Summary of main results

We included one trial in this review (Debus 2004). 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 were infants with a new diagnosis of West syndrome, exhibiting infantile spasms, and hypsarrhythmia or hemihypsarrhythmia. The exclusion criteria were a prior diagnosis of epilepsy, unless treated with phenytoin or phenobarbitone, however, it was not clear how many infants entered the trial having been treated with either of these antiepileptic drugs, or whether the dose was reduced or discontinued prior to the study.

The study recruited 37 infants, 20 in the intervention group and 17 in the control group. Six infants from the treatment group and none from the control group became seizure‐free during the study. Although this outcome did suggest that add‐on sulthiame is more effective for seizure control, the outcome did not reach statistical significance. Adverse 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 infants experiencing somnolence in each group. Time‐to‐treatment withdrawal was incompletely reported, and we could not conduct any meaningful analysis on the data reported. No data were reported for the outcomes: 50% or greater reduction in seizure frequency, mean seizure frequency, or quality of life.

Notably, although no data were reported for the primary outcome, 50% or greater reduction in seizure frequency, as specified in the review protocol, we did not have any concerns about the lack of reporting. This outcome is not considered clinically meaningful in West syndrome, and is subsequently not routinely reported in these studies. Two of the five secondary outcomes , treatment withdrawal and adverse effects, however, were incompletely reported and provided more reason for concern. Specifically, the author was unable to confirm the time to withdrawal for the placebo‐randomised infant. Additionally, the author could not provide any further data regarding the incidence rate of adverse effects, stating that the data had not been recorded. We therefore judged that, overall, the risk of reporting bias was high in this study.

Further to this, the risk of bias for randomisation and allocation concealment was unclear from the published details. The study author, however, subsequently provided us with methodological details that demonstrated adequate methods. We consequently changed our judgement to low risk of selection bias. We did not receive any more details regarding the methods of blinding, therefore, we continued to award unclear risk of bias. Similarly, we judged that the study was at unclear risk of other bias due to the limited baseline data. We did, however, rate that there was low attrition bias due to the intention‐to‐treat population used.

The results of the study suggest that sulthiame, compared to placebo, may increase the incidence of complete cessation of seizures for infants with West syndrome when used as an add‐on therapy to pyridoxine, however, we are very uncertain about the reliability of this finding. Due to the small sample size, short treatment duration, and the significant risk of bias described above, we have serious concerns about the certainty of the evidence presented. Notably, none of the reported outcomes reached statistical significance. No conclusions can be drawn regarding the occurrence of individual adverse effects or quality of life, as these two measures were either incompletely reported, or not reported at all.

Overall completeness and applicability of evidence

We were unable to conduct a meta‐analysis as originally intended, due to the lack of eligible studies and the subsequent inclusion of a single study. This meant that we could not conduct any subgroup or sensitivity analyses either.

There were further limitations, specifically concerning the data provided by the single included study. First, the study did not report data for our primary outcome (50% or greater reduction in seizure frequency), or for two of the planned secondary outcomes (mean seizure frequency, and quality of life). As a result, we were unable to reach any conclusions for these outcomes.

The second issue regards the generalisability of the data for the outcomes that were reported. Most notably, the included study only investigated the use of sulthiame in infants with West syndrome. As a result, the findings of this review are limited to this specific type of epilepsy, and cannot be generalised to all epilepsy syndromes. It is also important to note that the infants included in the Debus 2004 study did not, by definition, have drug‐resistant epilepsy. In this study, sulthiame was used as an add‐on to pyridoxine, a form of Vitamin B6, not in addition to another anti‐epileptic drug. Hence, the review does provide some insight into the use of sulthiame as an add‐on therapy, but not in the context of drug‐resistant epilepsy. As a result, the findings of the review might have limited applications in clinical practice.

All of the participants in the included study were younger than 15 months. We have no data concerning the effect of sulthiame in older children or adults. Therefore, the review findings restricted specifically to infants with West syndrome.

Moreover, the study comprised a very small sample size population (37 infants) and is thus, likely to be statistically underpowered. Consequently, it is not appropriate to assume that the effect estimated in this review will necessarily be generalisable to all infants with West syndrome. Therefore, it is evident that the evidence for this review is severely lacking in completeness.

Quality of the evidence

We judged the single study included in this review to be at high risk of bias. This mainly resulted from the incomplete reporting of several of the intended outcomes. The study publication lacked methodological details, which the study author confirmed during correspondence. However, the study author failed to provide details on the method by which blinding was achieved and maintained. Accordingly, we downgraded the certainty of evidence for all outcomes once for risk of bias, and twice more due to the insufficient number of events reported. This was largely as a consequence of the small sample size. As a result, we GRADE‐assessed the evidence for all three reported outcomes as being of very low certainty.

Potential biases in the review process

For the purposes of this review, we defined drug‐resistant epilepsy as epilepsy in which seizure control had not been adequately managed by one or more antiepileptic drugs. The definition of drug‐resistant epilepsy used here is not consistent with that endorsed by the International League Against Epilepsy (ILAE), which specifies that drug‐resistant epilepsy should refer to the failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom (Kwan 2010).

Although currently, none of the studies screened satisfied either definition of drug‐resistant epilepsy, the definition used for the purposes of this review should be reviewed before conducting future updates, to ensure that it remains consistent with current recommendations. Importantly, the definition of drug‐resistant epilepsy used here has direct implications for which studies are eligible for inclusion, and consequently, could alter the conclusions reached.

Agreements and disagreements with other studies or reviews

The conclusions of the present review update remain consistent with the conclusions of the previously published versions of this review, largely because we found no additional eligible studies (Milburn‐McNulty 2011; Milburn‐McNulty 2013; Milburn‐McNulty 2015). Independent of this review and the included study, few reports exist regarding the use of sulthiame as an add‐on therapy. We were able to identify two retrospective studies, which despite being ineligible for this review, remain informative about sulthiame as an add‐on therapy for epilepsy (Swiderska 2011; Caraballo 2018).

The most recent of the two studies investigated the use of add‐on sulthiame in participants, aged 4 to 16 years (mean age 9 years) with drug‐resistant Lennox‐Gastaut syndrome, a paediatric epilepsy characterised by multiple seizure types (Caraballo 2018). Eligible participants had failed treatment with four or more previous anti‐epileptic drugs, prior to commencing treatment with sulthiame. During the study, the medical records of 44 participants were reviewed and retrospectively analysed. Participants had received sulthiame 5 to 30 mg/kg/day in addition to their current anti‐epileptic treatment (median two concomitant anti‐epileptic drugs), over a treatment period of 12 to 60 months (mean treatment period 20 months). Twenty‐seven of the 44 participants (61%) involved in the study attained a 50% or greater reduction in seizure frequency, one of whom was rendered seizure‐free. Adverse effects were reported by ten of the 44 participants and included: hyperpnoea (n = 4), dyspnoea (n = 4), nausea (n = 1), drowsiness (n = 1), headache (n = 4), decreased appetite (n = 2), allergic skin rash (n = 2), and irritability (n = 2). The instances of hyperpnoea and dyspnoea responded to adjustments in the dosage of sulthiame. All reported adverse effects were mild and transient in nature, and in none of the reported cases did adverse effects lead to discontinuation of treatment.

The earlier study by Swiderska 2011 also reviewed the medical records of paediatric participants (aged 2 to 17 years; mean age 10.7 years) with drug‐resistant epilepsy (defined as people who failed to respond to treatment with two or more previous anti‐epileptic drugs). The medical records of 20 participants were analysed as part of the review. Participants received a median dose of sulthiame 8.2 mg/kg/day in addition to their anti‐epileptic drugs (range 1 to 3 anti‐epileptic drugs; mean 1.2 anti‐epileptic drugs) over a treatment period ranging form two to 37 months (mean treatment period 18 months). At three months, 14 of 20 participants (70%) reported a 50% or greater reduction in seizure frequency, however, at subsequent follow‐up points (11, 18, and 20 months), only four participants (20%) responded; three of whom were rendered seizure‐free. Seven participants reported one or more adverse effects, which included drowsiness (n = 2), cognitive slowing (n = 1), hypersalivation (n = 1), breathlessness (n = 1), tachypnoea (n = 1), and diarrhoea (n = 1). The adverse effects reported were largely mild in severity and responsive to reductions in dosage. In only two instances did participants withdraw from treatment as a result of adverse effects (one due to cognitive impairment, and one due to excessive drowsiness).

Both retrospective studies highlighted that sulthiame was effective when used as an add‐on treatment for epilepsy, similar to that implied by the findings of this current review. Notably, the studies evaluated the use of sulthiame over much longer treatment durations than the treatment period used by Debus 2004 (6 days). The efficacy noted after much longer treatment periods in these retrospective studies suggests that the therapeutic effect, reported with regards to seizure freedom, within the short treatment period used by Debus 2004, could potentially be maintained over much longer treatment durations. The good tolerability profile of sulthiame was also emphasised by both retrospective studies, with the majority of associated adverse effects being mild in severity. Correspondingly, in this review, and as reported by Debus 2004, an equal number of participants reported one or more adverse effects in both the sulthiame add‐on treatment group and in the placebo group, implying that sulthiame is well‐tolerated.

As a result, the conclusions of this review, which included data from one randomised controlled trial, appear to be fairly consistent with those of the retrospective studies, despite the significant differences in methodology (Caraballo 2018; Swiderska 2011).