Sulthiame add-on therapy for epilepsy

  • Review
  • Intervention

Authors


Abstract

Background

Epilepsy is a common neurological condition characterised by recurrent seizures. Most patients respond to conventional antiepileptic drugs, however, around 30% will continue to experience seizures despite multiple antiepileptic drugs. Sulthiame is a widely used antiepileptic drug in Europe and Israel. We present a summary of the evidence for the use of sulthiame as add-on therapy in epilepsy.

Objectives

To compare the efficacy and side-effect profile of sulthiame as add-on therapy compared with placebo or another antiepileptic drug.

Search methods

We searched the Cochrane Epilepsy Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and the WHO IRCTRP Search Portal on 28th August 2012. No language restrictions were imposed. We contacted the manufacturers of sulthiame and researchers in the field to seek any ongoing or unpublished studies.

Selection criteria

Randomised placebo-controlled add-on trials of sulthiame in people of any age with epilepsy of any aetiology.

Data collection and analysis

Two review authors independently selected trials for inclusion and extracted relevant data. The following outcomes were assessed: (1) reduction in seizure frequency of 50% or greater between baseline and end of follow-up (2) complete cessation of seizures during follow-up (3) mean seizure frequency (4) time to treatment withdrawal (5) adverse drug effects (6) quality of life scoring. Primary analyses were intention-to-treat. Narrative analysis is presented.

Main results

One trial was included representing 37 patients with a new diagnosis of West syndrome. Sulthiame was given as an add-on therapy to pyridoxine. No data were reported for outcomes (1), (3) or (6). Overall risk ratio (RR) with 95% confidence intervals (CI) for complete cessation of seizures during a nine-day follow-up period versus placebo was 0.71 (95% CI 0.53 to 0.96). Meaningful analysis of time to treatment withdrawal and adverse drug effects was impossible due to incomplete data.

Authors' conclusions

Sulthiame may lead to a cessation of seizures when used as an add-on therapy to pyridoxine in patients with West syndrome. The included study was small and had a significant risk of bias which limits the impact of the evidence. No conclusions can be drawn on the occurrence of adverse drug effects, change in quality of life or mean reduction in seizure frequency. No evidence exists for the use of sulthiame as an add-on therapy in patients with epilepsy outside West syndrome. Large, multi-centre randomised controlled trials are necessary to inform clinical practice if sulthiame is to be used as an add-on therapy for epilepsy.

Résumé scientifique

Le sultiame comme traitement associé dans l'épilepsie

Contexte

L'épilepsie est une maladie neurologique courante caractérisée par des convulsions récurrentes. La plupart des patients répondent aux médicaments antiépileptiques conventionnels, toutefois, environ 30 % continueront à subir des crises convulsives malgré les nombreux médicaments antiépileptiques. Le sultiame est un médicament antiépileptique couramment utilisé en Europe et en Israël. Nous présentons un résumé des données concernant l'utilisation du sultiame comme traitement associé dans l'épilepsie.

Objectifs

Comparer l'efficacité et le profil d'effets secondaires du sultiame comme traitement associé comparativement à un placebo ou un autre médicament antiépileptique.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur l'épilepsie, le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE et le portail de recherche d'essais cliniques du système d'enregistrement international des essais cliniques de l'OMS (IRCTRP) le 28 août 2012. Aucune restriction de langue n'a été imposée. Nous avons contacté les fabricants du sultiame et des chercheurs dans ce domaine pour obtenir d'éventuelles études en cours ou non publiées.

Critères de sélection

Des essais contrôlés par placebo, randomisés, portant sur le sultiame comme traitement associé chez des personnes de tout âge atteintes d'épilepsie quelle qu'en soit l'étiologie.

Recueil et analyse des données

Deux auteurs de la revue ont sélectionné les essais à inclure et extrait les données pertinentes de façon indépendante. Les critères de jugement suivants ont été évalués : (1) la réduction de la fréquence des crises convulsives de 50 % ou plus entre l'inclusion dans l'étude et la fin du suivi, (2) la cessation complète des crises convulsives durant le suivi, (3) la fréquence moyenne des crises convulsives, (4) le délai jusqu'à l'arrêt du traitement, (5) les effets indésirables liés au médicament, (6) les scores de qualité de vie. Les analyses principales ont été effectuées en intention de traiter. Une analyse narrative est présentée.

Résultats principaux

Un essai a été inclus représentant 37 patients avec un nouveau diagnostic de syndrome de West. Le sultiame a été administré comme traitement associé à la pyridoxine. Aucune donnée n'a été rapportée pour les résultats (1), (3) ou (6). Le risque relatif (RR) global avec un intervalle de confiance (IC) à 95 % pour la cessation complète des crises convulsives durant une période de suivi de neuf jours comparé au placebo était de 0,71 (IC à 95 % 0,53 à 0,96). L'analyse significative du délai jusqu'à l'arrêt du traitement et des effets indésirables liés au médicament n'a pas été possible en raison des données incomplètes.

Conclusions des auteurs

Le sultiame est susceptible d'entraîner la cessation des crises convulsives lorsqu'il est administré comme traitement associé à la pyridoxine chez des patients atteints du syndrome de West. L'étude incluse était à petite échelle et comportait un risque significatif de biais qui limite l'impact des preuves. Aucune conclusion ne peut être tirée sur l'occurrence des effets indésirables liés au médicament, le changement de la qualité de vie ou la réduction moyenne de la fréquence des crises d'épilepsie. Il n'existe aucune preuve concernant l'utilisation du sultiame comme traitement associé chez des patients atteints d'épilepsie sans rapport avec le syndrome de West. Il est nécessaire de réaliser des essais contrôlés randomisés, multicentriques, à grande échelle, pour orienter la pratique clinique si le sultiame doit être utilisé comme traitement associé dans l'épilepsie.

Plain language summary

Sulthiame add-on therapy for epilepsy

Epilepsy is a common neurological condition which is characterised by recurrent seizures. The majority of patients respond well to conventional antiepileptic drugs although 30% will not achieve remission. Sulthiame is an antiepileptic drug that is used widely in some European countries and in Israel. A search for randomised controlled trials comparing sulthiame as an add-on therapy to a placebo or active control was performed and one study was included. Although this single study suggests sulthiame may lead to a cessation of seizures in patients with West syndrome the evidence is limited by the small sample size and significant risk of bias. Further randomised controlled trials are required if meaningful conclusions are to be drawn on the efficacy and side-effect profile of sulthiame as an add-on therapy in epilepsy.

Résumé simplifié

Le sultiame comme traitement associé dans l'épilepsie

L'épilepsie est une maladie neurologique courante qui se caractérise par des convulsions récurrentes. La majorité des patients répondent bien aux médicaments antiépileptiques conventionnels même si 30 % n'obtiendront pas de rémission. Le sultiame est un médicament antiépileptique qui est couramment utilisé dans certains pays européens et en Israël. Une recherche d'essais contrôlés randomisés comparant le sultiame comme traitement associé avec un placebo ou un témoin actif a été effectuée et une étude a été incluse. Bien que cette unique étude suggère que le sultiame est susceptible d'entraîner la cessation des crises convulsives chez des patients atteints du syndrome de West, les preuves sont limitées par le petit effectif et un risque significatif de biais. D'autres essais contrôlés randomisés sont nécessaires pour nous permettre de tirer des conclusions significatives sur l'efficacité et le profil d'effets secondaires du sultiame comme traitement associé dans l'épilepsie.

Notes de traduction

Traduit par: French Cochrane Centre 22nd March, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux pour la France: Minist�re en charge de la Sant�

Summary of findings(Explanation)

Summary of findings for the main comparison. 
Sulthiame add-on therapy compared with placebo for epilepsy

Patient or population: Patients between 3 to 15 months with West syndrome

Settings: In-patient

Intervention: Sulthiame as add-on therapy to pyridoxine

Comparison: Placebo as add-on therapy to pyridoxine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
PlaceboSulthiame

Complete cessation of seizures

9 days

0 per 1000300 per 1000RR 0.71 (0.53 to 0.96)37
(1)
⊕⊕⊝⊝
Low
Single, small study.

Adverse effects - total

9 days

529 per 1000450 per 1000RR 1.17 (0.62 to 2.22)37
(1)
⊕⊝⊝⊝
very low

Single, small study.

Risk of publication bias.

Adverse effects - somnolence

9 days

59 per 1000200 per 1000RR 0.85 (0.66 to 1.09)37
(1)
⊕⊕⊝⊝
Low
Single, small study.
*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.

Background

Description of the condition

Epilepsy is a common neurological condition that is characterised by recurrent seizures. It has an estimated worldwide prevalence of between eight and 10 per 1000 of the general population (WHO 2001). The majority of patients will respond well to conventional antiepileptic drugs (AEDs) (International League Against Epilepsy 1997), although around 30% will not achieve remission (Sander 1993; Schmidt 1995; Brodie 1996) despite trying numerous antiepileptic drugs, often in combination. In an attempt to improve outcomes for these drug-refractory patients, a number of newer potential antiepileptic drugs have been assessed over the past 20 to 30 years.

Sulthiame (STM) is used widely as an AED in some European countries and in Israel (Gross-Selbeck 2001; Koepp 2002; Engler 2003; Ben-Zeev 2004; Chahem 2007; Swiderska 2011).

When used as monotherapy, STM has been reported to reduce the occurrence of seizures and reduce electroencephalographic (EEG) discharges in patients with benign epilepsy of childhood with centrotemporal spikes (Rating 2000; Bast 2003; Ben-Zeev 2004; Wirrell 2008), benign partial epilepsy of childhood (Engler 2003; Ben-Zeev 2004), symptomatic, localisation-related epilepsy, juvenile myoclonic epilepsy (Ben-Zeev 2004) and adults with refractory epilepsy and learning disability (Koepp 2002).

In addition, STM as an add-on therapy has been reported to reduce seizure activity in patients with refractory epilepsy (Livingston 1967; Chahem 2007; Miyajima 2009).

Reported adverse effects of STM include deterioration of reading ability, memory, attention skills and mathematical ability (Wirrell 2008), mixed respiratory and metabolic acidosis (a condition characterised by an abnormally low arterial blood pH) (Weissbach 2010) and crystalluria (the excretion of crystals in the urine) (Go 2005).

Description of the intervention

STM is usually taken in tablet form, with doses taken two to three times per day.

How the intervention might work

STM is a sulphonamide, which may exert its antiepileptic activity by producing a modest intracellular acidosis in central neurons via its action as a carbonic anhydrase inhibitor, thereby reducing the frequency of action potentials and epileptiform bursts (Leniger 2002).

Why it is important to do this review

A summary of the best available evidence about the efficacy and tolerability of STM for patients with refractory epilepsy is required to inform the use of this drug and to inform decisions about the further assessment of this drug.

Objectives

To compare the efficacy and side-effect profile of STM as an add-on therapy when compared with placebo or another AED.

Methods

Criteria for considering studies for this review

Types of studies

  1. Randomised controlled trials (RCTs).

  2. Double, single or unblinded trials.

  3. Placebo-controlled trials.

  4. Parallel group or cross-over studies.

Types of participants

  1. Patients with refractory epilepsy (defined as epilepsy in which seizure control is not adequately managed with one or more antiepileptic drugs).

  2. Patients of any age.

  3. Patients with epilepsy of any aetiology.

Types of interventions

  1. For the active treatment group, STM as an adjunct to the participant's AED regimen.

  2. For the control group, placebo or another AED added to the participant's AED regimen.

Types of outcome measures

Primary outcomes
  1. A reduction in seizure frequency of 50% or greater. We have selected this outcome as it is commonly reported in studies assessing the efficacy of AEDs.

Secondary outcomes
  1. Seizure freedom at the end of follow-up period.

  2. Mean seizure frequency.

  3. Time to treatment withdrawal; reflective of both intolerable adverse effects and lack of efficacy.

  4. Any reported adverse drug effects such as, but not limited to, deterioration in cognitive ability, crystalluria or respiratory and metabolic acidosis.

  5. Overall improvement or deterioration in quality of life.

Search methods for identification of studies

Electronic searches

We searched the following databases on 28th August 2012:

(a) The Cochrane Epilepsy Group Specialised Register, using the search term "sulthiame OR Ospolot";

(b) The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, issue 8, August 2012) using the search strategy outlined in Appendix 1;

(c) MEDLINE (Ovid, 1946 to 28/08/2012) using the search strategy outlined in Appendix 2;

(d) The International Clinical Trial Registry Platform (http://apps.who.int/trialsearch), using the search term "sulthiame OR Ospolot".

We did not impose any language restrictions.

Searching other resources

We checked the reference lists of retrieved reports for additional reports of relevant studies. We also contacted the manufacturers of STM for information about ongoing or unpublished studies.

Data collection and analysis

Selection of studies

Two review authors (PMM and GP) assessed studies for inclusion independently. Disagreements were resolved by discussion.

Data extraction and management

We extracted data from the trial and assessed the design of the trial and demographic makeup of the participants in addition to the outcomes listed in the Types of outcome measures section. Two review authors (PMM and GP) assessed studies independently and disagreements were resolved by discussion.

Trial design
  1. Method of randomisation

  2. Method of concealment

  3. Duration of baseline period

  4. Duration of treatment period

  5. Duration of "wash-out" period for cross-over studies

  6. Dose of STM

  7. Description of adverse effects

  8. Description of withdrawals and drop-outs

Demographic information
  1. Number of patients in treatment group

  2. Number of patients in control group

  3. Age

  4. Sex

  5. Type of seizures and epilepsy

  6. Mean baseline seizures frequency

  7. Which AED(s) participants were already established on

Assessment of risk of bias in included studies

Two review authors (PMM and GP) independently assessed the quality of each study's methodology using the factors outlined in the Data extraction and management section. Disagreements were resolved by discussion.

Measures of treatment effect

For binary data, relative treatment effects were expressed as risk ratios (RR) with 95% confidence intervals (CI) and for continuous data, we planned to use mean difference (MD) with 95% CI. When data were compared where one group had zero events, the RR was calculated by adding 0.5 to each value in the contingency table as per according to section 9.2.2.2 in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2008). A P value of less than 0.05 qualified statistical significance.

Dealing with missing data

Intention-to-treat analysis was performed, assuming treatment withdrawal to be due to either lack of efficacy or intolerable adverse effects. We planned to calculate any missing statistics from the raw data where possible.

Assessment of heterogeneity

We planned to assess methodological heterogeneity by comparing each trial for aspects outlined in the trial design section of Data extraction and management. We planned to assess clinical heterogeneity by comparing each trial for aspects outlined in the demographic information section of Data extraction and management. We planned to assess statistical heterogeneity using the I squared test using the following parameters as a guideline:

  • 0% to 40%: might not be important;

  • 30% to 60%: may represent moderate heterogeneity;

  • 50% to 90%: may represent substantial heterogeneity;

  • 75% to 100%: considerable heterogeneity.

Assessment of reporting biases

We reported bias according to Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2008). If we had identified sufficient RCTs, we planned to devise a funnel plot to help identify publication bias and investigate any visual asymmetry by exploratory analysis. We attempted to obtain source data for any studies included in the analysis in order to assess any non-reported outcomes.

Data synthesis

We planned to analyse data in a meta-analysis using a fixed-effect model within Review Manager 5 provided this was clinically appropriate and we found no evidence of substantial heterogeneity. If we had found evidence of substantial heterogeneity, we would have explored the factors for heterogeneity. If substantial heterogeneity could not be readily explained we would have used a random-effects model to perform meta-analysis. Primary analysis was by intention-to-treat , in which all participants were included in the treatment groups to which they were allocated, regardless of whether or not they received the treatment. A P value of <0.05 qualified statistical significance.

Subgroup analysis and investigation of heterogeneity

We planned to assess separately the effects of STM in patients with focal epilepsy and patients with generalised epilepsy.

Sensitivity analysis

We planned to assess the influence on results of studies of poor methodological quality by undertaking analyses with and without these studies.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

Our search identified 23 papers and two ongoing studies. After reviewing the titles and abstracts, 11 papers were excluded as it was clear that they were not randomised controlled add-on studies comparing sulthiame (STM) with placebo or active control in epilepsy. Further evaluation of the remaining papers is presented below and in the tables Characteristics of included studies and Characteristics of excluded studies.

Included studies

One study (Debus 2004) met our inclusion criteria. It was a randomised, double-blind, placebo-controlled, parallel group study. Patients with newly diagnosed West syndrome, which had to include the features of infantile spasms (IS) and either hypsarrhythmia (HA) or hemihypsarrhythmia, were recruited into the study. Patients with a history of epilepsy before the diagnosis of West syndrome were excluded unless treated with phenytoin (PHT) or phenobarbitone (PB), both of which are reported to be ineffective in West syndrome (Hrachovy 1991). Thirty-seven patients were included in the study. Twenty patients received STM and 17 received placebo.

The original publication reported that patients had a mean (range) age of 7.7 months (3.5 to 15 months). However, the author has provided previously unpublished data which is in conflict with this. In the intervention group there were 11 boys and nine girls and the mean (range) age was 7.5 months (two to 15 months). In the control group there were seven boys and 10 girls and the mean (range) age was 6.1 months (three to 13 months). The aetiological make up of each group is as follows: idiopathic - four (20%) in the intervention group, three (18%) in the control group; premature birth - five (25%) in the intervention group, three (18%) in the control group; tuberous sclerosis - three (15%) in the intervention group, four (24%) in the control group; malformations - two (10%) in the intervention group, two (12%) in the control group; birth asphyxia - two (10%) in the intervention group, one (6%) in the control group; trisomy 21 - one (5%) in the intervention group, one (6%) in the control group; congenital heart defect - one (5%) in the intervention group, one (6%) in the control group; porencephaly - none in the intervention group, one (6%) in the control group; encephalopathy - none in the intervention group, one (6%) in the control group; unclear - two (10%) in the intervention group, none in the control group. After three days of baseline pyridoxine (PDX) (150 to 300 mg/kg/day) patients were randomised to receive STM (5 mg/kg/day) or placebo. After a further three days non-responders had the dose of STM or placebo doubled. At the end of day nine the study medication was disclosed following an electroencephalograph (EEG) which had to include a period of sleep. Baseline seizure frequency was not reported and the author of the study has confirmed that this was not measured because the positive endpoint of the study was the absence of seizures regardless of seizure frequency before the start of the medication. The study does state that no "significant difference" in baseline seizure frequency existed between the intervention and control groups. It is not possible to perform a meta-analysis we therefore present our findings as a narrative analysis.

Excluded studies

Among the excluded studies were six RCTs. Three (Rating 1999; Bast 2003; Basnec 2005) compared STM with placebo as a monotherapy in epilepsy. Two were ongoing studies comparing STM with placebo as monotherapy (ISRCTN66730162; ISRCTN97864911) for which no data were available. One compared STM with placebo as a monotherapy in healthy patients with no history of epilepsy, measuring axonal excitability of cortical neurons as a primary outcome (Siniatchkin 2006).

Risk of bias in included studies

The study utilised clearly stated inclusion and exclusion criteria. Patients between the age of three and 18 months with a new diagnosis of West syndrome were required to exhibit IS and have the feature of either HA or hemihypsarrhythmia on EEG to meet the inclusion criteria. Patients with an established diagnosis of epilepsy preceding the diagnosis of West syndrome were excluded from the study unless they received treatment for their epilepsy with PHT or PB. No patients who had been treated with PHT or PB entered either arm of the study.

Allocation

The study stated that patients were randomised to either the intervention or control group but did not report the method of randomisation. The author of the study has provided the previously unpublished method of randomisation for the purpose of the Cochrane review. Patients were allocated a number between one and six after a pharmacist had rolled a die. Odd numbers were assigned to sulthiame, even numbers were assigned to placebo.

Blinding

The study stated that the treatment was started in a double-blind fashion but did not report the method or effectiveness of the blinding process. The author has provided previously unpublished details. Sealed envelopes with patient identification numbers written on the outside and a letter containing the allocation hidden on the inside were sent by the pharmacy with correspondingly numbered medication boxes.

Incomplete outcome data

Four patients did not complete the study period. An intention-to-treat analysis, including these patients, was reported.

Selective reporting

The study reports that four patients withdrew from the study (three from the intervention group and one from the control group). The time to treatment withdrawal for one patient in the intervention group is reported as day six but no timings are given for the remaining three patients. It is notable that the author has been able to provide previously unpublished data for two of these.

Adverse drug effects were also reported incompletely in this study. The total number of patients experiencing adverse drug effects in each group are reported (nine in the intervention group, nine in the control group) in addition to the number of patients experiencing somnolence (four in the treatment group, one in the control group). The remaining adverse drug effects (vomiting, restlessness, loss of appetite, diarrhoea and abdominal pain) are reported for their occurrence in the study population as a whole but the specific number of patients in each group experiencing each of these adverse drug effects was not reported. The author has informed us that these data were not recorded.

Effects of interventions

See: Summary of findings for the main comparison

A reduction in seizure frequency of 50% or greater

No data were reported for this outcome

Complete cessation of seizures during follow-up

The study reported that six patients in the intervention group and none of the patients in the control group showed a complete response, meaning cessation of infantile spasms and the disappearance of HA on EEG testing (P = 0.02). Overall RR with 95 % CIs for STM compared with placebo was 0.71 (95 % CI 0.53 to 0.96). The aetiology of the responding patients was: idiopathic aetiology three, premature birth one, trisomy 21 one, and congenital heart defect one.

Mean seizure frequency

No data were reported for this outcome.

Time to treatment withdrawal

The study reported one patient dropping out from the intervention group due to withdrawal of parental consent precipitated by excessive somnolence but does not state when this happened. The author has provided previously unpublished data on this; the patient withdrew on day six. The study also reported one patient dropping out from the control group due to erroneously receiving STM openly during the study period but did not report the time at which treatment withdrawal occurred. The author has stated that it is not clear when this occurred. In addition, the study reported a further two patients withdrawing from treatment but did not report the reasons for this or the time at which the treatment withdrawal occurred. The author has provided previously unpublished data on this; the patients were both allocated to the intervention group and withdrew from treatment on days five and six, both due to withdrawal of parental consent.

Adverse drug effects

The study reported a total of nine (45 %) adverse drug effects in the intervention group and nine (53 %) adverse drug effects in the control group (P = 0.63). The authors reported somnolence in four (20 %) of the intervention group and one (6 %) of the control group (P = 0.2). The authors reported the remaining individual adverse drug effects stating that they were distributed equally amongst each group without providing specific figures. Across the study group there was vomiting in 14 (38%), restlessness in six (16 %), loss of appetite in two (5.5 %), diarrhoea in one (3 %) and abdominal pain in one (3 %).

Quality of life

No data were reported for this outcome.

Discussion

One trial was included in this review. This trial assessed the effect of sulthiame as an add-on therapy for West syndrome after a baseline treatment with pyridoxine for three days. The inclusion criteria for the study was clearly stated as patients with a new diagnosis of West syndrome exhibiting infantile spasms (IS) and hypsarrhythmia (HA) or hemihypsarrhythmia. The exclusion criteria was also clearly stated as patients with a prior diagnosis of epilepsy unless treated with phenytoin (PHT) or phenobarbitone (PB), however, it is not clear how many patients entered the trial having been treated with either of these antiepileptic drugs (AEDs) or whether the dose was reduced or discontinued prior to the study.

The primary outcome specified in the protocol for this review was not reported. It is notable that this outcome is not considered clinically meaningful in West syndrome and is subsequently not routinely reported in studies. Three out of the five secondary outcomes specified in the protocol were reported. The risk of bias was high in this study due incomplete reporting of data on time to treatment withdrawal and adverse drug effects. The methodological quality of the trial was unclear from the published details, however, details provided from the author of the study reveal adequate methods of randomisation and allocation concealment.

The study involved 37 patients, 20 in the intervention group and 17 in the control group. Six patients from the treatment group and no patients from the control group became seizure-free during the study. This outcome met statistical significance. Adverse drug effects were incompletely reported. Overall, there was no significant difference between the total number of adverse effects reported in each group or the number of patients experiencing somnolence in each group. Time to treatment withdrawal was incompletely reported and no meaningful analysis can be performed on the data reported. No data were reported for a reduction in seizure frequency of 50% or more, mean seizure frequency or quality of life.

The results of the study included in this review suggest an increase in complete cessation of seizures in patients with West syndrome when sulthiame is used as an add-on therapy to pyridoxine (PDX). The study was small and of short duration with a significant risk of bias and can therefore not be considered as strong evidence. No conclusions can be drawn regarding the occurrence of adverse effects or quality of life.

Authors' conclusions

Implications for practice

In patients with West syndrome who have not received any AEDs excluding PHT or PB, the one included study suggests sulthiame (STM) may increase the chance of cessation of seizures and disappearance of HA when used as an add-on therapy to PDX compared with placebo. The single study was, however, small with a significant risk of bias which greatly limits the impact of the evidence. No conclusions can be drawn on the occurrence of adverse drug effects, change in quality of life or mean reduction in seizure frequency.

Implications for research

Several large, multi-centre, randomised controlled trials (RCTs) comparing STM as an add-on therapy with placebo or other AEDs will need to be conducted in order to adequately inform clinical practice. Baseline seizure frequency should be reported in addition to seizure frequency at the conclusion of the trial. Time to treatment withdrawal should be fully reported. Individual adverse drug effects should be reported for the treatment group and the control group and quality of life scores validated for use in epilepsy should be incorporated into any future RCT.

Acknowledgements

The authors would like to thank Alison Beamond for her help in devising a search strategy and obtaining papers for review.

Data and analyses

Download statistical data

Comparison 1. Sulthiame add-on versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Complete cessation of seizures137Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.53, 0.96]
2 Adverse effects - total137Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.62, 2.22]
3 Adverse effects - somnolence137Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.66, 1.09]
Analysis 1.1.

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

Analysis 1.2.

Comparison 1 Sulthiame add-on versus placebo, Outcome 2 Adverse effects - total.

Analysis 1.3.

Comparison 1 Sulthiame add-on versus placebo, Outcome 3 Adverse effects - somnolence.

Appendices

Appendix 1. Search strategy for CENTRAL

#1        MeSH descriptor Epilepsy explode all trees

#2        MeSH descriptor Seizures explode all trees

#3        epilep* or seizure* or convulsion*

#4        (sulthiame) or (ospolot)

#5        (#1 OR #2 OR #3)

#6        (#4 AND #5)

Appendix 2. Search strategy for MEDLINE

This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials published in Lefebvre 2009.

1. randomised controlled trial.pt.

2. controlled clinical trial.pt.

3. randomised.ab.

4. placebo.ab.

5. clinical trials as topic.sh.

6. randomly.ab.

7. trial.ti.

8. 1 or 2 or 3 or 4 or 5 or 6 or 7

9. exp animals/ not humans.sh.

10. 8 not 9

11. exp Epilepsy/

12. exp Seizures/

13. (epilep$ or seizure$ or convuls$).tw.

14. 11 or 12 or 13

15. sulthiame.tw.

16. Ospolot.tw.

17. 15 or 16

18. 10 and 14 and 17

Contributions of authors

P. Milburn-McNulty: systematic review of studies and composing final document

G. Powell: systematic review of studies

G. Sills: editing of final document

A. Marson: editing of final document

Declarations of interest

None known.

Differences between protocol and review

Due to the presence of only one study a meta-analysis was not suitable. In addition, measurements of heterogeneity amongst studies and sensitivity analysis was not appropriate.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Debus 2004

  1. a

    PDX: pyridoxine
    STM: sulthiame

MethodsDouble-blind, randomised placebo-controlled parallel study
Participants

37 patients

Mean (range) age 7.7 months (3 to 15 months)

West syndrome

Interventions

All patients received PDX (150 to 300 mg/kg/day) only during the first three days of the study

On day 4 STM (5 mg/kg/day) was added to the intervention group and placebo added to control

On day 7 the dose of STM and placebo were doubled in "non-responders"

Outcomes

Complete cessation of seizure activity during 9-day study (P = 0.02)

Adverse effects - all (P = 0.63)

Adverse effects - somnolence (P = 0.2)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAllocation by roll of dice
Allocation concealment (selection bias)Low riskAllocation concealed in sealed envelope for duration of study
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analysis performed
Selective reporting (reporting bias)High riskIncomplete data reported for time to treatment withdrawal and adverse drug effects
Other biasLow riskNone identified
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskMethod not stated
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskMethod not stated

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    STM: sulthiame

Basnec 2005STM used as monotherapy in intervention group
Bast 2003STM used as monotherapy in intervention group
Griffiths 1964Not a randomised controlled trial
Groppa 2006Study on the effect of STM as a monotherapy on axonal excitability of cortical neurons in subjects with no history of epilepsy - same study as Siniatchkin 2006
Ingram 1963Not a randomised controlled trial
ISRCTN66730162STM used as monotherapy in intervention group
ISRCTN97864911STM used as monotherapy in intervention group
Li 2000Unable to verify citation. We will attempt to contact the author and any verified results will be included in an update of the review if appropriate
Livingston 1967Not a randomised controlled trial
Moffat 1970Study assessing the effects of STM on aggressive behaviour in both epileptic and non-epileptic patients
Rating 1999STM used as monotherapy in the intervention group - same study as Rating 2000
Rating 2000STM used as monotherapy in the intervention group - same study as Rating 1999
Siniatchkin 2006Study on the effect of STM as a monotherapy on axonal excitability of cortical neurons in subjects with no history of epilepsy - same study as Groppa 2006

Ancillary