Intervention Review

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Sulthiame monotherapy for epilepsy

  1. Philip Milburn-McNulty1,*,
  2. Graham Powell1,
  3. Graeme J Sills2,
  4. Anthony G Marson2

Editorial Group: Cochrane Epilepsy Group

Published Online: 9 MAR 2014

Assessed as up-to-date: 24 OCT 2013

DOI: 10.1002/14651858.CD010062.pub2


How to Cite

Milburn-McNulty P, Powell G, Sills GJ, Marson AG. Sulthiame monotherapy for epilepsy. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD010062. DOI: 10.1002/14651858.CD010062.pub2.

Author Information

  1. 1

    The Walton Centre for Neurology & Neurosurgery NHS Foundation Trust, Liverpool, UK

  2. 2

    Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK

*Philip Milburn-McNulty, The Walton Centre for Neurology & Neurosurgery NHS Foundation Trust, Lower Lane, Fazakerley, Liverpool, L9 7LJ, UK. philmilburnmcnulty@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 9 MAR 2014

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Characteristics of included studies [ordered by study ID]
Basnec 2005

MethodsPlacebo-controlled, parallel-group, double-blind randomised controlled trial


ParticipantsParticipants between three and 11 years of age with a diagnosis of BECTS who had experienced only one seizure and had received no AED

34 participants were randomly assigned. Unclear how many participants were allocated to each group

Males versus females—not stated


InterventionsSulthiame versus placebo


OutcomesProportion of participants withdrawing from treatment

Proportion of participants experiencing a second seizure within six months

Proportion of participants experiencing a second seizure after six months

Proportion of participants experiencing status epilepticus


NotesAt the time of publication of this review, a full-text English translation is unavailable, and the above information is taken from the English translation of the abstract only


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskUnable to fully assess risk of bias because of lack of English language full-text manuscript

Allocation concealment (selection bias)Unclear riskUnable to fully assess risk of bias because of lack of English language full-text manuscript

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskUnable to fully assess risk of bias because of lack of English language full-text manuscript

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnable to fully assess risk of bias because of lack of English language full-text manuscript

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnable to fully assess risk of bias because of lack of English language full-text manuscript

Selective reporting (reporting bias)Unclear riskUnable to fully assess risk of bias because of lack of English language full-text manuscript

Other biasUnclear riskUnable to fully assess risk of bias because of lack of English language full-text manuscript

Li 2000

MethodsActive-controlled, parallel-group, double-blind randomised controlled trial with a third group receiving sulthiame openly

No historical baseline period, six-month treatment phase


ParticipantsParticipants with generalised tonic-clonic seizures who had experienced a seizure within three to six months of the study start date

Number of participants randomly assigned: 146

Number of participants in each group: intervention group: 32 (18 [56%] males and 14 [44%] females); control group: 32 (17 [53%] males and 15 [47%] females); open group: 82 (57 [70%] males and 25 [30%] females)

Mean (SD) age, years: intervention group: 29.53 (15.09); control group: 34.91 (15.12): open group: 27.69 (16.76)


InterventionsSulthiame (100 to 200 mg/d) versus phenytoin (100 mg TDS)


OutcomesAdverse effects

Treatment response defined as

  • Markedly improved: > 75% decrease in seizure frequency
  • Effective: 51% to 75% decrease in seizure frequency
  • Improved: 26% to 50% decrease in seizure frequency
  • Invalid or worsening: < 25% reduction in seizure frequency


Laboratory tests prestudy and poststudy

  • Blood count
  • Liver function
  • Kidney function
  • ECG
  • EEG


NotesThis paper provides no information regarding participants withdrawing from the trial after randomisation. All participants were subsequently included in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskMethod of randomisation not stated. High proportion of males versus females in open group

Allocation concealment (selection bias)High riskMethod of allocation concealment not stated

Blinding of participants and personnel (performance bias)
All outcomes
High riskMethod of blinding not stated

Blinding of outcome assessment (detection bias)
All outcomes
High riskMethod of blinding not stated

Incomplete outcome data (attrition bias)
All outcomes
High riskNo data provided on participants withdrawing from treatment

Selective reporting (reporting bias)High riskNo data on proportion of participants with a reduction in seizure frequency of 50% or greater, proportion of participants seizure free at 12 months or quality of life scale scores. Data provided on adverse effects include blinded and unblinded participants. It is unclear whether data provided on adverse effects is on number of events or number of participants experiencing an adverse effect.

Other biasHigh riskIncomplete information on inclusion and exclusion criteria and on combination of treatment and open groups when analysis of adverse effects was performed; separate data for the intervention group alone not provided

Rating 1999

MethodsPlacebo-controlled, parallel-group, double-blind randomised controlled trial

Six-month historical baseline followed by six-month treatment phase


ParticipantsParticipants between three and 10 years of age with a diagnosis of BECTS and at least two seizures in the past six months

Number of participants randomly assigned: 66

Number of participants in each group: intervention group: 31 (16 [52%] males and 15 [48%] females); control group: 35 (24 [69%] males and 11 [31%] females)

Median (range) age, years: intervention group: 8.2 (3.9 to 10.7); control group: 8.4 (3.1 to 10.3)


InterventionsSulthiame (5 mg/kg/d) versus placebo


OutcomesAdverse effects

Proportion of participants in each group seizure free at six months

Proportion of participants in each group experiencing a seizure during treatment period

Proportion of participants withdrawing from treatment

Proportion of participants withdrawing from treatment because of adverse effects

Comparison of EEG prestudy and poststudy defined by the following groups

  • No normalisation
  • Transient normalisation
  • Constant normalisation


Notes31 participants (six from the intervention group and 25 from the control group) withdrew from the study

  • Four participants from the intervention group withdrew because of seizure
  • Two participants from the intervention group withdrew because of early termination of the study
  • 21 participants from the control group withdrew because of seizure
  • Two participants from the control group withdrew because of withdrawal of parental consent
  • Two participants from the control group withdrew because of early termination of the study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskProvides partial explanation of how participants were allocated to each group. High proportion of males versus females in open group

Allocation concealment (selection bias)Low riskProvides clear explanation of how allocation was concealed

Blinding of participants and personnel (performance bias)
All outcomes
Low riskProvides clear explanation of blinding process

Blinding of outcome assessment (detection bias)
All outcomes
Low riskProvides clear explanation of blinding process

Incomplete outcome data (attrition bias)
All outcomes
High riskProvides number of participants withdrawing from treatment but does not state whether intention-to-treat analysis was performed

Selective reporting (reporting bias)High riskNo data on proportion of participants with a reduction in seizure frequency of 50% or greater, proportion of participants seizure free at 12 months or quality of life scale scores. Incomplete data on adverse effects

Other biasLow riskInclusion and exclusion criteria clearly stated

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Debus 2004STM used as add-on therapy in the intervention group

Griffiths 1964Not a randomised controlled trial

Groppa 2006Study on the effect of STM as monotherapy on axonal excitability of cortical neurons in participants with no history of epilepsy

Ingram 1963Not a randomised controlled trial

Livingston 1967Not a randomised controlled trial

Moffat 1970Study assessing the effects of STM on aggressive behaviour in both epileptic and non-epileptic participants

 
Characteristics of ongoing studies [ordered by study ID]
ISRCTN66730162

Trial name or titleInvestigating the relationship between sleep disturbance and learning in children with Benign Epilepsy of Childhood with Centrotemporal Spikes (BECCTS): a randomised double blind placebo controlled crossover trial

MethodsRandomised, double-blind, placebo-controlled, cross-over trial. Six-week treatment period (period A), followed by two-week washout period, followed by six weeks of alternate treatment (period B)

ParticipantsInclusion criteria

  • Male and female children six to 16 years of age
  • Within six months of diagnosis with BECCTS and onset of symptoms
  • With clinical electroencephalographic (EEG) characteristics consistent with typical BECCTS
  • With no current or prior treatment for BECCTS
  • Signed informed (parental) consent


Exclusion criteria

  • Inability to comply with assessments
  • Any serious intercurrent illness or uncontrolled disease that could compromise participation in the study
  • With contraindications for treatment with sulthiame


    • History of hypersensitivity to sulphonamides
    • History of acute porphyria
    • History of hyperthyroidism
    • History of arterial hypertension
    • Impaired renal function
    • Psychiatric disorder
    • Hereditary galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption syndrome

InterventionsSulthiame versus placebo

Outcomes
  • Frequency of interictal epileptic discharges (IEDs) during slow wave sleep (SWS) on active treatment, relative to placebo, as measured by EEG at baseline, end of treatment period A and end of treatment period B
  • Sleep quality (efficiency, number of awakenings, density of sleep spindles and percentage rapid eye movement (REM) and percentage SWS on polysomnography) on active treatment relative to placebo, as measured at baseline, end of treatment period A and end of treatment period B
  • Performance on consolidation of learning (CoL) tasks on active treatment, relative to placebo, as measured (by validated CoL tools) at baseline, end of treatment period A and end of treatment period B
  • Performance on cognitive assessments including IQ and event-related potential (ERP) utilising the commonly employed auditory oddball paradigm as a measure of basic sensory processing and attention, as measured at baseline, end of treatment period A and end of treatment period B

Starting date13 July 2011

Contact informationfinbar.ocallaghan@bristol.ac.uk

Notes

ISRCTN97864911

Trial name or titleHead-to-head evaluation of the antiepileptic drugs, levetiracetam versus sulthiame, in a German multicentre, double-blind, controlled trial in children with benign epilepsy with centrotemporal spikes

MethodsRandomised, double-blind, active-controlled, parallel trial. Six-month treatment period

ParticipantsInclusion criteria

  • Age between five and 14 years
  • Weight between 15 kg and 60 kg
  • At least two preceding seizures within the last six months before study start
  • Typical electroencephalogram (EEG) with Rolando focus (centrotemporal spike or sharp-wave focus)
  • Diagnosis of BECTS
  • Written informed consent from parents and child (if child is 8 years of age or older)


Exclusion criteria

  • Other forms of epilepsy (e.g. continuous spikes and waves during slow sleep (CSWS), Landau-Kleffner syndrome)
  • Preceding treatment with antiepileptic drugs
  • Mental retardation (intelligence quotient (IQ) < 85)
  • Focal neurological deficit
  • Relevant major internistic disease (e.g. hepatopathy, nephropathy, endocrinopathy)
  • Participation in another clinical trial within the last 30 days

InterventionsSulthiame versus levetiracetam

OutcomesPrimary outcome

  • "To evaluate the efficacy of levetiracetam in the treatment of children with BECTS compared to sulthiame". No further information on the primary outcome of this study is given


Secondary outcomes

  • Safety and tolerability
  • Efficacy on EEG pattern
  • Cognitive effects

Starting date1 June 2006

Contact informationflorian.heinen@med.uni-muenchen.de

Notes

 
Comparison 1. Adverse effects (numbers of events)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All adverse effects—sulthiame versus phenytoin1146Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.54, 2.07]

 2 Paraesthesia—sulthiame versus phenytoin1146Risk Ratio (M-H, Fixed, 95% CI)8.32 [0.51, 135.82]

 3 Dizziness—sulthiame versus phenytoin1146Risk Ratio (M-H, Fixed, 95% CI)3.16 [0.18, 55.62]

 4 Headache—sulthiame versus phenytoin1146Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.07, 29.15]

 5 Anorexia—sulthiame versus phenytoin1146Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.07, 2.41]

 6 Rash—sulthiame versus phenytoin1146Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.02, 4.36]

 7 Gingival hyperplasia—sulthiame versus phenytoin1146Risk Ratio (M-H, Fixed, 95% CI)0.03 [0.00, 0.58]

 8 Other—sulthiame versus phenytoin1146Risk Ratio (M-H, Fixed, 95% CI)1.40 [0.17, 11.59]

 
Summary of findings for the main comparison.

Sulthiame compared with placebo or phenytoin for epilepsy

Patient or population: participants with epilepsy

Settings: hospital

Intervention: sulthiame

Comparison: placebo or phenytoin

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlSulthiame

All adverse effectssulthiame versus placebo

(benign epilepsy of childhood with centrotemporal spikes)

Six months
943 per 10001935 per 1000Not estimableOne (66)⊕⊕⊝⊝
low
Single, small study. Data for number of adverse events provided, however, no data on number of participants experiencing adverse events provided.

All adverse effectssulthiame versus phenytoin

(generalised tonic-clonic seizures)

Six months
250 per 1000263 per 1000RR 1.05 (0.54 to 2.07)One (146)⊕⊝⊝⊝
very low
High risk of selection, performance, detection, attrition and reporting bias Inclusion of group with disproportionately large number of males. Unclear if data on adverse events reflects number of events or number of participants experiencing an event.

Paraesthesiasulthiame versus phenytoin

(generalised tonic-clonic seizures)

Six months
Zero per 1000123 per 1000RR 8.32 (0.51 to 135.82)One (146)⊕⊝⊝⊝
very low
High risk of selection, performance, detection, attrition and reporting bias Inclusion of group with disproportionately large number of males. Unclear if data on adverse events reflects number of events or number of participants experiencing an event.

Dizzinesssulthiame versus phenytoin

Six months
Zero per 100044 per 1000RR 3.16 (0.18 to 55.62)One (146)⊕⊝⊝⊝
very low
High risk of selection, performance, detection, attrition and reporting bias Inclusion of group with disproportionately large number of males. Unclear if data on adverse events reflects number of events or number of participants experiencing an event.

Headachesulthiame versus phenytoin

(generalised tonic-clonic seizures)

Six months
Zero per 100018 per 1000RR 1.43 (0.07 to 2.41)One (146)⊕⊝⊝⊝
very low
High risk of selection, performance, detection, attrition and reporting bias Inclusion of group with disproportionately large number of males. Unclear if data on adverse events reflects number of events or number of participants experiencing an event.

Anorexiasulthiame versus phenytoin

(generalised tonic-clonic seizures)

Six months
63 per 100026 per 1000RR 0.42 (0.07 to 2.41)One (146)⊕⊝⊝⊝
very low
High risk of selection, performance, detection, attrition and reporting bias Inclusion of group with disproportionately large number of males. Unclear if data on adverse events reflects number of events or number of participants experiencing an event.

Rashsulthiame versus phenytoin

(generalised tonic-clonic seizures)

Six months
31 per 10009 per 1000RR 0.28 (0.02 to 4.36)One (146)⊕⊝⊝⊝
very low
High risk of selection, performance, detection, attrition and reporting bias Inclusion of group with disproportionately large number of males. Unclear if data on adverse events reflects number of events or number of participants experiencing an event.

Gingival hyperplasiasulthiame versus phenytoin

(generalised tonic-clonic seizures)

Six months
125 per 1000Zero per 1000RR 0.03 (0.00 to 0.58)One (146)⊕⊝⊝⊝
very low
High risk of selection, performance, detection, attrition and reporting bias Inclusion of group with disproportionately large number of males. Unclear if data on adverse events reflects number of events or number of participants experiencing an event.

Othersulthiame versus phenytoin

(generalised tonic-clonic seizures)

Six months
31 per 100044 per 1000RR 1.4 (0.17 to 11.59)One (146)⊕⊝⊝⊝
very low
High risk of selection, performance, detection, attrition and reporting bias Inclusion of group with disproportionately large number of males. Unclear if data on adverse events reflects number of events or number of participants experiencing an event.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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).
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.