The impact of early life seizures on cognitive development

Cognitive impairment has consistently been shown to be a common comorbidity of epileptic syndromes throughout the lifespan, typically in relation to etiology, age at onset, treatment and seizure type, severity and duration, and significantly impacting function and quality of life in affected patients. However, evidence related to the impact of seizure events occurring in isolation, without defining or being part of any broader syndrome has been equivocal.   Evidence supports significant physiological alterations following early-life status epilepticus (SE), arguably the most severe form of seizure as symptoms persist for at least 30 minutes, which has further been linked to long-term cognitive residua related to altered development, global intelligence, learning capacities and executive function, particularly as they occur in the developing brain. Understanding cognitive outcome following SE events can orient our understanding of the impact of less severe forms of seizures on the developing brain, namely febrile seizures. Febrile seizures (FS), which represent a group of seizures (i.e., simple and complex types) that occur in association with a febrile illness in the absence of a CNS infection, are the most common form of childhood seizure, for which cognitive outcome remains unclear. Although physiological alterations have been shown, particularly but not exclusively in the most severe forms of FS, cognitive and behavioral outcome has been understudied to date and remains controversial. Few studies have investigated the impact of development immediately following the most severe form of FS, and evidence demonstrates unaltered global intelligence in later life. However, the evolution of the impact of FS on cognitive development from infancy into childhood using standardized, specific and objective measures has yet to be studied.  The general objectives of the current thesis were two-fold. The first objective was to understand cognitive outcome following SE through a review of the literature (Article 1). The second objective was to investigate development and cognition following an initial complex FS from onset to school-age, in the context of known risk factors for poor outcome, including all types of complex features (Article 2). More specifically, we aimed to study development within the first year-post onset (Article 2, Infant Cohort). Furthermore, we aimed to examine cognitive development in a cohort of children old enough for cognitive functions to be sufficiently differentiated (i.e., school-age) to allow specific, objective and standardized assessment of the impact of different complex features on specific functions, particularly related to learning/memory and executive function (Article 2, School-age cohort).   Results of the clinical investigation revealed normal cognitive and behavioral development within the first year-post complex FS onset as compared to controls, without impact of seizure duration or age at seizure onset. At school-age, results revealed unaltered global intelligence following early-life complex FS.  Significant group differences however indicated difficulties in specific cognitive domains, including executive functioning, and to a lesser extent, learning and memory in these children, as a function of seizure duration. Emotional challenges, particularly perfectionism, were further noted in children having suffered complex FS, as a function of precocity of seizure onset.   Taken together, our findings demonstrate that although development was unaltered following early-life FS, cognitive sequelae are apparent at school-age, characterized by challenges in executive functioning and learning/memory. Overall, the current results support the hypothesis that complex FS, even without meeting criteria for FSE, may affect the development of specific cognitive functions, although to a lesser extent than those observed following SE. Future research is nevertheless required to better understand the heterogeneous nature of FS, as well as their outcome and impact on quality of life.

Keyphrases: Status Epilepticus, Convulsion fébrile complexe, Cognition, Febrile Seizures, Complex febrile seizure, Behavior, Executive function, Neuropsychology, Children