Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents

Francesco Brigo; Stanley C Igwe

doi:10.1002/14651858.CD003032.pub3

Etosuksymid, walproinian sodu lub lamotrygina w leczeniu padaczki z napadami nieświadomości u dzieci i młodzieży

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Referencias

References to studies included in this review

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estudios excluidos
otras referencias
otras versiones publicadas

Basu S, Bhattacharyya KB, Das K, Das D. Comparative study of sodium valproate and lamotrigine as monotherapy in the management of typical absence seizures. Epilepsia 2005;46(6):277.

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References to studies excluded from this review

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estudios incluidos
otras referencias
otras versiones publicadas

Besag FMC, Wallace SJ, Dulac O, Alving J, Spencer SC, Hosking G. Lamotrigine for the treatment of epilepsy in childhood. Journal of Pediatrics 1995;127(6):991‐7.

Buoni S, Grosso S, Fois A. Lamotrigine in typical absence epilepsy. Brain and Development 1999;21:303‐6.

Erenberg G, Rothner AD, Henry CE, Cruse RP. Valproic acid in the treatment of intractable absence seizures in children: a single‐blind clinical and quantitative EEG study. American Journal of Diseases of Children 1982;136(June):526‐9.

Ferrie CD, Robinson RO, Knott C, Panayiotopoulos CP. Lamotrigine as an add‐on drug in typical absence seizures. Acta Neurologica Scandinavica 1995;91:200‐2.

Holmes GL, Frank LM, Sheth RD, Philbrook B, Wooten JD, Vuong A, et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children. Epilepsy Research 2008;2(82):124‐32.

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Additional references

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Glauser T, Ben‐Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kälviäinen R, et al. ILAE Subcommission on AED Guidelines. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54:551‐63.

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Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. Journal of Medical Genetics 2000;37(7):489‐97.

Panayiotopoulos C P. Treatment of typical absence seizures and related epileptic syndromes. Paediatric Drugs 2001;3(5):379‐403.

Schmitt B, Kovacevic‐Preradovic T, Critelli H, Molinari L. Is ethosuximide a risk factor for generalised tonic‐clonic seizures in absence epilepsy?. Neuropediatrics 2007;38:83‐7.

Tenney JR, Glauser TA. The current state of absence epilepsy: can we have your attention?. Epilepsy Currents 2013;13(3):135‐40.

Wang XQ, Xiong J, Xu WH, Yu SY, Huang XS, Zhang JT, et al. Risk of a lamotrigine‐related skin rash: current meta‐analysis and postmarketing cohort analysis. Seizure 2015;25:52‐61.

References to other published versions of this review

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estudios incluidos
estudios excluidos
otras referencias

EB Posner, K Mohamed, AG Marson. Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. Cochrane Database of Systematic Reviews 2003, Issue 3. [DOI: 10.1002/14651858.CD003032]

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Posner EB, Mohamed K, Marson AG. A systematic review of treatment of typical absence seizures in children and adolescents with ethosuximide, sodium valproate or lamotrigine. Seizure 2005;14(2):117‐22.

Posner EB, Mohamed KK, Marson AG. Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. Cochrane Database of Systematic Reviews 2005, Issue 4. [DOI: 10.1002/14651858.CD003032.pub2]

Characteristics of studies

Characteristics of included studies [ordered by year of study]

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estudios excluidos

Sato 1982

Methods	Randomised double‐blind response ‐ conditional cross‐over study. VPS with PCB for 6 weeks followed by ESM with PCB for 6 weeks for one group. The other group followed the same regimen in a reverse order. Follow‐up 3 months.
Participants	45 naive and drug resistant participants aged 3 to 18 years with absence seizures (not specified if typical or atypical). 18 male.
Interventions	Drug naive participants were on monotherapy (ESM or VPS) while refractory to previous treatment participants were on polytherapy.
Outcomes	Reduction in seizure frequency as judged by 12‐hour EEG telemetry, 100% for drug naive and 80% for drug‐resistant participants.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported how patients were randomly assigned to treatments.
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study was described as "double‐blinded" without further details.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Study was described as "double‐blinded" without further details.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Study was described as "double‐blinded" without further details.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data.
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes.

Callaghan 1982

Methods	Randomised, parallel open study designed to compare ESM with VPS treatment. Followed up for 18 months to 4 years, mean 3 years.
Participants	28 drug naive participants (13 male, 15 female), aged between 4 to 15 years. All participants with typical absence seizures.
Interventions	Monotherapy with ESM or VPS.
Outcomes	Complete or partial (50% to 90%) remission of seizures confirmed by 6 hours telemetry and observation by parents and teachers.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement.
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data.
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes.

Martinovic 1983

Methods	Participants randomly assigned to either ESM or VPS treatment. Parallel open design. All were followed up for 1 to 2 years. 6 participants did not co‐operate; they were not included in the analysis.
Participants	20 participants with recent (less than 6 weeks) onset of 'simple absences' only, other types of seizures observed in 4 out of 5 participants whose seizures were not completely controlled. Age: 5 to 8 years old, 5 were male.
Interventions	Monotherapy with ESM or VPS.
Outcomes	Number of seizures per day as observed by parents. EEG . Number of children who achieved partial (50% to 75% decrease in seizure frequency) or full remission. Time to achieve complete seizure control.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement.
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes.

Frank 1999

Methods	Randomised using 1:1 ratio, double‐blind, parallel design. This study was a second phase of a trial designed as 'responder‐enriched'. It followed an open‐label dose escalation trial. The LTG therapy was tapered over 2 weeks in the PCB group. The length of follow‐up for the randomised double‐blind study was 4 weeks.
Participants	The individuals who became seizure free on LTG during a pre‐randomisation baseline randomised to continue LTG or to PCB. All participants who entered the preceding study were newly diagnosed children with typical absence seizures. 29 participants were randomised, 15 into LTG group and 14 into PCB. 1 person in the LTG group withdrew consent. In the PCB group the age was 8.8+/‐3.1 years, 36% boys. In the LTG group the age was 6.9+/‐2.3 years, 36% were boys.
Interventions	Monotherapy with LTG or PCB.
Outcomes	Proportion of participants that remained seizure free, as measured by hyperventilation EEG.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement.
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement.
Blinding (performance bias and detection bias) All outcomes	Low risk	Lamotrigine was and placebo were identically matched.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Lamotrigine was and placebo were identically matched.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Lamotrigine was and placebo were identically matched.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data.
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes.

Coppola 2004

Methods	Randomised, parallel group unblinded study. Follow‐up for 12 months.
Participants	38 drug naive participants, all with typical absence seizures, age 3 to 13 years.
Interventions	Monotherapy with VPS or LTG.
Outcomes	Total seizures freedom defined by clinical reports, 24 hours EEG and hyperventilation test.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random sequence was generated using a randomisation code.
Allocation concealment (selection bias)	Low risk	Central allocation.
Blinding (performance bias and detection bias) All outcomes	High risk	No blinding. It is not stated whether tables of VPA and LTG were indistinguishable.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding. It is not stated whether tables of VPA and LTG were indistinguishable.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding. It is not stated whether tables of VPA and LTG were indistinguishable.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data.
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes.

Basu 2005

Methods	Randomised, open‐label, parallel group design. Follow‐up 12 months.
Participants	30 patients with typical absence seizures (males 16; females 14. Age between 5 and 14 years) 15 patients allocated to VPA and 15 to LTG.
Interventions	No detailed information on drug dosages. The doses of both the drugs were escalated according to the clinical response, starting from a low dose. Lamotrigine was titrated very slowly at 2‐weekly intervals to avoid unwanted side effects (maximum 10 mg/kg/day).
Outcomes	Seizure freedom.
Notes	Results of this study were published as abstract.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement.
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement.
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement.

Huang 2009

Methods	Randomised, parallel group unblinded study. Follow‐up 12 months.
Participants	48 drug naive participants, all with typical absence seizures, age 6 to 10 years
Interventions	Monotherapy with VPS or LTG.
Outcomes	Seizure freedom at 1, 3, 6 and 12 months. Complete normalisation of EEG with seizure freedom.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement.
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement.
Blinding (performance bias and detection bias) All outcomes	High risk	No blinding.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data.
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes.

Glauser 2013a

Methods	Parallel, randomised, double‐blind study, with partial cross‐over to open‐label (at treatment failure only) with subsequent follow‐up. Follow‐up 12 months.
Participants	453 drug naive participants (193 male, 260 female), aged between 7 months to 12 years 11 months. All participants with typical absence seizures.
Interventions	Monotherapy with LTG, VPS, or ESM.
Outcomes	Freedom from treatment failure assessed 12 months after randomisation.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random sequence was generated using permuted blocks.
Allocation concealment (selection bias)	Low risk	Central allocation.
Blinding (performance bias and detection bias) All outcomes	Low risk	Placebo and active drugs indistinguishable.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo and active drugs indistinguishable.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Placebo and active drugs indistinguishable.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data.
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes.

EEG: electroencephalogram
ESM: ethosuximide
LTG: lamotrigine
PCB: placebo
VPA: valproic acid
VPS: sodium valproate

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos

Study	Reason for exclusion
Besag 1995	No randomisation.
Buoni 1999	No randomisation.
Erenberg 1982	No randomisation.
Ferrie 1995	Retrospective study.
Holmes 2008	No randomisation.
Kang 2012	No patients with absence seizures included.
Najad 2009	No patients with childhood absence seizures included.
Santavuori 1983	Retrospective study.
Schlumberger 1994	No randomisation.
Suzuki 1972	No randomisation.

Data and analyses

Open in table viewer

Comparison 1. Ethosuximide versus valproate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure free Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.1 Comparison 1 Ethosuximide versus valproate, Outcome 1 Seizure free.
1.1 Drug naive	4		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 80% or greater reduction in seizure frequency Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.2 Comparison 1 Ethosuximide versus valproate, Outcome 2 80% or greater reduction in seizure frequency.
2.1 Previously treated	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 50% or greater reduction in seizure frequency Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.3 Comparison 1 Ethosuximide versus valproate, Outcome 3 50% or greater reduction in seizure frequency.

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Comparison 2. Lamotrigine versus valproate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure free Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.1 Comparison 2 Lamotrigine versus valproate, Outcome 1 Seizure free.
1.1 Seizure free at 1 month	2		Risk Ratio (M‐H, Fixed, 95% CI)	8.42 [2.77, 25.59]
1.2 Seizure free at 3 months	3		Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [1.16, 2.31]
1.3 Seizure freedom at 6 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.88, 2.28]
1.4 Seizure free at 12 months	4		Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [1.32, 2.11]
2 Normalization fo the EEG Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.2 Comparison 2 Lamotrigine versus valproate, Outcome 2 Normalization fo the EEG.

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Comparison 3. Ethosuximide versus lamotrigine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure free at 12 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 3.1 Comparison 3 Ethosuximide versus lamotrigine, Outcome 1 Seizure free at 12 months.

Figure 1

Study flow diagram (results refer only to the updated version of the review).

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Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Ethosuximide versus valproate, Outcome 1 Seizure free.

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Analysis 1.2

Comparison 1 Ethosuximide versus valproate, Outcome 2 80% or greater reduction in seizure frequency.

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Analysis 1.3

Comparison 1 Ethosuximide versus valproate, Outcome 3 50% or greater reduction in seizure frequency.

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Analysis 2.1

Comparison 2 Lamotrigine versus valproate, Outcome 1 Seizure free.

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Analysis 2.2

Comparison 2 Lamotrigine versus valproate, Outcome 2 Normalization fo the EEG.

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Analysis 3.1

Comparison 3 Ethosuximide versus lamotrigine, Outcome 1 Seizure free at 12 months.

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Table 1. Adverse effects on valproate: number of participants experiencing each event

Event	Callaghan 1982	Sato 1982	Martinovic 1983	Coppola 2004	Huang 2009	Glauser 2013
Acute pancreatitis	1
Obesity/Weight gain	1			1		14
Drowsiness		4
Nausea		5	3			12*
Vomiting		1	2			12*
Decreased platelet numbers		2	4
Increased appetite						15
Poor appetite		1				8
Diarrhoea				1		7
Dizziness		1				2
Hyperactivity						23
Attention problems						24
Hostility						22
Concentration decreased						18
Personality change						17
Sleep problem						17
Depression						11
Slow process speed						11
Memory problem						10
Apathy						9
Fatigue						27
Headache		1				18
Leukopenia		2
Elevated liver function tests		1			7
Elevated LDH		1
Rash						2
* Nausea, vomiting, or both LDH: lactate dehydrogenase Numbers of individuals within each study undertaking valproate: 14 (Callaghan 1982), 22 (Sato 1982), 10 (Martinovic 1983), 19 (Coppola 2004), 23 (Huang 2009), 146 (Glauser 2013a).

Table 1. Adverse effects on valproate: number of participants experiencing each event

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Table 2. Adverse effects on ethosuximide: number of participants experiencing each event

Event	Callaghan 1982	Sato 1982	Martinovic 1983	Glauser 2013
Drowsiness	1	5
Tiredness			2
Nausea		3	2	29*
Vomiting		3		29*
Increased appetite				6
Poor appetite		1		10
Diarrhoea				9
Dizziness		1		10
Headache		2		23
Leukopenia		3
Hiccups		1
Moodiness		1
Hyperactivity				13
Attention problems				8
Hostility				4
Concentration decreased				6
Personality change				6
Sleep problem				11
Depression				4
Slow process speed				3
Memory problem				0
Apathy				4
Fatigue				26
Rash				6
* Nausea, vomiting, or both Numbers of individuals within each study undertaking ethosuximide: 14 (Callaghan 1982), 23 (Sato 1982), 10 (Martinovic 1983), 154 (Glauser 2013a).

Table 2. Adverse effects on ethosuximide: number of participants experiencing each event

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Table 3. Adverse effects on lamotrigine: number of participants experiencing each event

Event	Frank 1999	Coppola 2004	Huang 2009	Glauser 2013
Abdominal pain	5
Headache	2	2		14
Nausea	3			2*
Vomiting				2*
Poor appetite	2			9
Increased appetite		1		10
Diarrhoea				2
Dizziness	3		5	5
Hyperkinesia	2
Hyperactivity				12
Attention problems				11
Hostility				11
Concentration decreased				9
Personality change				10
Sleep problem				5
Depression				11
Slow process speed				7
Memory problem				8
Apathy				3
Fatigue			1	18
Rash	10	1	2	6
Nervousness		1
Diplopia		1
* Nausea, vomiting, or both Numbers of individuals within each study undertaking lamotrigine: 15 (Frank 1999), 19 (Coppola 2004), 24 (Huang 2009), 146 (Glauser 2013a).

Table 3. Adverse effects on lamotrigine: number of participants experiencing each event

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Comparison 1. Ethosuximide versus valproate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure free Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Drug naive	4		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 80% or greater reduction in seizure frequency Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 Previously treated	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 50% or greater reduction in seizure frequency Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 1. Ethosuximide versus valproate

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Comparison 2. Lamotrigine versus valproate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure free Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Seizure free at 1 month	2		Risk Ratio (M‐H, Fixed, 95% CI)	8.42 [2.77, 25.59]
1.2 Seizure free at 3 months	3		Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [1.16, 2.31]
1.3 Seizure freedom at 6 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.88, 2.28]
1.4 Seizure free at 12 months	4		Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [1.32, 2.11]
2 Normalization fo the EEG Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Lamotrigine versus valproate

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Comparison 3. Ethosuximide versus lamotrigine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure free at 12 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 3. Ethosuximide versus lamotrigine

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Referencias

References to studies included in this review

Basu 2005 {published data only}

Callaghan 1982 {published data only}

Coppola 2004 {published data only}

Frank 1999 {published data only}

Glauser 2013a {published data only}

Huang 2009 {published data only}

Martinovic 1983 {published data only}

Sato 1982 {published data only}

References to studies excluded from this review

Besag 1995 {published data only}

Buoni 1999 {published data only}

Erenberg 1982 {published data only}

Ferrie 1995 {published data only}

Holmes 2008 {published data only}

Kang 2012 {published data only}

Najad 2009 {published data only}

Santavuori 1983 {published data only}

Schlumberger 1994 {published data only}

Suzuki 1972 {published data only}

Additional references

Berg 2010

Berkovic 1993

Chadwick 1987

Christe 1989

Duncan 1995

Glauser 2002

Glauser 2006

Glauser 2013b

Lefebvre 2011

Moore 2000

Panayiotopoulos 2001

Schmitt 2007

Tenney 2013

Wang 2015

References to other published versions of this review

Posner 2003

Posner 2005a

Posner 2005b

Characteristics of studies

Characteristics of included studies [ordered by year of study]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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