From Lesion to Dysmaturation: The Evolving Neuropathological Landscape of Encephalopathy of Prematurity

Encephalopathy of prematurity (EoP), a complex neurodevelopmental disorder encompassing brain injury and dysmaturation in preterm infants, has undergone a major conceptual shift over the past several decades. While early neuropathological studies emphasized focal cystic periventricular leukomalacia (PVL), contemporary cohorts predominantly present with diffuse white matter injury (DWMI). The hallmark features of DWMI include hypomyelination or delayed myelination driven by differentiation failure of oligodendrocyte (OL) lineage cells, accompanied by axonopathy and reactive gliosis. Recent insights have broadened this framework beyond isolated white matter abnormalities, demonstrating widespread dysmaturation of neurons, glia, and neural circuits across both white and gray matter structures. At the cellular and molecular levels, diffuse injury is underpinned by the selective vulnerability of pre-OLs to oxidative stress, excitotoxicity, and proinflammatory cascades, which cause differentiation arrest and persistent hypomyelination rather than progenitor cell depletion. Concurrently, activated microglia and astrocytes interact with these oxidative, excitotoxic, and inflammatory pathways, resulting in the disruption of dendritic arborization, interneuron migration, and synaptic pruning, thereby impairing neural circuit assembly. Consequently, EoP is increasingly conceptualized as a multi-factorial neurodevelopmental disorder shaped by the dynamic interplay among destructive injury, developmental dysmaturation, compensatory neuroplasticity, and endogenous repair. These mechanistic insights provide critical implications for therapeutic development. While conventional neuroprotective and neurorestorative strategies remain essential, targeting inhibitory signaling and extracellular matrix barriers to promote OL differentiation and myelination, while concurrently fostering neural plasticity through multimodal interventions, such as gut–brain axis modulation and environmental enrichment, offers unprecedented opportunities to improve functional outcomes.