Effect of sex on neuropsychiatric comorbidities in childhood epilepsy

Objective: Neuropsychiatric comorbidities are prevalent in children with epilepsy and often pose greater concerns than the seizures themselves. Identifying children at risk for these conditions is crucial for developing effective therapies. In prepubescent rodents, sex significantly influences cognitive dysfunction related to seizures, with prepubescent male rats exhibiting more severe adverse effects than females. However, it remains unclear whether sex plays a similar role in cognitive and behavioral outcomes in children. This review aims to assess the literature on whether sex is a biological factor affecting behavioral and cognitive outcomes in pediatric epilepsy. Materials and Methods: We conducted a literature review to explore the impact of sex on cognitive and behavioral outcomes in children (up to age 18 years) with epilepsy of all types. Studies were categorized into observational and interventional types. We analyzed population studies involving children with epilepsy, as well as those addressing genetic factors, surgical interventions, status epilepticus, infantile spasms, pharmacological treatments, and the ketogenic diet. Results: Few adequately powered studies have examined sex as a biological variable in relation to cognitive and behavioral impairments in children with epilepsy. In addition, many studies failed to examine sex-related differences in behavior and cognition in children without epilepsy. Generally, the sex-related differences in cognitive and behavioral impairments in children with epilepsy match those seen in children without epilepsy. One exception is that in several studies girls with epilepsy had a similar risk for attention deficit hyperactive disorder (ADHD) as boys, whereas in children without epilepsy ADHD is more common in boys than girls. Although there is a modest trend indicating worse cognitive outcomes for boys with epilepsy compared to girls, consistency across studies is lacking. Conclusion: Sex is not yet a well-explored prognostic factor for outcomes following childhood epilepsy, though some small differences were identified for specific outcomes. More rigorously designed studies are necessary to report outcomes by sex while controlling for potential confounders. The variability in methods for assessing neurodevelopmental outcomes underscores the need for standardized and comprehensive evaluations of cognitive and behavior in children with epilepsy.