Localized shape abnormalities in the thalamus and pallidum are associated with secondarily generalized seizures in mesial temporal lobe epilepsy
Introduction
Mesial temporal lobe epilepsy (mTLE) is a common type of focal epilepsy, and is usually accompanied by hippocampal sclerosis. Seizures that occur in TLE with hippocampal sclerosis (TLE–HS) are typically resistant to antiepileptic drugs, which are associated with severe cognitive impairment, affective disorders, and stigmatization [1], [2]. Among the seizure types associated with TLE–HS, secondarily generalized tonic–clonic seizures (sGTCS) are the most debilitating type and these in turn put the patients at additional risk of fatal injuries. Additionally, patients with TLE and sGTCS demonstrated worse surgical outcomes after anterior temporal lobectomy compared to those without sGTCS [3], [4].
Advancing the treatment strategies of sGTCS requires a detailed and clear understanding of the mechanism as to how the seizures are initiated, propagated, and terminated. However, the mechanism underlying the genesis of the sGTCS in mTLE has not been fully elucidated. Changes of cerebral blood flow (CBF) in the thalamus, basal ganglia, and fronto-parietal cortex during the transition from partial seizures to secondarily generalization have been reported in patients with a mixed group of temporal and extra-temporal lobe epilepsy [5]. Some electrophysiological studies suggested that the basal ganglia exert an inhibitory effect against sGTCS in patients with mTLE [6], [7], [8]. Also, changes in the blood oxygen level-dependent (BOLD) signals were associated with generalized spike-wave (GSW) activity in the thalamo–cortical network. These were found in both primarily and secondarily generalized epilepsies, using simultaneous electroencephalogram and functional magnetic resonance imaging (EEG–fMRI) [9], [10]. These lines of evidence suggest functional involvement of the basal ganglia-thalamo-cortical network in sGTCS. However, it remains unknown whether the structural alterations in these key nodes such as basal ganglia, thalamus, and cortex are involved in the pathophysiological mechanism of sGTCS.
Clinically, some patients with mTLE have sGTCS despite taking appropriate medication treatment, while some other patients have only partial seizures even though not on medications. This discrepancy in susceptibility to sGTCS might be associated with differences in the epileptogenic network, which may be reflected by morphometric analysis. In the present study, we investigated the relationship between cortical and subcortical gray matter (GM) alterations and the occurrence of sGTCS in a cohort of patients with unilateral TLE-HS. In particular, we initially applied sophisticated morphometric approaches to investigate the regional alterations in cortical volume and the surface shape of the thalamus and basal ganglia in patients with sGTCS versus those without sGTCS (non-sGTCS). Subsequently, we compared the structural alterations in patients with sGTCS that were not controlled by appropriate medical treatment (uncontrolled-sGTCS) versus those with medically controlled sGTCS (controlled-sGTCS).
Section snippets
Participants
From April 2014 to June 2016, consecutive Chinese patients with unilateral TLE–HS, as confirmed by the clinical workup and imaging findings, were included in this study. Hippocampal sclerosis was defined if both hippocampal atrophy and increased T2 signals were observed on MRI [11]. All the patients were diagnosed by at least two experienced epileptologists based on history, seizure semiology, long-term scalp video-EEG monitoring, neuroimaging findings, and neuropsychological assessments. Some
Demographic and clinical data
Thirty-nine patients with unilateral TLE–HS were enrolled. Of these, three of them were diagnosed with stereo-EEG evaluation and postoperative pathologic findings. The mean age was 31.2 ± 9.7 years and 15 of them (38.5%) were male. The age at onset was 15.6 ± 8.8 years, with a mean duration of 15.6 ± 10.4 years. Twenty patients (56.4%) had left TLE–HS.
Based on the seizure type, the patients were divided into two groups: sGTCS (n = 21), and non-sGTCS (n = 18). The two groups showed no statistically
Discussion
Our study firstly revealed the structural alterations underlying the occurrence of sGTCS. In the mTLE study cohort, regional atrophy of the ipsilateral thalamus, pallidum, MFG, and contralateral PCC was associated with occurrence of sGTCS. Furthermore, the uncontrolled-sGTCS subgroup showed more pronounced atrophy in the ipsilateral thalamus than the controlled-sGTCS subgroup. These findings suggest that sGTCS in mTLE are not associated with diffused GM loss but rather are related to localized
Conclusion
Localized atrophy in the ipsilateral basal ganglia, thalamus, as well as bilateral cortical regions forms the structural basis of sGTCS in mTLE. This morphologic analysis supports the basal ganglia–thalamo–cortical network as playing an important role in the genesis of sGTCS.
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical standard
The study was approved by the Medical Ethics Committee of the Second Affiliated Hospital, Zhejiang University School of Medicine and written informed consent was obtained from all subjects (Study No. 2014-151).
Acknowledgement
This research was supported by the National Natural Science Foundation of China (No. 81271435, 81671282 and 91332202).
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These authors contributed equally.