Absence Seizures in Children
Content
Child health
Absence seizures in children
Search date October 2007 Ewa Posner QUESTIONS What are the effects of treatments for typical absence seizures in children?. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 INTERVENTIONS TREATMENTS FOR TYPICAL ABSENCE SEIZURES Trade off between benefits and harms Ethosuximide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Lamotrigine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Valproate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Unknown effectiveness Clonazepam. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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. 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 [1] 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. 5 Gabapentin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 To be covered in future updates Acetazolamide Atypical absence seizures Clobazam
© BMJ Publishing Group Ltd 2007
........................... 1 ...........................
BMJ Clin Evid 2008;01:317
Child health
Absence seizures in children
INCIDENCE/ PREVALENCE About 10% of seizures in children with epilepsy are typical absence seizures. Annual incidence has been estimated at 0.7–4.6/100,000 people in the general population, and 6–8/100,000 in children [2] aged 0–15 years. Prevalence is 5–50/100,000 people in the general population. Similar figures were found in the USA (Connecticut) and in Europe-based (Scandinavia, France) population [2] studies. Age of onset ranges from 3–13 years, with a peak at 6–7 years.
[1]
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 .
© BMJ Publishing Group Ltd 2007
...................................................................... 2
Child health
Absence seizures in children
Benefits: We found three systematic reviews (search date 2005, search date 2002, search date not reported).
[8] [9] [10]
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 3–15 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-naïve 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
© BMJ Publishing Group Ltd 2007
Child health
Absence seizures in children
one did the investigator consider it to be causally related to lamotrigine. The children from this RCT were recruited into an open-label continuation study (252 children; 43 [17%] with absence [13] seizures), which looked at long-term tolerability of lamotrigine. A high proportion of these children (125/252 [50%]) discontinued, mostly because of inadequate response or for administrative reasons. The average duration of lamotrigine exposure was 96.7 weeks. The study found that the most common adverse effects were dizziness (23/252 [9%]), somnolence (20/252 [8%]), nausea (16/252 [6%]), vomiting (13/252 [5%]), and headache (13/252 [5%]). We also found two open-label add-on studies (study participants were receiving treatment for absence seizures at the time of enrolment, and continued the treatment during the study) that reported on adverse events with lamotrigine. [14] [15] The first add-on study (117 children aged 0–17 years with various drug-resistant epilepsies) reported adverse effects in 25/117 (21%) children during treatment with lamotrigine, primarily skin rash in 12 children (10 of whom were also receiving valproic acid), but also including ataxia, [15] drowsiness, headache, and vomiting at 1–18 days after initiation of lamotrigine. No correlation was found with lamotrigine blood levels. The second add-on study (285 children aged less than 13 years with refractory epilepsies and at least 2 seizure types) found that rash was the most common adverse effect leading to discontinuation of lamotrigine (total withdrawal rate 36/285 [13%]; [14] withdrawal caused by rash 21/285 [7%]). Lamotrigine versus valproate: Adverse effects were less common with lamotrigine than with valproate (adverse effects: 2/19 [11%] with lamotrigine v 6/19 [32%] with valproate; P value not reported). There were no withdrawals caused by adverse effects, which were generally mild and transient and included headache, weight [12] gain, and diplopia. Comment: The RCT comparing lamotrigine versus placebo randomised a group of children who responded [8] to treatment with lamotrigine in an open-label trial (potentially introducing selection bias). VALPROATE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
[11]
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 naïve] aged 4–15 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 3–18 years with absence seizures, including children with other seizure types, children refractory to anticonvulsant treatment, and treatment-naïve 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 (naïve: 6/7 [86%] with valproic acid
© BMJ Publishing Group Ltd 2007
......................................................................
4
Child health
Absence seizures in children
v 4/9 [44%] with ethosuximide; RR 1.93, 95% CI 0.88 to 4.25; refractory: 3/15 [20%] with valproic acid v 4/14 [29%] with ethosuximide; RR 0.70, 95% CI 0.19 to 2.59). The third RCT (20 children aged 5–8 years) compared sodium valproate versus ethosuximide for up to 2 years in children with [18] recent (within 6 months) onset of absence seizures. Seizure frequency was assessed using EEG recordings and parent-completed record cards. The RCT found no significant difference in complete remission of seizures between sodium valproate and ethosuximide (AR for remission of seizures [time to follow-up not reported]: 7/10 [70%] with sodium valproate v 8/10 [80%] with ethosuximide; RR 0.88, 95% CI 0.53 to 1.46). Valproate versus lamotrigine: See benefits of lamotrigine, p 3 . Valproate versus other anticonvulsants: [8] [9] [10] The reviews found no RCTs. Harms: Common adverse effects associated with valproate include dyspepsia, weight gain, tremor, transient hair loss, and haematological abnormalities. Rare adverse effects include behavioural and cognitive [1] abnormalities, potentially fatal liver necrosis, and pancreatitis. The first RCT included in the review reported acute pancreatitis (1 child) and weight gain not responding to dietary restriction (1 child) with sodium valproate, and drowsiness (1 child receiving a high dose of ethosuximide). The second RCT included in the review reported adverse events in children who had not previously received [17] any anticonvulsant treatment. The adverse events with valproate and ethosuximide included nausea, vomiting, poor appetite, drowsiness, dizziness, headache, and leukopenia. Transient thrombocytopenia occurred with valproate in two children. No child withdrew from the trial because of these events.The third RCT reported infrequent adverse events with both sodium valproate (transient nausea and vomiting, decreased number of platelets without thrombocytopenia) and [18] ethosuximide (fatigue). Valproate versus lamotrigine: See harms of lamotrigine, p 3 . Comment: The RCTs comparing sodium valproate versus ethosuximide suggest a beneficial effect with both [16] [17] [18] sodium valproate and ethosuximide. CLONAZEPAM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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
......................................................................
5
Child health
Absence seizures in children
Benefits: We found two systematic reviews.
[9] [10]
Gabapentin versus placebo: [9] [10] [21] The reviews identified one RCT (33 children aged 4–16 years with absence seizures) comparing gabapentin (15–20 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 15–20 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;3:379–403. [PubMed] Jallon P and Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia 2005;46(suppl 9):10–14. Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev 2000;22:75–80. [PubMed] Hom CS, Ater SB, Hurst DL. Carbamazepine-exacerbated epilepsy in children and adolescents. Pediatr Neurol 1986;2:340–345. [PubMed] Parker AP, Agathonikou A, Robinson RO, et al. Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Dev Med Child Neurol 1998;40:517–519. [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;13:203–211. 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, ix–118. 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;40:973–979. [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;45:1049–1053. [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;17:278–285. [PubMed] Besag FM, Wallace SJ, Dulac O, et al. Lamotrigine for the treatment of epilepsy in childhood. J Pediatr 1995;127:991–997. [PubMed] Schlumberger E, Chavez F, Palacios L, et al. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia 1994;35:359–367. [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;24:830–836. [PubMed] Sato S, White BG, Penry JK, et al. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 1982;32:157–163. [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, 1983:301–305. Dreifuss FE, Penry JK, Rose SW, et al. Serum clonazepam concentrations in children with absence seizures. Neurology 1975;25:255–258. [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 naïve childhood absence epilepsy: results from two double-blind, placebo-controlled, multicenter studies. J Child Neurol 1996;11:470–475. [PubMed]
13.
6. 7. 8.
19. 20. 21.
9.
10.
© BMJ Publishing Group Ltd 2007
......................................................................
6
Child health
Absence seizures in children
Ewa Posner Consultant Paediatrician University Hospital of North Durham Durham UK
Competing interests: EP declares that she has no competing interests.
TABLE
Important outcomes Number of studies (participants)
[16]
GRADE evaluation of interventions for absence seizures in children
Seizures, adverse effects Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of treatments for typical absence seizures in children? 3 (93)
[17] [18]
Seizures
Ethosuximide v valproate
4
–1
0
–1
0
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
4
–3
0
–1
0
Very low
1 (38)
[12]
Seizures
Lamotrigine v valproate
4
–1
–1
0
0
Low
1 (33)
[21]
Seizures
Gabapentin v placebo
4
–2
0
–1
0
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
© BMJ Publishing Group Ltd 2007
......................................................................
7
Absence seizures in children
Search date October 2007 Ewa Posner QUESTIONS What are the effects of treatments for typical absence seizures in children?. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 INTERVENTIONS TREATMENTS FOR TYPICAL ABSENCE SEIZURES Trade off between benefits and harms Ethosuximide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Lamotrigine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Valproate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Unknown effectiveness Clonazepam. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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. 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 [1] 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. 5 Gabapentin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 To be covered in future updates Acetazolamide Atypical absence seizures Clobazam
© BMJ Publishing Group Ltd 2007
........................... 1 ...........................
BMJ Clin Evid 2008;01:317
Child health
Absence seizures in children
INCIDENCE/ PREVALENCE About 10% of seizures in children with epilepsy are typical absence seizures. Annual incidence has been estimated at 0.7–4.6/100,000 people in the general population, and 6–8/100,000 in children [2] aged 0–15 years. Prevalence is 5–50/100,000 people in the general population. Similar figures were found in the USA (Connecticut) and in Europe-based (Scandinavia, France) population [2] studies. Age of onset ranges from 3–13 years, with a peak at 6–7 years.
[1]
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 .
© BMJ Publishing Group Ltd 2007
...................................................................... 2
Child health
Absence seizures in children
Benefits: We found three systematic reviews (search date 2005, search date 2002, search date not reported).
[8] [9] [10]
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 3–15 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-naïve 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
© BMJ Publishing Group Ltd 2007
Child health
Absence seizures in children
one did the investigator consider it to be causally related to lamotrigine. The children from this RCT were recruited into an open-label continuation study (252 children; 43 [17%] with absence [13] seizures), which looked at long-term tolerability of lamotrigine. A high proportion of these children (125/252 [50%]) discontinued, mostly because of inadequate response or for administrative reasons. The average duration of lamotrigine exposure was 96.7 weeks. The study found that the most common adverse effects were dizziness (23/252 [9%]), somnolence (20/252 [8%]), nausea (16/252 [6%]), vomiting (13/252 [5%]), and headache (13/252 [5%]). We also found two open-label add-on studies (study participants were receiving treatment for absence seizures at the time of enrolment, and continued the treatment during the study) that reported on adverse events with lamotrigine. [14] [15] The first add-on study (117 children aged 0–17 years with various drug-resistant epilepsies) reported adverse effects in 25/117 (21%) children during treatment with lamotrigine, primarily skin rash in 12 children (10 of whom were also receiving valproic acid), but also including ataxia, [15] drowsiness, headache, and vomiting at 1–18 days after initiation of lamotrigine. No correlation was found with lamotrigine blood levels. The second add-on study (285 children aged less than 13 years with refractory epilepsies and at least 2 seizure types) found that rash was the most common adverse effect leading to discontinuation of lamotrigine (total withdrawal rate 36/285 [13%]; [14] withdrawal caused by rash 21/285 [7%]). Lamotrigine versus valproate: Adverse effects were less common with lamotrigine than with valproate (adverse effects: 2/19 [11%] with lamotrigine v 6/19 [32%] with valproate; P value not reported). There were no withdrawals caused by adverse effects, which were generally mild and transient and included headache, weight [12] gain, and diplopia. Comment: The RCT comparing lamotrigine versus placebo randomised a group of children who responded [8] to treatment with lamotrigine in an open-label trial (potentially introducing selection bias). VALPROATE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
[11]
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 naïve] aged 4–15 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 3–18 years with absence seizures, including children with other seizure types, children refractory to anticonvulsant treatment, and treatment-naïve 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 (naïve: 6/7 [86%] with valproic acid
© BMJ Publishing Group Ltd 2007
......................................................................
4
Child health
Absence seizures in children
v 4/9 [44%] with ethosuximide; RR 1.93, 95% CI 0.88 to 4.25; refractory: 3/15 [20%] with valproic acid v 4/14 [29%] with ethosuximide; RR 0.70, 95% CI 0.19 to 2.59). The third RCT (20 children aged 5–8 years) compared sodium valproate versus ethosuximide for up to 2 years in children with [18] recent (within 6 months) onset of absence seizures. Seizure frequency was assessed using EEG recordings and parent-completed record cards. The RCT found no significant difference in complete remission of seizures between sodium valproate and ethosuximide (AR for remission of seizures [time to follow-up not reported]: 7/10 [70%] with sodium valproate v 8/10 [80%] with ethosuximide; RR 0.88, 95% CI 0.53 to 1.46). Valproate versus lamotrigine: See benefits of lamotrigine, p 3 . Valproate versus other anticonvulsants: [8] [9] [10] The reviews found no RCTs. Harms: Common adverse effects associated with valproate include dyspepsia, weight gain, tremor, transient hair loss, and haematological abnormalities. Rare adverse effects include behavioural and cognitive [1] abnormalities, potentially fatal liver necrosis, and pancreatitis. The first RCT included in the review reported acute pancreatitis (1 child) and weight gain not responding to dietary restriction (1 child) with sodium valproate, and drowsiness (1 child receiving a high dose of ethosuximide). The second RCT included in the review reported adverse events in children who had not previously received [17] any anticonvulsant treatment. The adverse events with valproate and ethosuximide included nausea, vomiting, poor appetite, drowsiness, dizziness, headache, and leukopenia. Transient thrombocytopenia occurred with valproate in two children. No child withdrew from the trial because of these events.The third RCT reported infrequent adverse events with both sodium valproate (transient nausea and vomiting, decreased number of platelets without thrombocytopenia) and [18] ethosuximide (fatigue). Valproate versus lamotrigine: See harms of lamotrigine, p 3 . Comment: The RCTs comparing sodium valproate versus ethosuximide suggest a beneficial effect with both [16] [17] [18] sodium valproate and ethosuximide. CLONAZEPAM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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
......................................................................
5
Child health
Absence seizures in children
Benefits: We found two systematic reviews.
[9] [10]
Gabapentin versus placebo: [9] [10] [21] The reviews identified one RCT (33 children aged 4–16 years with absence seizures) comparing gabapentin (15–20 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 15–20 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;3:379–403. [PubMed] Jallon P and Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia 2005;46(suppl 9):10–14. Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev 2000;22:75–80. [PubMed] Hom CS, Ater SB, Hurst DL. Carbamazepine-exacerbated epilepsy in children and adolescents. Pediatr Neurol 1986;2:340–345. [PubMed] Parker AP, Agathonikou A, Robinson RO, et al. Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Dev Med Child Neurol 1998;40:517–519. [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;13:203–211. 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, ix–118. 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;40:973–979. [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;45:1049–1053. [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;17:278–285. [PubMed] Besag FM, Wallace SJ, Dulac O, et al. Lamotrigine for the treatment of epilepsy in childhood. J Pediatr 1995;127:991–997. [PubMed] Schlumberger E, Chavez F, Palacios L, et al. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia 1994;35:359–367. [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;24:830–836. [PubMed] Sato S, White BG, Penry JK, et al. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 1982;32:157–163. [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, 1983:301–305. Dreifuss FE, Penry JK, Rose SW, et al. Serum clonazepam concentrations in children with absence seizures. Neurology 1975;25:255–258. [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 naïve childhood absence epilepsy: results from two double-blind, placebo-controlled, multicenter studies. J Child Neurol 1996;11:470–475. [PubMed]
13.
6. 7. 8.
19. 20. 21.
9.
10.
© BMJ Publishing Group Ltd 2007
......................................................................
6
Child health
Absence seizures in children
Ewa Posner Consultant Paediatrician University Hospital of North Durham Durham UK
Competing interests: EP declares that she has no competing interests.
TABLE
Important outcomes Number of studies (participants)
[16]
GRADE evaluation of interventions for absence seizures in children
Seizures, adverse effects Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of treatments for typical absence seizures in children? 3 (93)
[17] [18]
Seizures
Ethosuximide v valproate
4
–1
0
–1
0
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
4
–3
0
–1
0
Very low
1 (38)
[12]
Seizures
Lamotrigine v valproate
4
–1
–1
0
0
Low
1 (33)
[21]
Seizures
Gabapentin v placebo
4
–2
0
–1
0
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
© BMJ Publishing Group Ltd 2007
......................................................................
7
