Neonatal Epilepsy: Beyond Seizures in a Developing Brain-A Narrative Review

Neonatal seizures represent the most common neurological emergency in the neonatal period and arise within a uniquely immature and highly dynamic brain. Their recognition is challenging due to frequent electroclinical dissociation, with many seizures remaining purely electrographic and therefore detectable only through continuous electroencephalogram (cEEG) monitoring. This narrative review provides an integrated and updated overview of neonatal seizures, bridging developmental neurobiology, diagnostic challenges, etiological classification, and therapeutic strategies. The immature brain is characterized by an imbalance between excitation and inhibition, transient network architectures, and activity-dependent developmental processes, all of which contribute to the distinct electroclinical features of neonatal seizures. cEEG remains essential for accurate diagnosis and quantification of seizure burden, which may influence outcome. Etiology represents the primary determinant of prognosis, with hypoxic-ischemic encephalopathy (HIE), stroke, and genetic disorders among the most frequent causes. Advances in genetic testing have improved diagnostic precision and enabled targeted therapies in selected cases, supporting a precision medicine approach. Several key findings emerge from the current evidence base: (i) the neonatal brain is a developmentally constrained system in which excitation-inhibition imbalance, transient circuits and immature long-range connectivity shape an electroclinically distinct seizure phenotype; (ii) cEEG is the gold standard for detection and quantification of seizure burden, since the majority of neonatal seizures are electrographic-only and bedside clinical recognition systematically underestimates true seizure burden; (iii) etiology-chiefly HIE, stroke, and genetic causes-remains the strongest determinant of outcome, while seizure burden acts as an independent and potentially modifiable prognostic modifier; (iv) phenobarbital retains an evidence-based advantage in acute electrographic seizure control, whereas levetiracetam offers a favorable safety profile in the absence of robust long-term human neurotoxicity data; (v) rapid genomic diagnostics, artificial intelligence-assisted EEG analysis and multimodal neuromonitoring are converging toward a precision-neonatology framework, but their translation into routine practice requires validation, standardization, and equitable access. Future neonatal seizure care should extend beyond seizure control to the preservation and optimization of neurodevelopmental outcomes.