Topiramate monotherapy for juvenile myoclonic epilepsy

Jia Liu; Lu‐Ning Wang; Yu‐Ping Wang

doi:10.1002/14651858.CD010008.pub2

Monotherapie mit Topiramat bei juveniler myoklonischer Epilepsie

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Referencias

References to studies included in this review

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otras versiones publicadas

Biton V, Bourgeois BF, YTC/YTCE Study Investigators. Topiramate in patients with juvenile myoclonic epilepsy. Archives of Neurology 2005;62:1705‐8.

Levisohn PM, Holland KD. Topiramate or valproate in patients with juvenile myoclonic epilepsy: a randomized open‐label comparison. Epilepsy & Behavior 2007;10:547‐52.

Park KM, Kim SH, Nho SK, Shin KJ, Park J, Ha SY, et al. A randomized open‐label observational study to compare the efficacy and tolerability between topiramate and valproate in juvenile myoclonic epilepsy. Journal of Clinical Neuroscience 2013;20:1079‐82.

References to studies excluded from this review

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estudios incluidos
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Sousa Pda S, Araújo Filho GM, Garzon E, Sakamoto AC, Yacubian EM. Topiramate for the treatment of juvenile myoclonic epilepsy. Arquivos de Neuro‐psiquiatria 2005;63:733‐7.

Additional references

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Alfradique I, Vasconcelos MM. Juvenile myoclonic epilepsy. Arquivos de Neuro‐psiquiatria 2007;65:1266‐71.

Biton V, Montouris GD, Ritter F, Riviello JJ, Reife R, Lim P, et al. A randomized, placebo‐controlled study of topiramate in primary generalized tonic‐clonic seizures. Neurology 1999;52:1330‐7.

Calleja S, Salas‐Puig J, Ribacoba R, Lahoz CH. Evolution of juvenile myoclonic epilepsy treated from the outset with sodium valproate. Seizure 2001;10:424‐7.

Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta‐analyses involving cross‐over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140‐9.

Guberman A, Neto W, Gassmann‐Mayer C, EPAJ‐119 Study Group. Low‐dose topiramate in adults with treatment‐resistant partial‐onset seizures. Acta Neurologica Scandinavica 2002;106:183‐9.

Hanaya R, Sasa M, Ujihara H, Ishihara K, Serikawa T, Iida K, et al. Suppression by topiramate of epileptiform burst discharges in hippocampal CA3 neurons of spontaneously epileptic rat in vitro. Brain Research 1998;789:274‐82.

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [update March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Jallon P, Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia 2005;46 (Suppl 9):S10‐4.

Janz D. Epilepsy with impulsive petit mal (juvenile myoclonic epilepsy). Acta Neurologica Scandinavica 1985;72:449‐59.

Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, et al. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ 2010;340:c365.

Lefebvre C, Manheimer E, Glanville J. Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Montouris G, Abou‐Khalil B. The first line of therapy in a girl with juvenile myoclonic epilepsy: should it be valproate or a new agent?. Epilepsia 2009;50(Suppl 8):16‐20.

Panayiotopoulos CP, Tahan R, Obeid T. Juvenile myoclonic epilepsy: factors of error involved in the diagnosis and treatment. Epilepsia 1991;32:672‐6.

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.

Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G. Topiramate YL Study Group. A double‐blind, randomized trial of topiramate in Lennox‐Gastaut syndrome. Neurology 1999;52:1882‐7.

Sharpe DV, Patel AD, Abou‐Khalil B, Fenichel GM. Levetiracetam monotherapy in juvenile myoclonic epilepsy. Seizure 2008;17:64‐8.

White HS, Brown SD, Woodhead JH, Skeen GA, Wolf HH. Topiramate modulates GABA‐evoked currents in murine cortical neurons by a nonbenzodiazepine mechanism. Epilepsia 2000;41 Suppl 1:S17‐20.

Zona C, Ciotti MT, Avoli M. Topiramate attenuates voltage‐gated sodium currents in rat cerebellar granule cells. Neuroscience Letters 1997;231:123‐6.

References to other published versions of this review

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Liu J, Wang LN. Topiramate monotherapy for juvenile myoclonic epilepsy. Cochrane Database of Systematic Reviews 2012, Issue 8. [DOI: 10.1002/14651858.CD010008]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Biton 2005

Methods	Randomized, double‐blind, placebo‐controlled study
Participants	22 participants with juvenile myoclonic epilepsy
Interventions	Starting dose of topiramate 50 mg/day or equivalent placebo tablets was maintained for 4 weeks, then increased at 2‐week intervals to target dosages of 400 mg/day in adults or 6 mg/kg/day in children. Treatment was continued for an additional 12 weeks
Outcomes	Reduction in PGTCS, myoclonic, absence and total generalized seizures, adverse events
Notes	The baseline period was 8 weeks. The protocol can be identified from Biton 1999
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer‐generated randomization schedule was prepared by the Robert Wood Johnson Pharmaceutical Research Institute before the beginning of the trial
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	During the double‐blind phase, investigators, participants, study monitors and observers remained masked to codes until after the clinical database was finalized
Blinding of outcome assessment (detection bias) All outcomes	Low risk	During the double‐blind phase, investigators, participants, study monitors and observers remained masked to codes until after the clinical database was finalized
Incomplete outcome data (attrition bias) All outcomes	High risk	2 participants taking topiramate (18%) and 1 (9%) participant taking placebo discontinued treatment owing to adverse events
Selective reporting (reporting bias)	Unclear risk	No prepublished protocol
Other bias	Low risk	No other bias was found

Levisohn 2007

Methods	Pilot, randomized controlled trial
Participants	28 participants with juvenile myoclonic epilepsy
Interventions	Participants were assigned as 2:1 ratio to topiramate (19 participants) or valproate (9 participants) for 26 weeks. The topiramate target dosage was 3‐4 mg/kg/day (maximum 9 mg/kg/day) for participants aged 12‐16 years and 200 mg/day (maximum 600 mg/day) for participants aged > 16 years. Valproate target dosages were 10 mg/kg/day in participants aged 12‐16 years and 750 mg/day in participants aged >16 years (overall maximum 60 mg/kg/day). Medications were titrated at 1‐ to 2‐week intervals according to clinical response and were administered in divided doses
Outcomes	Seizure reduction, evaluation of improvement, systemic toxicity and neurotoxicity scores, adverse events
Notes	The baseline period was 3 months before study entry. A 14‐week titration phase was followed by a 12‐week maintenance phase
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blinded randomization was achieved by providing study sites with individual envelopes containing medication assignments generated by computer
Allocation concealment (selection bias)	Low risk	Blinded randomization was achieved by providing study sites with individual envelopes containing medication assignments generated by computer
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The participant, investigator and pharmacist remained blinded to medication assignment until screening was completed and the envelope was opened
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The participant, investigator and pharmacist remained blinded to medication assignment until screening was completed and the envelope was opened
Incomplete outcome data (attrition bias) All outcomes	High risk	7 (37%) participants treated with topiramate and 2 (22%) participants treated with valproate discontinued before the endpoint
Selective reporting (reporting bias)	Unclear risk	No prepublished protocol
Other bias	Low risk	No other bias was found

Park 2013

Methods	Randomized open‐label observational study
Participants	33 participants with juvenile myoclonic epilepsy
Interventions	Participants were assigned as 1:1 ratio to topiramate (16 participants) or valproate (17 participants) for 32 weeks. The assigned antiepileptic drug was titrated up to 1200 mg/day for valproate or 100 mg/day for topiramate. The dose of valproate was titrated up 300 mg/day for 2 weeks, whereas topiramate was increased 25 mg/day for 2 weeks. In participants with a poor response to medication during the 24‐week maintenance phase, the dose of valproate was increased 300 mg/day for 1 month to a maximum dose of 2400 mg/day, and the dose of topiramate was increased 50 mg/day for 1 month to a maximum 300 mg/day
Outcomes	Number of days without myoclonic seizures during the 24‐week maintenance period, adverse events
Notes	Baseline period was not clear. An 8‐week titration phase was followed by a 24‐week maintenance phase
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants underwent computerized randomization in a 1 : 1 ratio to primary treatment with topiramate or valproate
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	High risk	1 (6%) participant who was randomized to topiramate was removed from the study due to severe anorexia. 4 (25%) participants from the topiramate group and 1 (6%) participant from the valproate group were lost to follow‐up
Selective reporting (reporting bias)	Unclear risk	No prepublished protocol
Other bias	Low risk	No other bias was found

PGTCS: primarily generalized tonic‐clonic seizures.

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos

Study	Reason for exclusion
Sousa Pda 2005	Not a randomized controlled trial

Data and analyses

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Comparison 1. Topiramate versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of responders (at least 50% seizure frequency reduction in PGTCS) Show forest plot	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [1.08, 14.75]
Open in figure viewer Analysis 1.1 Comparison 1 Topiramate versus placebo, Outcome 1 Proportion of responders (at least 50% seizure frequency reduction in PGTCS).
2 Nausea Show forest plot	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.52, 5.33]
Open in figure viewer Analysis 1.2 Comparison 1 Topiramate versus placebo, Outcome 2 Nausea.
3 Upper respiratory tract infection Show forest plot	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	1.5 [0.31, 7.30]
Open in figure viewer Analysis 1.3 Comparison 1 Topiramate versus placebo, Outcome 3 Upper respiratory tract infection.
4 Abnormal vision Show forest plot	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.21, 18.98]
Open in figure viewer Analysis 1.4 Comparison 1 Topiramate versus placebo, Outcome 4 Abnormal vision.
5 Diarrhoea Show forest plot	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.21, 18.98]
Open in figure viewer Analysis 1.5 Comparison 1 Topiramate versus placebo, Outcome 5 Diarrhoea.

Open in table viewer

Comparison 2. Topiramate versus valproate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of responders (at least 50% seizure frequency reduction in myoclonic seizures) Show forest plot	1	23	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.67, 1.15]
Open in figure viewer Analysis 2.1 Comparison 2 Topiramate versus valproate, Outcome 1 Proportion of responders (at least 50% seizure frequency reduction in myoclonic seizures).
2 Proportion of responders (at least 50% seizure frequency reduction in PGTCS) Show forest plot	1	16	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.68, 2.21]
Open in figure viewer Analysis 2.2 Comparison 2 Topiramate versus valproate, Outcome 2 Proportion of responders (at least 50% seizure frequency reduction in PGTCS).
3 Number of participants with seizure‐free Show forest plot	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.61, 2.11]
Open in figure viewer Analysis 2.3 Comparison 2 Topiramate versus valproate, Outcome 3 Number of participants with seizure‐free.
4 Paraesthesia Show forest plot	2	61	Risk Difference (M‐H, Fixed, 95% CI)	0.19 [0.02, 0.35]
Open in figure viewer Analysis 2.4 Comparison 2 Topiramate versus valproate, Outcome 4 Paraesthesia.
5 Weight gain Show forest plot	2	61	Risk Difference (M‐H, Fixed, 95% CI)	‐0.30 [‐0.49, ‐0.10]
Open in figure viewer Analysis 2.5 Comparison 2 Topiramate versus valproate, Outcome 5 Weight gain.
6 Tremor Show forest plot	1	33	Risk Difference (M‐H, Fixed, 95% CI)	‐0.24 [‐0.45, ‐0.02]
Open in figure viewer Analysis 2.6 Comparison 2 Topiramate versus valproate, Outcome 6 Tremor.
7 Headache Show forest plot	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	2.37 [0.32, 17.42]
Open in figure viewer Analysis 2.7 Comparison 2 Topiramate versus valproate, Outcome 7 Headache.
8 Concentration difficulty Show forest plot	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.17, 11.83]
Open in figure viewer Analysis 2.8 Comparison 2 Topiramate versus valproate, Outcome 8 Concentration difficulty.
9 Fatigue Show forest plot	2	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.17, 2.21]
Open in figure viewer Analysis 2.9 Comparison 2 Topiramate versus valproate, Outcome 9 Fatigue.
10 Alopecia Show forest plot	2	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.06, 1.02]
Open in figure viewer Analysis 2.10 Comparison 2 Topiramate versus valproate, Outcome 10 Alopecia.
11 Dizziness Show forest plot	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.10, 9.13]
Open in figure viewer Analysis 2.11 Comparison 2 Topiramate versus valproate, Outcome 11 Dizziness.
12 Weight loss Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	0.11 [‐0.09, 0.30]
Open in figure viewer Analysis 2.12 Comparison 2 Topiramate versus valproate, Outcome 12 Weight loss.
13 Psychomotor slowing Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	0.11 [‐0.09, 0.30]
Open in figure viewer Analysis 2.13 Comparison 2 Topiramate versus valproate, Outcome 13 Psychomotor slowing.
14 Somnolence Show forest plot	2	61	Risk Difference (M‐H, Fixed, 95% CI)	0.08 [‐0.05, 0.21]
Open in figure viewer Analysis 2.14 Comparison 2 Topiramate versus valproate, Outcome 14 Somnolence.
15 Nausea Show forest plot	2	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.04, 1.18]
Open in figure viewer Analysis 2.15 Comparison 2 Topiramate versus valproate, Outcome 15 Nausea.
16 Appetite increase Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	‐0.22 [‐0.50, 0.05]
Open in figure viewer Analysis 2.16 Comparison 2 Topiramate versus valproate, Outcome 16 Appetite increase.
17 Insomnia Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	‐0.22 [‐0.50, 0.05]
Open in figure viewer Analysis 2.17 Comparison 2 Topiramate versus valproate, Outcome 17 Insomnia.
18 Abnormal vision Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	‐0.22 [‐0.50, 0.05]
Open in figure viewer Analysis 2.18 Comparison 2 Topiramate versus valproate, Outcome 18 Abnormal vision.
19 Rash Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	‐0.22 [‐0.50, 0.05]
Open in figure viewer Analysis 2.19 Comparison 2 Topiramate versus valproate, Outcome 19 Rash.
20 Anorexia Show forest plot	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	3.19 [0.37, 27.58]
Open in figure viewer Analysis 2.20 Comparison 2 Topiramate versus valproate, Outcome 20 Anorexia.
21 Hallucination Show forest plot	1	33	Risk Difference (M‐H, Fixed, 95% CI)	0.06 [‐0.09, 0.22]
Open in figure viewer Analysis 2.21 Comparison 2 Topiramate versus valproate, Outcome 21 Hallucination.
22 Diarrhoea Show forest plot	1	33	Risk Difference (M‐H, Fixed, 95% CI)	‐0.12 [‐0.30, 0.06]
Open in figure viewer Analysis 2.22 Comparison 2 Topiramate versus valproate, Outcome 22 Diarrhoea.

Figure 1

Study flow diagram.

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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 Topiramate versus placebo, Outcome 1 Proportion of responders (at least 50% seizure frequency reduction in PGTCS).

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Analysis 1.2

Comparison 1 Topiramate versus placebo, Outcome 2 Nausea.

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Analysis 1.3

Comparison 1 Topiramate versus placebo, Outcome 3 Upper respiratory tract infection.

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Analysis 1.4

Comparison 1 Topiramate versus placebo, Outcome 4 Abnormal vision.

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Analysis 1.5

Comparison 1 Topiramate versus placebo, Outcome 5 Diarrhoea.

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Analysis 2.1

Comparison 2 Topiramate versus valproate, Outcome 1 Proportion of responders (at least 50% seizure frequency reduction in myoclonic seizures).

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Analysis 2.2

Comparison 2 Topiramate versus valproate, Outcome 2 Proportion of responders (at least 50% seizure frequency reduction in PGTCS).

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Analysis 2.3

Comparison 2 Topiramate versus valproate, Outcome 3 Number of participants with seizure‐free.

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Analysis 2.4

Comparison 2 Topiramate versus valproate, Outcome 4 Paraesthesia.

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Analysis 2.5

Comparison 2 Topiramate versus valproate, Outcome 5 Weight gain.

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Analysis 2.6

Comparison 2 Topiramate versus valproate, Outcome 6 Tremor.

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Analysis 2.7

Comparison 2 Topiramate versus valproate, Outcome 7 Headache.

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Analysis 2.8

Comparison 2 Topiramate versus valproate, Outcome 8 Concentration difficulty.

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Analysis 2.9

Comparison 2 Topiramate versus valproate, Outcome 9 Fatigue.

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Analysis 2.10

Comparison 2 Topiramate versus valproate, Outcome 10 Alopecia.

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Analysis 2.11

Comparison 2 Topiramate versus valproate, Outcome 11 Dizziness.

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Analysis 2.12

Comparison 2 Topiramate versus valproate, Outcome 12 Weight loss.

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Analysis 2.13

Comparison 2 Topiramate versus valproate, Outcome 13 Psychomotor slowing.

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Analysis 2.14

Comparison 2 Topiramate versus valproate, Outcome 14 Somnolence.

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Analysis 2.15

Comparison 2 Topiramate versus valproate, Outcome 15 Nausea.

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Analysis 2.16

Comparison 2 Topiramate versus valproate, Outcome 16 Appetite increase.

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Analysis 2.17

Comparison 2 Topiramate versus valproate, Outcome 17 Insomnia.

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Analysis 2.18

Comparison 2 Topiramate versus valproate, Outcome 18 Abnormal vision.

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Analysis 2.19

Comparison 2 Topiramate versus valproate, Outcome 19 Rash.

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Analysis 2.20

Comparison 2 Topiramate versus valproate, Outcome 20 Anorexia.

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Analysis 2.21

Comparison 2 Topiramate versus valproate, Outcome 21 Hallucination.

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Analysis 2.22

Comparison 2 Topiramate versus valproate, Outcome 22 Diarrhoea.

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Topiramate compared with placebo for juvenile myoclonic epilepsy
Patient or population: people with juvenile myoclonic epilepsy Settings: 18 centers in the United States; 10 centers in Europe; 1 center in Costa Rica Intervention: topiramate Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Topiramate
Proportion of responders (at least 50% seizure frequency reduction in PGTCS)	182 per 1000	727 per 1000 (197 to 1000)	RR 4.00 (1.08 to 14.75)	22 (1 study)	⊕⊝⊝⊝ very low^1,2	More participants taking topiramate responded with a 50% or more reduction in PGTCS compared with placebo (P = 0.03)
Proportion of participants who experienced at least one AE and individual AEs	See comment	See comment	NA	22 (1 study)	⊕⊝⊝⊝ very low^1,2	Number of participants experiencing at least one AE was not reported. Individual AEs: no significant differences were found in nausea, upper respiratory tract infection, abnormal vision, or diarrhoea between topiramate versus placebo
Number of participants who were seizure‐free	Not reported	Not reported	NA
The basis for the assumed risk* was the event rate in the control group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AE: Adverse event;CI: Confidence interval; RR: Risk Ratio; URTI: Upper respiratory tract infection
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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: We are very uncertain about the estimate.
¹ The included trials were reported as randomized, double‐blind trials with insufficient methodological information ² A relatively small number of patients

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Topiramate compared with valproate for juvenile myoclonic epilepsy
Patient or population: people with juvenile myoclonic epilepsy Settings: Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; Haeundae Paik Hospital, Busan, Republic of Korea Intervention: topiramate Comparison: valproate
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Valproate	Topiramate
Proportion of responders (at least 50% seizure frequency reduction in myoclonic seizures)	1000 per 1000	857 per 1000 (670 to 1000)	RR 0.88 (0.67 to 1.15)	28 (1 study)	⊕⊝⊝⊝ very low^1,2	No significant difference was found
Proportion of responders (at least 50% seizure frequency reduction in PGTCS)	750 per 1000	917 per 1000 (510 to 1000)	RR 1.22 (0.68 to 2.21)	28 (1 study)	⊕⊝⊝⊝ very low^1,2	No significant difference was found
Proportion of participants who experienced at least one AE and individual AEs	See comment	See comment	NA	61 (2 studies)	⊕⊝⊝⊝ very low^1,2	Number of participants experiencing at least one AE was not reported. In Levisohn 2007 and Park 2013, we found significant differences in the AEs of paraesthesia, weight gain and tremor. Moreover, no significant difference was found in headache, concentration difficulty, fatigue, alopecia, dizziness, weight loss, psychomotor slowing, somnolence, nausea, appetite increase, insomnia, abnormal vision, rash, anorexia, hallucination or diarrhoea.
Number of participants who were seizure‐free	563 per 1000	636 per 1000 (343 to 1188)	RR 1.13 (0.61 to 2.11)	33 (1 study)	⊕⊝⊝⊝ very low^1,2	No significant difference was found (P = 0.08)
The basis for the assumed risk* was the event rate in the control group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AE: Adverse event; CI: Confidence interval; RR: Risk Ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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: We are very uncertain about the estimate.
¹ The included trials were reported as randomized, double‐blind trials with insufficient methodological information ² A relatively small number of patients

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Comparison 1. Topiramate versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of responders (at least 50% seizure frequency reduction in PGTCS) Show forest plot	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [1.08, 14.75]

2 Nausea Show forest plot	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.52, 5.33]

3 Upper respiratory tract infection Show forest plot	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	1.5 [0.31, 7.30]

4 Abnormal vision Show forest plot	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.21, 18.98]

5 Diarrhoea Show forest plot	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.21, 18.98]

Comparison 1. Topiramate versus placebo

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Comparison 2. Topiramate versus valproate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of responders (at least 50% seizure frequency reduction in myoclonic seizures) Show forest plot	1	23	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.67, 1.15]

2 Proportion of responders (at least 50% seizure frequency reduction in PGTCS) Show forest plot	1	16	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.68, 2.21]

3 Number of participants with seizure‐free Show forest plot	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.61, 2.11]

4 Paraesthesia Show forest plot	2	61	Risk Difference (M‐H, Fixed, 95% CI)	0.19 [0.02, 0.35]

5 Weight gain Show forest plot	2	61	Risk Difference (M‐H, Fixed, 95% CI)	‐0.30 [‐0.49, ‐0.10]

6 Tremor Show forest plot	1	33	Risk Difference (M‐H, Fixed, 95% CI)	‐0.24 [‐0.45, ‐0.02]

7 Headache Show forest plot	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	2.37 [0.32, 17.42]

8 Concentration difficulty Show forest plot	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.17, 11.83]

9 Fatigue Show forest plot	2	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.17, 2.21]

10 Alopecia Show forest plot	2	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.06, 1.02]

11 Dizziness Show forest plot	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.10, 9.13]

12 Weight loss Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	0.11 [‐0.09, 0.30]

13 Psychomotor slowing Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	0.11 [‐0.09, 0.30]

14 Somnolence Show forest plot	2	61	Risk Difference (M‐H, Fixed, 95% CI)	0.08 [‐0.05, 0.21]

15 Nausea Show forest plot	2	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.04, 1.18]

16 Appetite increase Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	‐0.22 [‐0.50, 0.05]

17 Insomnia Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	‐0.22 [‐0.50, 0.05]

18 Abnormal vision Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	‐0.22 [‐0.50, 0.05]

19 Rash Show forest plot	1	28	Risk Difference (M‐H, Fixed, 95% CI)	‐0.22 [‐0.50, 0.05]

20 Anorexia Show forest plot	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	3.19 [0.37, 27.58]

21 Hallucination Show forest plot	1	33	Risk Difference (M‐H, Fixed, 95% CI)	0.06 [‐0.09, 0.22]

22 Diarrhoea Show forest plot	1	33	Risk Difference (M‐H, Fixed, 95% CI)	‐0.12 [‐0.30, 0.06]

Comparison 2. Topiramate versus valproate

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Referencias

References to studies included in this review

Biton 2005 {published data only}

Levisohn 2007 {published data only}

Park 2013 {published data only}

References to studies excluded from this review

Sousa Pda 2005 {published data only}

Additional references

Alfradique 2007

Biton 1999

Calleja 2001

Elbourne 2002

Guberman 2002

Hanaya 1998

Higgins 2011

Jallon 2005

Janz 1985

Kirkham 2010

Lefebvre 2011

Montouris 2009

Panayiotopoulos 1991

RevMan 2014 [Computer program]

Sachdeo 1999

Sharpe 2008

White 2000

Zona 1997

References to other published versions of this review

Liu J

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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