lamotrigine. Skin rash was reported in 10/29 (35%) children, but only in ...................................................................... 3
Child health
OPTION
Seizures 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 ). Compared with lamotrigine Valproate may be more effective than lamotrigine at reducing seizures in children with absence seizures (low-quality evidence). Adverse effects Valproate is associated with rare but serious adverse effects, including behavioural and cognitive abnormalities, liver necrosis, and pancreatitis. Note We found no direct information about whether valproate is better than no active treatment. There is, however, consensus that valproate (sodium valproate or valproic acid) is beneficial. We found no clinically important results about the effects of valproate compared with other anticonvulsants in children with absence seizures. For GRADE evaluation of absence seizures in children, see table, p 7 . Benefits: We found three systematic review (search date 2005). Valproate versus placebo: [8] The reviews found no RCTs.
[9] [10] [8] [9] [10]
Valproate versus ethosuximide: [8] [9] [10] [16] [17] [18] The reviews found three small RCTs. Results from the RCTs could not be pooled because each assessed different outcomes. The first RCT (28 children and adolescents who had not previously received any anticonvulsant treatment [treatment nave] aged 415 years with typical absence seizures) compared sodium valproate versus ethosuximide for up to 4 years. [16] Response was measured by 6-hour telemetry at two intervals 6 months apart, and by parent and teacher reports of seizure frequency. The RCT found no significant difference in overall improvement between sodium valproate and ethosuximide (AR for greater than 50% decrease in the seizure frequency over 6 months: 12/14 [86%] with sodium valproate v 11/13 [85%] with ethosuximide; RR 1.01, 95% CI 0.74 to 1.39). The second RCT (45 children and adolescents aged 318 years with absence seizures, including children with other seizure types, children refractory to anticonvulsant treatment, and treatment-nave children) compared valproic acid versus ethosuximide [17] followed by a crossover after 6 weeks. Response to treatment was defined as no generalised spike wave discharges on 12 hour telemetered EEG. The RCT found no significant difference in response between valproic acid and ethosuximide at 6 weeks (nave: 6/7 [86%] with valproic acid
BMJ Publishing Group Ltd 2007
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Child health
OPTION
We found no clinically important results about the effects of clonazepam for the treatment of typical absence seizures in children. For GRADE evaluation of absence seizures in children, see table, p 7 . Benefits: Harms: Comment: We found no RCTs about the effects of clonazepam. We found no RCTs. 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, hyperac[19] tivity, personality change, and weight gain. Clinical guide: Clonazepam is used only occasionally for the treatment of typical absence seizures in children; it [20] is not recommended as a first-line drug. OPTION GABAPENTIN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Seizures 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 ). Adverse effects Gabapentin has been associated with somnolence and dizziness. Note We found no clinically important results about the effects of gabapentin compared with other anticonvulsants in children with absence seizures. For GRADE evaluation of absence seizures in children, see table, p 7 .
BMJ Publishing Group Ltd 2007
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Child health
Gabapentin versus placebo: [9] [10] [21] The reviews identified one RCT (33 children aged 416 years with absence seizures) comparing gabapentin (1520 mg/kg daily) versus placebo. The RCT consisted of a 2-week double blind treatment phase followed by a 6-week open label phase. Response was assessed as the change from baseline in seizure frequency (measured with quantified EEG) after 2 weeks. The RCT found no significant difference after 2 weeks between gabapentin and placebo in frequency of typical absence seizures. However, the trial may have lacked power to detect clinically important [21] effects ( see comment below, p 6 ). Gabapentin versus other anticonvulsants: [9] [10] The reviews identified no RCTs. Harms: The RCT found that somnolence and dizziness were the most frequent adverse events. All reported adverse effects were mild to moderate and no children withdrew from the study because of adverse effects of treatment. The RCT was of short duration and used relatively small doses of gabapentin. The target dosage range was 1520 mg/kg daily, although the current maintenance dose used in children with other types of epilepsy is 30 mg/kg daily.
[21] [21]
Comment:
GLOSSARY
Hyperventilation test The test is performed by asking a child to breathe slowly and deeply for 3 minutes. In 90% of children with childhood absence epilepsy this will precipitate an absence attack. 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.
SUBSTANTIVE CHANGES
Ethosuximide Two systematic reviews added , neither of which identified any additional RCTs. Categorisation unchanged (Trade-off between benefits and harms). [9] [10] Gabapentin Two systematic reviews added, neither of which identified any additional RCTs. Categorisation unchanged (Unknown effectiveness). [9] [10] Lamotrigine Two systematic reviews added, neither of which identified any additional RCTs. Categorisation unchanged (Trade-off between benefits and harms).
[9] [10]
REFERENCES
1. 2. 3. 4. 5. Panayiotopoulos CP. Treatment of typical absence seizures and related epileptic syndromes. Paediatr Drugs 2001;3:379403. [PubMed] Jallon P and Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia 2005;46(suppl 9):1014. Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev 2000;22:7580. [PubMed] Hom CS, Ater SB, Hurst DL. Carbamazepine-exacerbated epilepsy in children and adolescents. Pediatr Neurol 1986;2:340345. [PubMed] Parker AP, Agathonikou A, Robinson RO, et al. Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Dev Med Child Neurol 1998;40:517519. [PubMed] Panayiotopoulos CP, Agathonikou A, Sharoqi IA, et al. Vigabatrin aggravates absences and absence status. Neurology 1997;49:1467. Panayiotopoulos CP. A clinical guide to epileptic syndromes and their treatment. Oxfordshire, UK: Bladon Medical Publishing, 2002:132. 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. 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;13:203211. Connock M, Frew E, Evans B-W, et al. The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy: a systematic review. Health Technol Assess 2006;10:iii, ix118. 17. 18. 14. 15. 16. 11. 12. Frank LM, Enlow T, Holmes GL, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 1999;40:973979. [PubMed] 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;45:10491053. [PubMed] Duchowny M, Gilman J, Messenheimer J, et al. Long-term tolerability and efficacy of lamotrigine in pediatric patients with epilepsy. J Child Neurol 2002;17:278285. [PubMed] Besag FM, Wallace SJ, Dulac O, et al. Lamotrigine for the treatment of epilepsy in childhood. J Pediatr 1995;127:991997. [PubMed] Schlumberger E, Chavez F, Palacios L, et al. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia 1994;35:359367. [PubMed] 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;24:830836. [PubMed] Sato S, White BG, Penry JK, et al. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 1982;32:157163. [PubMed] 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, 1983:301305. Dreifuss FE, Penry JK, Rose SW, et al. Serum clonazepam concentrations in children with absence seizures. Neurology 1975;25:255258. [PubMed] Hitiris N, Brodie MJ. Evidence-based treatment of idiopathic generalized epilepsies with older antiepileptic drugs. Epilepsia 2005;46:149-153 Trudeau V, Myers S, LaMoreaux L, et al. Gabapentin in nave childhood absence epilepsy: results from two double-blind, placebo-controlled, multicenter studies. J Child Neurol 1996;11:470475. [PubMed]
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Child health
TABLE
Important outcomes Number of studies (participants)
[16]
What are the effects of treatments for typical absence seizures in children? 3 (93)
[17] [18]
Seizures
Ethosuximide v valproate
Low
Quality point deducted for sparse data. Directness point deducted for wide inclusion criteria Quality points deducted for sparse data, no blinding, and short follow-up. Directness point deducted for inclusion of treatment responders only Quality point deducted for sparse data. Consistency point deducted for conflicting results Quality points deducted for sparse data and short follow-up. Directness point deducted for use of extremely low dose
3 (92)
[10]
[8]
[9]
Seizures
Lamotrigine v placebo
Very low
1 (38)
[12]
Seizures
Lamotrigine v valproate
Low
1 (33)
[21]
Seizures
Gabapentin v placebo
Very low
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio
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