Neurobehavioural comorbidities of epilepsy: towards a network-based precision taxonomy

Cognitive and behavioural comorbidities are prevalent in childhood and adult epilepsies and impose a substantial human and economic burden. Over the past century, the classic approach to understanding the aetiology and course of these comorbidities has been through the prism of the medical taxonomy of epilepsy, including its causes, course, characteristics and syndromes. Although this ‘lesion model’ has long served as the organizing paradigm for the field, substantial challenges to this model have accumulated from diverse sources, including neuroimaging, neuropathology, neuropsychology and network science. Advances in patient stratification and phenotyping point towards a new taxonomy for the cognitive and behavioural comorbidities of epilepsy, which reflects the heterogeneity of their clinical presentation and raises the possibility of a precision medicine approach. As we discuss in this Review, these advances are informing the development of a revised aetiological paradigm that incorporates sophisticated neurobiological measures, genomics, comorbid disease, diversity and adversity, and resilience factors. We describe modifiable risk factors that could guide early identification, treatment and, ultimately, prevention of cognitive and broader neurobehavioural comorbidities in epilepsy and propose a road map to guide future research.