Epilepsy, Cognitive, and Behavioral Outcomes in Neurocutaneous Syndromes: A Comparative Review of NF1, TSC, and...

Neurocutaneous syndromes (NCS), including neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC), and Sturge-Weber syndrome (SWS), are rare neurodevelopmental disorders frequently associated with epilepsy, cognitive impairment, and behavioural difficulties. Although caused by different genetic alterations, these disorders share biological mechanisms that influence brain development, neuronal connectivity, and network excitability. Beyond being a common neurological manifestation, epilepsy is increasingly recognized as an important factor influencing cognitive and behavioural outcomes in neurocutaneous syndromes.

This narrative review summarizes current evidence on the relationship between epilepsy, cognitive dysfunction, and behavioural manifestations in major neurocutaneous syndromes. Attention is given to epileptogenic mechanisms, shared molecular pathways, and factors influencing long-term neurodevelopmental outcomes.

Epilepsy is consistently associated with cognitive and behavioural outcomes in neurocutaneous syndromes, particularly in disorders characterized by early-onset and treatment-resistant seizures. Early seizure onset, poor seizure control, and persistent network dysfunction have been associated with intellectual disability, executive dysfunction, attention deficits, autism spectrum features, and impaired adaptive functioning. In TSC and SWS, epilepsy burden is strongly associated with cognitive outcome, particularly in interaction with underlying structural, vascular, and molecular abnormalities. In neurofibromatosis type 1, cognitive and behavioural difficulties are more often related to altered neuronal connectivity and dysregulated signalling pathways, although epilepsy may further contribute to neurodevelopmental impairment in a subset of patients. Despite their distinct genetic origins, these disorders converge on dysregulated RAS/MAPK, PI3K/AKT/mTOR, and Gαq-mediated signalling pathways that influence both epileptogenesis and brain development.

Despite their distinct genetic origins, major neurocutaneous syndromes converge on common pathways linking epilepsy, network dysfunction, and neurodevelopmental impairment. Understanding how these processes interact may facilitate earlier intervention and more accurate prognostic assessment, ultimately improving long-term outcomes for affected children.