Safety and Efficacy of Rational Polytherapy with Sodium Valproate and Lamotrigine for Pediatric Drug-Resistant Epilepsy: A Systematic Review and Meta-Analysis

Background: Drug-resistant epilepsy (DRE) affects approximately one-third of individuals with epilepsy, where seizures remain uncontrolled despite appropriate trials of at least two antiseizure medications (ASMs). Neuroinflammation, specifically chronic microglial activation, plays an important role in epileptogenesis, seizure perpetuation, and pharmacoresistance. Traditionally, antiseizure medications (ASMs) target neuronal excitability through modulation of ion channels and neurotransmitter systems; however, several ASMs, including sodium valproate and lamotrigine, have demonstrated anti-inflammatory and microglia-modulating properties beyond their conventional antiseizure mechanisms. Rational polytherapy involving combinations of ASMs with complementary mechanisms and anti-neuroinflammatory effects may provide enhanced seizure control while minimizing adverse effects. Among available combinations, sodium valproate and lamotrigine have consistently been regarded as one of the few combinations demonstrating potential pharmacodynamic synergism. Although several clinical studies have evaluated this combination in pediatric DRE, the overall evidence has not been quantitatively synthesized. Objectives: To systematically evaluate the efficacy and safety of rational polytherapy with sodium valproate plus lamotrigine in children with drug-resistant epilepsy. Methods: Electronic databases, including PubMed, Medline, Scopus, Embase, Web of Science, Google Scholar, PubMed Central, ScienceDirect, Cochrane Library, and clinicaltrials.gov, were systematically searched. Studies involving pediatric patients aged 18 years or less with DRE receiving polytherapy regimens containing sodium valproate plus lamotrigine were included. Primary outcomes were total treatment effect defined as ≥50% seizure reduction and seizure freedom. Secondary outcomes included changes in seizure frequency, adverse events, treatment discontinuation, and serious adverse events. Risk of bias was assessed using the Cochrane Risk of Bias tool and Newcastle–Ottawa Scale. Meta-analyses were performed using random-effects models. Results: A total of 7 studies met the eligibility criteria. The pooled proportion of patients achieving an overall treatment response was 65.3% (95% CI 51.8–78.8%), with high heterogeneity (I2 = 63.4%, p = 0.027). Rational polytherapy with sodium valproate plus lamotrigine combination provided preliminary comparative evidence of higher responder rates in a single comparative trial, requiring confirmation in larger randomized trials. Overall, sodium valproate plus lamotrigine was well tolerated, and most reported adverse events were mild to moderate in severity. The pooled adverse event rate was 18.1% (95% CI 8.3–28.0%), with high heterogeneity (I2 = 64.3%, p = 0.024). Conclusions: Rational polytherapy with sodium valproate plus lamotrigine that have both complementary antiseizure and immunomodulatory mechanisms appears to represent an effective and generally well-tolerated therapeutic strategy for pediatric drug-resistant epilepsy. However, the basis of this conclusion is derived mainly from observational studies, requiring confirmation in larger randomized trials. This systematic review provides quantitative evidence supporting its clinical use while highlighting the need for larger prospective comparative studies to strengthen the evidence base.