Dysmature superficial white matter microstructure in developmental focal epilepsy

Abstract

Benign epilepsy with centrotemporal spikes is a common childhood epilepsy syndrome that predominantly affects boys, characterized by self-limited focal seizures arising from the perirolandic cortex and fine motor abnormalities. Concurrent with the age-specific presentation of this syndrome, the brain undergoes a developmentally choreographed sequence of white matter microstructural changes, including maturation of association u-fibres abutting the cortex. These short fibres mediate local cortico-cortical communication and provide an age-sensitive structural substrate that could support a focal disease process. To test this hypothesis, we evaluated the microstructural properties of superficial white matter in regions corresponding to u-fibres underlying the perirolandic seizure onset zone in children with this epilepsy syndrome compared with healthy controls. To verify the spatial specificity of these features, we characterized global superficial and deep white matter properties. We further evaluated the characteristics of the perirolandic white matter in relation to performance on a fine motor task, gender and abnormalities observed on EEG. Children with benign epilepsy with centrotemporal spikes (n = 20) and healthy controls (n = 14) underwent multimodal testing with high-resolution MRI including diffusion tensor imaging sequences, sleep EEG recordings and fine motor assessment. We compared white matter microstructural characteristics (axial, radial and mean diffusivity, and fractional anisotropy) between groups in each region. We found distinct abnormalities corresponding to the perirolandic u-fibre region, with increased axial, radial and mean diffusivity and fractional anisotropy values in children with epilepsy (P = 0.039, P = 0.035, P = 0.042 and P = 0.017, respectively). Increased fractional anisotropy in this region, consistent with decreased integrity of crossing sensorimotor u-fibres, correlated with inferior fine motor performance (P = 0.029). There were gender-specific differences in white matter microstructure in the perirolandic region; males and females with epilepsy and healthy males had higher diffusion and fractional anisotropy values than healthy females (P ≤ 0.035 for all measures), suggesting that typical patterns of white matter development disproportionately predispose boys to this developmental epilepsy syndrome. Perirolandic white matter microstructure showed no relationship to epilepsy duration, duration seizure free, or epileptiform burden. There were no group differences in diffusivity or fractional anisotropy in superficial white matter outside of the perirolandic region. Children with epilepsy had increased radial diffusivity (P = 0.022) and decreased fractional anisotropy (P = 0.027) in deep white matter, consistent with a global delay in white matter maturation. These data provide evidence that atypical maturation of white matter microstructure is a basic feature in benign epilepsy with centrotemporal spikes and may contribute to the epilepsy, male predisposition and clinical comorbidities observed in this disorder.

Persistent abnormalities in Rolandic thalamocortical white matter circuits in childhood epilepsy with centrotemporal spikes

“…First, spike rate is not a reliable biomarker of disease progression in CECTS. 38,39 This is further supported by previous findings that centrotemporal spikes are not sufficient for the development of CECTS and are associated with a number of other epilepsy and neurocognitive disorders. 40 Other compensatory mechanisms, such as those mentioned above, may contribute to spike rate, requiring a more…”

“…There are a number of potential physiologic explanations for this unexpected finding. First, spike rate is not a reliable biomarker of disease progression in CECTS 38,39 . This is further supported by previous findings that centrotemporal spikes are not sufficient for the development of CECTS and are associated with a number of other epilepsy and neurocognitive disorders 40 .…”

“…Alternatively, the electrophysiological impact of structural abnormalities in the Rolandic thalamocortical circuit may be mitigated by other structural or physiologic changes across development. For example, subcortical association fibers integrating Rolandic cortical regions compete with thalamocortical input, mature during childhood and adolescence, and are also abnormal in children with CECTS 37,38 . Overall, these data reveal that children with CECTS do not have a transient disease, but rather develop successful compensatory mechanisms that result in transient symptomatology.…”

“…For example, subcortical association fibers integrating Rolandic cortical regions compete with thalamocortical input, mature during childhood and adolescence, and are also abnormal in children with CECTS. 37,38 Overall, these data reveal that children with CECTS do not have a transient disease, but rather develop successful compensatory mechanisms that result in transient symptomatology.…”

Identifying Common Genes, Cell Types and Brain Regions Between Diseases of the Nervous System

“…The relationships between white matter and these three diseases were well studied. A recent study has discovered the relationship between white matter and epilepsy by evaluating the microstructural properties of superficial white matter in regions corresponding to u-fibers (Ostrowski et al, 2019). The relationship between white matter and migraine was evaluated by a study using magnetization transfer imaging (Arkink et al, 2019).…”