Focal to bilateral tonic-clonic seizures are associated with widespread network abnormality in temporal lobe epilepsy.

Nishant Sinha,Yujiang Wang,Jane De Tisi,Natalie Peternell,Gabrielle M Schroeder,Gavin P Winston,John S Duncan,Sjoerd B Vos,Peter N Taylor

doi:10.1111/epi.16819

Abstract

ObjectiveOur objective was to identify whether the whole‐brain structural network alterations in patients with temporal lobe epilepsy (TLE) and focal to bilateral tonic–clonic seizures (FBTCS) differ from alterations in patients without FBTCS.MethodsWe dichotomized a cohort of 83 drug‐resistant patients with TLE into those with and without FBTCS and compared each group to 29 healthy controls. For each subject, we used diffusion‐weighted magnetic resonance imaging to construct whole‐brain structural networks. First, we measured the extent of alterations by performing FBTCS‐negative (FBTCS−) versus control and FBTCS‐positive (FBTCS+) versus control comparisons, thereby delineating altered subnetworks of the whole‐brain structural network. Second, by standardizing each patient's networks using control networks, we measured the subject‐specific abnormality at every brain region in the network, thereby quantifying the spatial localization and the amount of abnormality in every patient.ResultsBoth FBTCS+ and FBTCS− patient groups had altered subnetworks with reduced fractional anisotropy and increased mean diffusivity compared to controls. The altered subnetwork in FBTCS+ patients was more widespread than in FBTCS− patients (441 connections altered at t > 3, p < .001 in FBTCS+ compared to 21 connections altered at t > 3, p = .01 in FBTCS−). Significantly greater abnormalities—aggregated over the entire brain network as well as assessed at the resolution of individual brain areas—were present in FBTCS+ patients (p < .001, d = .82, 95% confidence interval = .32–1.3). In contrast, the fewer abnormalities present in FBTCS− patients were mainly localized to the temporal and frontal areas.SignificanceThe whole‐brain structural network is altered to a greater and more widespread extent in patients with TLE and FBTCS. We suggest that these abnormal networks may serve as an underlying structural basis or consequence of the greater seizure spread observed in FBTCS.

Highlights

Many studies have suggested that impairments in specific brain regions support Focal to bilateral tonic–clonic seizures (FBTCS), after finding disrupted structure and function in circuits mediated by thalamus and basal ganglia.[6,12,13,14,15,16,17,18]
Our main objective was to investigate whether the deviation in brain network structure from the normal range would be greater in patients with a history of FBTCS
We investigated the alterations in brain networks of patients at the resolution of individual connections to identify the abnormal subnetwork and assess how large that subnetwork is in FBTCS+ and FBTCS− patients

Summary

Introduction

Focal to bilateral tonic–clonic seizures (FBTCS) of temporal lobe origin rapidly propagate to widespread brain areas, with variable patient-specific propagation patterns and clinical characteristics.[1,2] FBTCS are the most severe form of epileptic seizures that predispose patients to high risk of sudden unexpected death in epilepsy and seizure-related injuries.[3,4,5] FBTCS are an adverse prognostic factor for seizure freedom after temporal lobe resection.[6,7,8] It remains unclear why temporal lobe seizures generalize in some patients but not in others.[9,10] It is crucial to identify factors that make some patients susceptible to FBTCS despite taking seizuresuppressing medications.Recognizing the need to quantify patient susceptibility to FBTCS, some studies have investigated a range of clinical factors to differentiate patients with and without FBTCS,[7,11] showing positive association with the presence of hippocampal sclerosis and negative association with ictal speech and pedal automatism.[7]. Many studies have suggested that impairments in specific brain regions support FBTCS, after finding disrupted structure and function in circuits mediated by thalamus and basal ganglia.[6,12,13,14,15,16,17,18] It has been suggested that FBTCS have a different mechanism to primary generalized seizures, with more complex patient-specific spread.[10,19,20,21,22,23] There is a need to investigate the full complexity of brain networks,[24] beyond the canonical thalamocortical pathways,[12] to delineate networks underlying FBTCS

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Results

Conclusion