Sulthiame add‐on therapy for epilepsy

Rebecca Bresnahan; Kirsty J Martin‐McGill; Philip Milburn‐McNulty; Graham Powell; Graeme J Sills; Anthony G Marson

doi:10.1002/14651858.CD009472.pub4

Tratamiento complementario con sultiame para la epilepsia

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Referencias

References to studies included in this review

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Debus OM, Kurlemann G. Sulthiame in the primary therapy of West syndrome: a randomized, double‐blind placebo‐controlled add‐on trial on baseline pyridoxine medication. Epilepsia 2004;45(2):103‐8.

References to studies excluded from this review

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otras referencias
otras versiones publicadas

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Additional references

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Ben‐Zeev B, Watemberg N, Lerman P, Barash I, Brand N, Lerman‐Sagie T. Sulthiame in childhood epilepsy. Paediatrics International 2004;46(5):521‐4.

Brodie MJ, Dichter MA. Antiepileptic drugs. New England Journal of Medicine 1996;334(3):168‐75.

Caraballo RH, Flesler S, Reyes VG, Fortini S, Chacón S, Ross L, et al. Sulthiame add‐on therapy in children with Lennox‐Gastaut syndrome: a study of 44 patients. Seizure: European Journal of Epilepsy 2018;62:55‐8.

Chahem J, Bauer J. Treatment of epilepsy with third‐line antiepileptic drugs. Felbamate, tiagabine, and sulthiame. Der Nervenarzt 2007;78(12):1407‐12.

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Swiderska N, Hawcutt D, Eaton V, Stockton F, Kumar R, Kneen R, et al. Sulthiame in refractory paediatric epilepsies: an experience of an 'old' antiepileptic drug in a tertiary paediatric neurology unit. Seizure 2011;20(10):805‐8.

Weissbach A, Tirosh I, Scheuerman O, Hoffer V, Garty BZ. Respiratory alkalosis and metabolic acidosis in a child treated with sulthiame. Pediatric Emergency Care 2010;26(10):752‐3.

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Wirrel E, Sherman EMS, Vanmastrigt R, Hamiwka L. Deterioration in cognitive function in children with benign epilepsy of childhood with central temporal spikes treated with sulthiame. Journal of Child Neurology 2008;23(1):14‐21.

References to other published versions of this review

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estudios incluidos
estudios excluidos
otras referencias

Milburn‐McNulty P, Powell G, Sills GJ, Marson AG. Sulthiame add‐on therapy for epilepsy. Cochrane Database of Systematic Reviews 2011, Issue 12. [DOI: 10.1002/14651858.CD009472]

Milburn‐McNulty P, Powell G, Sills GJ, Marson AG. Sulthiame add‐on therapy for epilepsy. Cochrane Database of Systematic Reviews 2013, Issue 3. [DOI: 10.1002/14651858.CD009472.pub2]

Milburn‐McNulty P, Powell G, Sills GJ, Marson AG. Sulthiame add‐on therapy for epilepsy. Cochrane Database of Systematic Reviews 2015, Issue 10. [DOI: 10.1002/14651858.CD009472.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Debus 2004

Methods	Double‐blind, randomised, placebo‐controlled parallel study
Participants	37 participants (sulthiame: N = 20; placebo: N = 17) Mean age (range): 7.7 months (3 to 15 months) Type of epilepsy: West syndrome
Interventions	All participants received PDX (150 to 300 mg/kg/day) only, during the first 3 days of the study On day 4, sulthiame 5 mg/kg/day was added to the intervention group, and placebo was added to the control On day 7, the dose of sulthiame and placebo were doubled in participants who had not achieved complete cessation of seizures ('non‐responders')
Outcomes	Complete cessation of seizure activity during 9‐day study Adverse effects for entire trial population Adverse effects for entire population ‐ somnolence
Notes	Trial funded by DESITIN Pharma (Hamburg, Germany)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation by roll of dice.
Allocation concealment (selection bias)	Low risk	Allocation concealed in sealed envelope for duration of study.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Method not stated.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Method not stated.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis performed.
Selective reporting (reporting bias)	High risk	Incomplete data reported for time to treatment withdrawal and adverse effects.
Other bias	Unclear risk	Baseline period was not defined. Limited participant demographic data provided.

PDX: pyridoxine

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos

Study	Reason for exclusion
Basnec 2005	Sulthiame used as monotherapy in intervention group
Bast 2003	Sulthiame used as monotherapy in intervention group
Borggraefe 2013	Sulthiame used as monotherapy in intervention group
Griffiths 1964	Not a randomised controlled trial
Ingram 1963	Not a randomised controlled trial
ISRCTN66730162	Sulthiame used as monotherapy in intervention group
Li 2000	Sulthiame used as monotherapy in intervention group
Livingston 1967	Not a randomised controlled trial
Moffat 1970	Study assessing the effects of sulthiame on aggressive behaviour in both epileptic and non‐epileptic participants
Rating 2000	Sulthiame used as monotherapy in the intervention group
Siniatchkin 2006	Study on the effect of sulthiame as monotherapy on axonal excitability of cortical neurons in subjects with no history of epilepsy

Data and analyses

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Comparison 1. Sulthiame add‐on versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cessation of seizures Show forest plot	1	37	Risk Ratio (M‐H, Fixed, 95% CI)	11.14 [0.67, 184.47]
Open in figure viewer Analysis 1.1 Comparison 1 Sulthiame add‐on versus placebo, Outcome 1 Complete cessation of seizures.
2 Adverse effects ‐ Total number of participants experiencing one or more adverse effects Show forest plot	1	37	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.44, 1.64]
Open in figure viewer Analysis 1.2 Comparison 1 Sulthiame add‐on versus placebo, Outcome 2 Adverse effects ‐ Total number of participants experiencing one or more adverse effects.
3 Adverse effects ‐ Somnolence Show forest plot	1	37	Risk Ratio (M‐H, Fixed, 95% CI)	3.4 [0.42, 27.59]
Open in figure viewer Analysis 1.3 Comparison 1 Sulthiame add‐on versus placebo, Outcome 3 Adverse effects ‐ Somnolence.

Figure 1

Study flow diagram

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Figure 2

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 Sulthiame add‐on versus placebo, Outcome 1 Complete cessation of seizures.

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Analysis 1.2

Comparison 1 Sulthiame add‐on versus placebo, Outcome 2 Adverse effects ‐ Total number of participants experiencing one or more adverse effects.

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Analysis 1.3

Comparison 1 Sulthiame add‐on versus placebo, Outcome 3 Adverse effects ‐ Somnolence.

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Summary of findings for the main comparison. Sulthiame add‐on compared to placebo for epilepsy (event)

Sulthiame add‐on compared to placebo for epilepsy
Patient or population: patients between 3 to 15 months of age with West syndrome Setting: inpatient Intervention: sulthiame as add‐on therapy to pyridoxine Comparison: placebo as add‐on therapy to pyridoxine
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with Sulthiame add‐on
50% or greater reduction in seizure frequency						Outcome was not reported by Debus 2004
Complete cessation of seizures during follow‐up Follow‐up: 9 days	Study population		RR 11.14 (0.67 to 184.47)	37 (1 RCT)	⊕⊝⊝⊝ VERY LOW^a,b,c
	0 per 1,000	0 per 1000 (0 to 0)
Mean seizure frequency						Outcome was not reported by Debus 2004
Time‐to‐treatment withdrawal						Outcome was not reported by Debus 2004
Adverse effects: total number of participants experiencing one or more adverse effects Follow‐up: 9 days	Study population		RR 0.85 (0.44 to 1.64)	37 (1 RCT)	⊕⊝⊝⊝ VERY LOW^a,b
	529 per 1,000	450 per 1000 (233 to 868)
Adverse effects: somnolence Follow‐up: 9 days	Study population		RR 3.40 (0.42 to 27.59)	37 (1 RCT)	⊕⊝⊝⊝ VERY LOW^a,b,d
	59 per 1,000	200 per 1000 (25 to 1000)
Quality of life						Outcome was not reported by Debus 2004
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aDowngraded once for risk of bias: Debus 2004 did not describe how blinding was achieved or maintained, and we suspected reporting bias for the adverse effect outcomes. ^bDowngraded twice for imprecision: small study population, therefore, the number of events failed to suffice optimal information size. ^cEvidence was not upgraded for effect size: normally, the evidence would be upgraded twice when a RR is greater than 5.00, however, due to the concerns regarding risk of bias and small sample size, we were unable to upgrade the evidence. ^dEvidence was not upgraded for effect size: normally, the evidence would be upgraded once when a RR is greater than 2.00, however, due to the concerns regarding risk of bias and small sample size, we were unable to upgrade the evidence.

Summary of findings for the main comparison. Sulthiame add‐on compared to placebo for epilepsy (event)

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Comparison 1. Sulthiame add‐on versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cessation of seizures Show forest plot	1	37	Risk Ratio (M‐H, Fixed, 95% CI)	11.14 [0.67, 184.47]

2 Adverse effects ‐ Total number of participants experiencing one or more adverse effects Show forest plot	1	37	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.44, 1.64]

3 Adverse effects ‐ Somnolence Show forest plot	1	37	Risk Ratio (M‐H, Fixed, 95% CI)	3.4 [0.42, 27.59]

Comparison 1. Sulthiame add‐on versus placebo

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Referencias

References to studies included in this review

Debus 2004 {published and unpublished data}

References to studies excluded from this review

Basnec 2005 {published data only}

Bast 2003 {published data only}

Borggraefe 2013 {published data only}

Griffiths 1964 {published data only}

Ingram 1963 {published data only}

ISRCTN66730162 {published data only}

Li 2000 {published data only}

Livingston 1967 {published data only}

Moffat 1970 {published data only}

Rating 2000 {published data only}

Siniatchkin 2006 {published data only}

Additional references

Ben‐Zeev 2004

Brodie 1996

Caraballo 2018

Chahem 2007

Engler 2003

Go 2005

GRADEpro 2015 [Computer program]

Gross‐Selbeck 2001

Higgins 2011

Hrachovy 1991

International League Against Epilepsy 1997

Koepp 2002

Kwan 2010

Lefebvre 2011

Leniger 2002

Miyajima 2009

RevMan 2014 [Computer program]

Sander 1993

Schmidt 1995

Schünemann 2013

Sterne 2011

Swiderska 2011

Weissbach 2010

WHO 2019

Wirrell 2008

References to other published versions of this review

Milburn‐McNulty 2011

Milburn‐McNulty 2013

Milburn‐McNulty 2015

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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