Results of the search

See Figure 1.

Figure 1

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Study flow diagram (results refer only to the updated version of the review). The previous versions of the review (Posner 2003; Posner 2005a; Posner 2005b; Brigo 2017; Brigo 2019) included eight studies.

The previous versions of the review (Posner 2003; Posner 2005a; Posner 2005b; Brigo 2017; Brigo 2019) included eight studies.

The updated search strategy described yielded 22 results (19 Cochrane Register of Studies (CRS Web), three MEDLINE). After removing one duplicate and 16 obviously irrelevant items, we assessed five articles for possible inclusion and excluded all of them. Since the last version of this review, we have found no new studies. Below we provide details of the studies included in the previous versions of this review.

Included studies

Callaghan 1982
This was a randomised, parallel open study, which compared monotherapy with ethosuximide and sodium valproate. Ethosuximide was initially given at 250 mg/day and, whenever required, incremented by 250 mg to a maximum of 1500 mg/day. Valproate was started at 400 mg/day and, if deemed necessary, gradually incremented by 200 mg up to 2400 mg/day. Participants (total 28) had typical absence seizures (AS), were between four and 15 years, and were previously untreated. Follow‐up ranged from 18 months to four years. The report acknowledged support from Warner‐Lambert Pharmaceuticals, manufacturers of ethosuximide.

Sato 1982
This study used a complex response‐conditional design and recruited drug‐naive participants as well as participants already on treatment, with a total of 45 participants recruited. In the first phase of this trial; participants were randomised to receive either valproate (and placebo) or ethosuximide (and placebo) and followed up for six weeks. Participants responding to randomised treatment continued with the randomised drug for a further six weeks. Responders included previously untreated participants who became seizure free and participants who had been previously treated and had an 80% or greater reduction in AS frequency. Non‐responders and those with adverse effects were crossed over to the alternative treatment and followed up for a further six weeks. The age range of participants was three to 18 years. Apart from AS, some participants also had other types of seizures. The report does not specify if the AS were typical or atypical. Some of the participants were drug naive and some drug resistant. Participants of the study were selected from those who attended the epilepsy clinic at the Clinical Research Center, University of Virginia Hospital, USA. The work was supported by a contract from the Institute of Neurological and Communicative Disorders and Stroke (NINCDS).

Martinovic 1983
This was a parallel, open‐design study comparing ethosuximide and sodium valproate. Participants were between five and eight years old with a recent (less than six weeks) onset of seizures. All participants (total 20) had 'simple absences' and were followed up for one to two years. Six individuals did not co‐operate and were therefore not included in the analysis. No information about sponsorship by a pharmaceutical company is given.

Frank 1999
This was a double‐blind study using a 'responder enriched' design. Participants (total 29) had newly diagnosed typical AS and were aged between three to 15 years. Prior to randomisation, all participants received treatment with lamotrigine. After four weeks or more of treatment, participants who were seizure free and had a negative 24‐hour electroencephalogram (EEG) with hyperventilation, were randomised to either continue lamotrigine or to placebo and were followed up for four weeks. This study was sponsored by Glaxo Wellcome (now GlaxoSmithKline), makers of lamotrigine.

Coppola 2004
This was a randomised, parallel group unblinded study comparing lamotrigine and sodium valproate. All participants (n = 38) were drug naive, aged three to 13 years old with typical AS. The follow‐up time was 12 months. The primary outcome measure was total seizure freedom, measured at one, three and 12 months. This study was not sponsored by any commercial organisation.

Basu 2005
Results of this study were published as an abstract. We contacted the main author of this study via email three times (30 October and 4 November 2015, and 7 January 2016) asking for further information; we did not receive a reply. This was a randomised, open‐label, parallel group design comparing sodium valproate with lamotrigine used in monotherapy for treatment of typical AS (diagnosed clinically and by EEG support). Thirty patients were included (males 16; females 14 – aged between five and 14 years). Patients with other comorbidities were excluded. Fifteen patients were randomly allocated to receive valproate and 15 to receive lamotrigine. The follow‐up was 12 months. The primary outcome was seizure freedom and no EEG evidence of seizure. Drug dosages were not explicitly reported. The dosages were escalated according to the clinical response, starting from a low dose. Lamotrigine was titrated very slowly at two‐weekly intervals to avoid unwanted side effects (maximum 10 mg/kg/day). After one month of treatment nine patients (60%) receiving valproate and none (0%) receiving lamotrigine were seizure free. After three months, 11 patients (73.3%) in the sodium valproate and eight patients (53.3%) in the lamotrigine group receiving lamotrigine were seizure free. After 12 months, 12 patients (80%) receiving sodium valproate and 10 patients (66.6%) treated with lamotrigine were seizure free (P > 0.05). Minimal adverse events (not explicitly reported) were observed in 26.6% of patients treated with sodium valproate and in 20% of patients receiving lamotrigine. No dropouts were observed. No information about sponsorship by a pharmaceutical company was available.

Huang 2009

This study (Huang 2009), compared valproate with lamotrigine monotherapy in drug‐naive children (n = 48, six to 10 years) with newly diagnosed childhood AS (typical seizures). Included patients were 17 males and 31 females (no detailed descriptions in each group, respectively). The follow‐up time was 12 months. The outcome measure was total seizure freedom, measured at one, three, six and 12 months. Complete normalisation of EEG with seizure freedom and occurrence of adverse effects were also considered. In the valproate group, sustained‐release tablets or oral solution were administered twice daily (totally 15 mg/kg per day); in case of persisting seizures after one week, the dose was increased to 20 mg/kg per day, twice daily (maximum dose daily 30 mg/kg). In case of persisting seizures despite a maximum dose of 30 mg/kg within a month, combination with lamotrigine 0.15 mg/kg daily to 2 mg to 5 mg/kg was administrated. In the lamotrigine group, patients received a starting dose of lamotrigine of 0.5 mg/kg daily, administered twice, increased to 0.15 mg/kg per two weeks. The daily maintenance dose was 2 mg to 5 mg/kg, and the maximum daily dose 10 mg/kg. In case of persisting seizures despite a maximum dose within a month, combination with valproate 10 mg/kg daily to 20 mg/kg was administrated. No information about sponsorship by a pharmaceutical company was available.

Glauser 2013a
This was a randomised, parallel double‐blind controlled trial comparing ethosuximide, lamotrigine and sodium valproate in children with newly diagnosed childhood absence epilepsy. The study design also included a partial cross‐over to open‐label (at treatment failure only) with subsequent follow‐up: participants reaching a treatment‐failure criterion in the double‐blind treatment phase were given the opportunity to enter into the open‐label phase, during which participants were randomised to one of the two other antiepileptic drugs. Participants (total 453 enrolled) had typical AS, were between seven months and 12 years 11 months, and were previously untreated. Among the 453 patients enrolled, seven were withdrawn, hence 446 participants were included in subsequent effectiveness analyses and 451 participants included in the safety analyses. Follow‐up was up to 12 months. Study drugs were titrated as tolerated in predetermined increments every one to two weeks over 16 weeks. Ethosuximide and valproic acid doses were incremented of 5 mg to 10 mg/kg/day at intervals of two weeks, whilst lamotrigine doses were incremented of 0.3 mg to 0.6 mg/kg/day at intervals of two weeks. The maximal target doses were ethosuximide 60 mg/kg/day or 2000 mg/day (whichever was lower), valproic acid 60 mg/kg/day or 3000 mg/day (whichever was lower), and lamotrigine 12 mg/kg/day or 600 mg/day (whichever was lower). The main effectiveness outcome was the freedom from treatment failure assessed 12 months after randomisation. Freedom from treatment failure was also assessed at 16 to 20 weeks. Treatment failure was defined as failure either due to lack of seizure control, or meeting safety exit criteria, or withdrawal from the study for any other reason. This study was not sponsored by any commercial organisation.

Excluded studies

For this update, we excluded five studies for the following reasons: three studies were commentaries, one study was a review, and one study wasn't relevant to our current review.

Allocation

Only two of the studies described explicitly the methods of allocation concealment (Coppola 2004; Glauser 2013a).

Blinding

The studies reported by Sato (Sato 1982), Frank (Frank 1999), and Glauser (Glauser 2013a) were double‐blinded, whilst the studies reported by Martinovic (Martinovic 1983), Callaghan (Callaghan 1982), Coppola (Coppola 2004), and Huang (Huang 2009) were unblinded (high risk of bias). In two out of the three double‐blinded studies, placebo and active drugs were indistinguishable (Frank 1999; Glauser 2013a) and were considered to have a low risk of bias.

Incomplete outcome data

Five studies described losses to follow‐up or exclusions from analyses. Frank 1999 reports that one participant withdrew consent before treatment but after randomisation and that one participant did not comply but was included in the analysis. Martinovic 1983 reports that six of the initially recruited participants did not co‐operate and were not included in the analysis. Coppola 2004 reports loss of nine patients overall, all due to lack of efficacy, these patients exited the study at three months follow‐up; all randomised patients were included in the analysis. Huang 2009 reports that one patient in the valproate group was lost to follow‐up (no further specifications), whereas two patients in the lamotrigine group were withdrawn due to severe adverse effects (systemic anaphylaxis rash). Glauser 2013a reports that among the 453 patients enrolled, seven were withdrawn due to ineligibility at baseline, so that 446 participants were included in subsequent effectiveness analyses and 451 participants in safety analyses. Two reports (Callaghan 1982; Sato 1982) did not make an explicit statement that participants were not lost to follow‐up or excluded from analyses.

Selective reporting

Seven of the studies were assessed at low risk of bias (Callaghan 1982; Coppola 2004; Frank 1999; Glauser 2013a; Huang 2009; Martinovic 1983; Sato 1982); the remaining study was assessed at unclear risk of bias (Basu 2005).

Lamotrigine versus placebo

We found one study (Frank 1999) comparing lamotrigine with placebo which recruited 29 participants. As outlined in Description of studies above, this trial used a responder‐enriched design where participants responding to lamotrigine during a pre‐randomisation baseline phase were randomised to continue lamotrigine or have it withdrawn. This trial therefore compares the effect of continuing versus withdrawing lamotrigine. The results were as follows:

1. in the initial open‐label dose‐escalation phase, 71% of the participants became seizure free on lamotrigine using a 24‐hour EEG/video telemetry recording;

2. in the placebo‐controlled phase 64% of the participants on lamotrigine remained seizure free versus 21% receiving placebo (P < 0.03).

Valproate versus placebo

We found no trials comparing valproate versus placebo.

Ethosuximide versus placebo

We found no trials comparing ethosuximide versus placebo.

Ethosuximide versus valproate

We found four studies comparing valproate with ethosuximide (Callaghan 1982; Sato 1982; Martinovic 1983; Glauser 2013a). Due to differences in study design, participants and length of follow‐up we did not think it appropriate to pool results in a meta‐analysis. For our chosen outcome 'seizure freedom', we were unable to extract data for this outcome at the time points we had specified (one, six and 18 months). Rather than not present any data for this outcome, we have summarised results for individual trials, where the proportion of participants seizure free during follow‐up was reported. Results for individual studies are presented below as well as in Analysis 1.1, Analysis 1.2 and Analysis 1.3.

Lamotrigine versus valproate

We found four studies comparing valproate with lamotrigine (Coppola 2004; Basu 2005; Huang 2009; Glauser 2013a). Due to differences in study design, participants and length of follow‐up, we did not think it appropriate to pool results in a meta‐analysis. For our chosen outcome 'seizure freedom', we were unable to extract data for this outcome at the time points we had specified (one, six and 18 months). Rather than not present any data for this outcome, we have summarised results for individual trials, where the proportion of participants seizures free during follow‐up was reported. Results for individual studies are presented below as well as in Analysis 2.1 and Analysis 2.2.

Ethosuximide versus lamotrigine

One study (Glauser 2013a), compared ethosuximide and lamotrigine in drug‐naive patients with childhood AS. The main effectiveness outcome was the freedom from treatment failure assessed 12 months after randomisation. Freedom from treatment failure was also assessed at 16 to 20 weeks, and in between 16 and 20 weeks and month 12. Treatment failure was defined as failure either due to lack of seizure control, or meeting safety exit criteria, or withdrawal from the study for any other reason. Seizure freedom at 12 months after randomisation was higher in patients taking ethosuximide (70/154, 45%) than in patients taking lamotrigine (31/146, 21%; P < 0.001). At 16 to 20 weeks, freedom from treatment failure was observed in 81/154 (53%) patients taking ethosuximide and 43/146 (29%) patients taking lamotrigine. Adopting the GRADE methodology, we assessed the certainty of the evidence for seizure freedom at 12 months as high (summary of findings Table 3).

Adverse effects related to the use of ethosuximide, sodium valproate or lamotrigine

This section and the related tables apply to all studies and comparisons.

The most common adverse effects of treatment with valproate reported by the studies assessing this drug (Callaghan 1982; Sato 1982; Martinovic 1983; Huang 2009; Glauser 2013a) were fatigue, nausea, vomiting, increased appetite with weight gain, behavioural/psychiatric changes (decreased concentration, personality change, hyperactivity, attention problems, hostility), and thrombocytopenia (Table 1).

Ethosuximide treatment was mostly associated with nausea, vomiting, and behavioural/psychiatric changes (Table 2).

The most common adverse effects of treatment with lamotrigine were fatigue, and behavioural/psychiatric changes (Table 3). In one lamotrigine study (Frank 1999), the most commonly reported adverse event was rash (reported on 11 occasions in 10 patients). However, only in one of the individuals was this thought to be related to lamotrigine. There were two serious adverse events during the treatment, but they were judged to be unrelated to treatment. In one study (Huang 2009), systemic anaphylaxis rash during lamotrigine treatment led to patients' withdrawal from the study. In the Glauser 2013a study, no side effects (including rash, reported in two patients taking valproate, six patients taking ethosuximide, and six patients taking lamotrigine) occurred more frequently in the lamotrigine cohort compared to the other treatment groups (valproate and ethosuximide). In this study, the frequency of treatment failures due to intolerable adverse events was significantly different among the treatment groups, with the largest proportion of proportion of adverse events in the valproic acid group (48/146, 33%) compared to the ethosuximide (38/154, 25%) and the lamotrigine (29/146, 20%) groups (P < 0.037).