Atrophy in the Left Amygdala Predicted Drug Responses in Idiopathic Generalized Epilepsy Patients With Tonic–Clonic Seizures

Abstract

We aimed to determine the alterations in the subcortical structures of patients with idiopathic generalized epilepsy with tonic–clonic seizures (IGE-GTCS) via MRI volumetry and vertex-based shape analysis and to evaluate the relationships between MRI measures and drug responses. In a follow-up sample of 48 patients with IGE-GTCS and 48 matched normal controls (NCs), high-resolution 3D T1WI was performed at baseline. After 1 year of follow-up, 31 patients were classified as seizure free (SF) and 17 as drug resistant (DR). The volumes of subcortical structures were extracted, and vertex-based shape analysis was performed using FSL-Integrated Registration and Segmentation Toolbox (FSL-FIRST). Comparisons among groups were calculated adjusting for covariates [age, sex, and intracranial volume (ICV)]. Analysis of the relationships among imaging biomarkers along with frequency and duration was assessed using partial correlations. The differential imaging indicators were used as features in a linear support vector machine (LSVM). The DR group displayed significant regional atrophy in the volume of the left amygdala compared with NCs (p = 0.004, false discovery rate corrected) and SF patients (p = 0.029, uncorrected). Meanwhile, vertex-based shape analysis showed focal inward deformation in the basolateral subregion of the left amygdala in DR compared with the results for SF and NC (p < 0.05, FWE corrected). There were significant correlations between the volume changes and seizure frequency (r = −0.324, p = 0.030) and between shape (r = −0.438, p = 0.003) changes and seizure frequency. Moreover, the volume of the left thalamus in the DR group was significantly correlated with seizure frequency (r = −0.689, p = 0.006). The SVM results revealed areas under the receiver operating characteristic curve of 0.82, 0.68, and 0.88 for the classification between SF and DR, between SF and NC, and between DR and NC, respectively. This study indicates the presence of focal atrophy in the basolateral region of the left amygdala in patients with IGE drug resistance; this finding may help predict drug responses and suggests a potential therapeutic target.

Drug resistance in idiopathic generalized epilepsies: Evidence and concepts

“…In contrast, McKavanagh et al 60 described bihemispheric structural and network alterations that differed between drug‐resistant and nonresistant patients. Li et al 61 also found differences between drug‐resistant and nonresistant patients, where atrophy of the basolateral region of the left amygdala was associated with drug resistance. In summary, no reproducible structural changes have yet been identified in drug‐resistant patients.…”

“…The network hypothesis is supported by evidence from fMRI, EEG, and (with limitations) neuropsychological studies that suggests altered functional connectivity in IGE patients compared to healthy controls, indicating that IGEs are network diseases 11 . Different resting state networks have been studied, and drug‐resistant patients seem to be more affected by alterations than drug responders 57,60,61 . This makes their brain more susceptible to seizures and explains the praxis induction and cognitive and psychiatric problems seen in IGE patients 54‐56 .…”

“… 11 Different resting state networks have been studied, and drug‐resistant patients seem to be more affected by alterations than drug responders. 57 , 60 , 61 This makes their brain more susceptible to seizures and explains the praxis induction and cognitive and psychiatric problems seen in IGE patients. 54 , 55 , 56 Network alterations in drug‐resistant patients, apart from giving possible explanations for drug resistance, may lead the way for new treatment options, like deep brain stimulation, previously not used in IGE patients.…”

Alterations of the intrinsic amygdala‐hippocampal network in juvenile myoclonic epilepsy

“…Another study performed mice haploinsufficient in Brd2 , a gene associated with JME, and found decreased numbers of GABA neurons in the basolateral amygdala, which was consistent with the increase in aggressive behavior (Chachua et al., 2014). In addition, a previous study which investigated the alterations in the subcortical structures of patients with genetic generalized epilepsy, indicated the relationship between presence of focal atrophy in the basolateral amygdala and drug resistance (Li et al., 2021). Taken together, all of these findings suggested that the amygdala–hippocampus may play a key role in the pathogenesis of JME.…”

Chemoarchitectural Signatures of Subcortical Shape Alterations in Generalized Epilepsy

“…Subcortical nuclei are essential for multiple cognitive and motor functions, and thus are hypothesized to play a central role in the neural circuitry pathology underlying GGE [6][7][8] . Numerous volumetric structural studies have determined the volume alterations of subcortical nuclei in GGE, but the results have been inconsistent, with both atrophy and expansion reported in the thalamus [9][10][11][12] . Volumetric analysis methods do not capture the shape complexities of subcortical structures, and therefore, are not well-suited for characterizing detailed morphological abnormalities that may be present in GGE 13 .…”