Francesco Brigo and colleagues conducted a comprehensive review of randomized or quasirandomized controlled trials from the Cochrane Research Register and PubMed, aiming to evaluate the efcacy of ethosuximide, valproic acid, and lamotrigine for treating absence seizures in children and adolescents compared to that of placebo or one another. While eight small trials (a total of 691 participants) were included from previous reviews, there were no placebo-controlled trials for ethosuximide or valproic acid; thus, evidence from randomized controlled trials to support their specic effects on absence seizures is lacking. Due to methodological differences among trials comparing ethosuximide, lamotrigine, and sodium valpro­ate, a meta-analysis was deemed inappropriate. In a large randomized, parallel,

double-blinded controlled trial involving 453 newly diagnosed children with absence epilepsy, the effectiveness of ethosuximide, lamotrigine, and valproate treatment was compared. At the 12-month mark, patients on ethosuximide exhibited greater seizure freedom than those on lamotrigine, while valproic acid showed com­parable effectiveness to ethosuximide. Signicant differences in treatment failure rates due to intolerable adverse events were observed among the groups, with the valproic acid group experiencing the greatest proportion of adverse events com­pared to the ethosuximide and lamotrigine groups. Overall, this extensive study indicates that, in comparison to lamotrigine, ethosuximide and valproic acid dem­onstrate superior efcacy as initial monotherapies in managing seizures without intolerable adverse effects in children with unresponsive epilepsy. The study’s nd­ings provide a high level of condence in the data’s outcomes. Regarding efcacy and tolerability, ethosuximide has emerged as the optimal initial empiric mono­therapy for children and adolescents with absence seizures. If absence and general­ized tonic–clonic seizures cooccur, valproate is preferred, as ethosuximide may not effectively treat these seizures [75]. A PubMed search was conducted by Victoria Elisa Rinaldi etal. to identify all articles regarding the management and treatment of childhood absence epilepsy (CAE) from 1979 to 2021. The search aimed to sum­marize recent research and emerging concepts in CAE treatment, with a particular focus on refractory cases. CAE is a common generalized epilepsy syndrome in chil­dren. Ethosuximide remains the preferred medication for traditional anticonvulsant therapy for CAE, followed by valproic acid and lamotrigine. If initial treatment has been shown to be ineffective, combination therapy is typically introduced following two single-drug treatments. Ethosuximide is preferred for typical absence seizures due to its lack of inhibition of focal or generalized tonic–clonic seizures. Although its mechanism of action remains unclear, ethosuximide seems to block transient, low-threshold calcium currents in the thalamus, resulting in synchronous activation of spike-and-wave discharges characteristic of absence seizures. The main side effects of ethosuximide include gastrointestinal disturbances, headaches, drowsi­ness, and less common adverse reactions, such as behavioral and psychiatric disor­ders, blood dysplasia, and allergic reactions [76]. Barbara Mostacci etal. conducted a review of recent literature on ASMs and assessed their teratogenic potential in idiopathic generalized epilepsy (IGE). In girls and women with reproductive poten­tial, levetiracetam and lamotrigine should be considered the drugs of choice for simple generalized tonic–clonic seizures and adolescent myoclonic epilepsy, and ethosuximide should be considered for children with absence epilepsy. According to the 2013 ILAE evidence review, ethosuximide demonstrated established efcacy for absence episodes (evidence level A). These ndings stem from a Class I study involving 446 of the initially enrolled 453 children who were randomly assigned to receive treatment with ethosuximide (n= 156), sodium valproate (n = 148), or lamotrigine (n=149). The rates of freedom from treatment failure at 16–20weeks were comparable between ethosuximide and sodium valproate (53% and 58%, respectively), and both rates were greater than that of lamotrigine (29%). Attention decits were signicantly more common in the 2-valproate group than in the etho­suximide group. Although the analysis was based on a limited number of exposures,

children with well-managed seizures for a minimum of 6months against those with persistent seizures revealed substantially lower IQ, visual perception, and atten­tional scores in the latter group. The authors posit that this phenomenon could stem from either the direct impact of seizures on cognitive function or underlying patho­physiological effects. Nevertheless, the diminished fuzzy cognitive function (activa­tion, alertness, sustained auditory attention, speed of attentional switching) cannot be solely attributed to persistent seizures, as there was no discernible difference in test outcomes between seizure cohorts, alluding to a plausible direct inuence of ethosuximide on cognition. It was concluded that ethosuximide had only a slight effect on cognitive ability [78].