Altered neurostructural development in magnetic resonance imaging-negative pediatric epilepsy: A large-scale multicenter study of 1919 children

Yingfan Wang ¹, Minghao Li ¹, Huijun Li ²

⁰Department of Neurology, Affiliated Brain Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.

Epilepsia +

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December 24, 2025

View abstract on PubMed

Summary

Pediatric epilepsy disrupts neurodevelopment, causing transient delays in brain structure from ages 4-9, followed by persistent gray matter expansion. These findings reveal distinct developmental signatures in children with epilepsy.

Area Of Science

Neuroscience
Developmental Pediatrics
Medical Imaging

Background

Pediatric epilepsy's impact on neurodevelopment is poorly understood.
Magnetic resonance imaging (MRI)-negative epilepsy presents unique challenges in assessing neurodevelopmental trajectories.

Purpose Of The Study

To delineate age- and sex-stratified neurostructural trajectories in MRI-negative pediatric epilepsy.
To identify critical periods of developmental divergence from healthy controls.

Main Methods

Analysis of T1-weighted MRI data from 957 pediatric epilepsy patients and 962 controls (aged 4-12 years).
Utilized generalized additive models for location, scale, and shape to model sex-stratified developmental trajectories.
Employed voxel- and surface-based morphometry to compare cortical morphology and regional gray matter volume (GMV) across age groups.

Main Results

Patients exhibited reduced total intracranial volume, GMV, cerebrospinal fluid volume, cortical thickness, and increased white matter hyperintensity (WMH) burden compared to controls.
Identified atypical total surface area trajectory, premature cortical thickness peak (~age 7), and WMH burden peak (~age 8).
Observed widespread cortical morphological delays (ages 4-9), primarily in limbic and sensorimotor networks, with normalization after age 10; distinct from adult GMV atrophy, pediatric patients showed limbic expansion, thalamic hypertrophy, and cerebellar volumetric shifts.

Conclusions

Pediatric epilepsy is characterized by aberrant neurodevelopment with two signatures: a transient 4-9-year vulnerability window with delays and a progressive gray matter expansion.
These signatures offer distinct biomarkers for differentiating transient disruption from ongoing network reorganization.
Findings highlight critical periods for potential timed interventions in pediatric epilepsy neurodevelopment.

Keywords:

MRI‐negative cortical morphology gray matter volume neurodevelopmental trajectories pediatric epilepsy structural MRI