The Effect Of Metabolic,Functional And Structural Changes Of Hippocampus On Resistant Mechanism In Patients With Idiopathic Generalized Epilepsy With Generalized Tonic-Clonic Seizure

OBJECTIVE:By investigation of the metabolic,functional and structural changes of hippocampus using multi-modal magnetic resonance imaging?MRI?in patients with idiopathic generalized epilepsy with generalized tonic clonic seizure?IGE-GTCS?,we analyzed the role of hippocampus on drug resistant mechanism in patients with IGE-GTCS and provided an imaging marker of early clinical assessment and prognosis for patients with epilepsy.Methods:From 2012 to 2016,sixty-two patients with IGE-GTCS?age:25.2±10.7;male/female:34/28?from Neurology Department of Drum Tower Hospital were included in this study.Seventeen healthy young adults?age:25.1±0.8;male/female:8/9?were recruited as normal controls?NC?.Imaging acquisitions,including 1H-MR spectroscopy?1H-MRS?of bilateral hippocampi,resting state functional MRI?rest-fMRI?and structural imaging?three dimensional T1 weighted imaging,3DT1WI?,were performed by a 3.0 Tesla MR scanner?Achieva 3.0 T TX dual Medical Systems;Philips Medical Systems,Eindhoven,Netherlands?.After over 12-month follow-up,according to the definition of drug resistant epilepsy by the International League Against Epilepsy,patients were devided into the following three groups:After standardized and adequate antiepileptic therapy,patients with seizure-free duration three times longer than the longest seizure interictal duration or seizure-free duration over 12 months were identified as drug sensitive group?DS,N=22?,otherwise identified as drug resistant group?DR,N=14?.And patients with seizure-free duration three times longer than the longest seizure interictal duration and with total seizure-free duration less than 12 months were identified as uncertain group?UC,N=26?,which were excluded in this study.Part1.Using MRS to evaluate the neuronal damages of hippocampus in patients with IGE-GTCS.Philips's Extended Workspace?EWS?Spectroview package was used to detect the concentrations of N-acetylaspartate?NAA?,myo-inositol?MI?and choline?Cho?,and to calculate the metabolites ratios to creatine?Cr?.Part2.Using the rest-fMRI to detect the functional connectivity?FC?impairment of hippocampus in patients with drug resistant IGE-GTCS and the prediction to drug resistance.The rest-fMRI were processed by DPARSF and rest for placing seeds in bilateral hippocampi and calculating FC between seeds and global network.One-way analysis of variance?ANOVA?and Post Hoc Tests were performed to detect the differences of FC among the groups.Spearman's Correlation Test and receiver operating characteristic?ROC?were performed to evaluate the correlations between FC and clinical assessments and to determine the discrimination threshold of FC,respectively.Part3.Using volumetric analysis to assess the hippocampal damage and the prediction to drug resistance of volumetric reduction.Structural imaging were processed by FreeSurfer?version 5.3.0?,for volumetry segmentation and the hippocampus was further segmented into subfields.ANOVA and Post Hoc Tests,and Spearman ' s Correlation Test were performed to detect the hippocampal volumetric changes and to evaluate the correlations between clinical assessments and hippocampal atrophy in patients with drug-resistant IGE-GTCS,respectively.RESULTS:Part1.Decreased NAA/Cr and increased MI/Cr were found in left hippocampus in DR and DS patients.The trend of NAA/Cr ratio among the groups was DR<DS<NC while the trend of MI/Cr ratio was NC<DS<DR.No asymetry changes of NAA/Cr?p=0.33,p=0.32?and MI/Cr?p=0.33,p=0.11?were found in left and right hippocampimong the groups.No correlations of metabolites changes and clinical assessments were found.Part2.1.ANOVA?Alphasim correction:p<0.01?:Variable areas were left thalumas,left putamen,left insular,and right precentral gyru among the groups when placing seed in the left hippocampus,while variable area was found in right precentral gyru when placing the seed in the right hippocampus.2.Post Hoc Tests?Alphasim correction:p<0.05?of FC between seeds and variable areas:In compared with DS and NC subjects respectively,significant decreased FC was found among DR patients between left hippocamus seed and the left thalumas?p<0.001,p=0.012?,left putamen?p<0.001,p=0.003?and left precuneus?p<0.001,p=0.042?,while increased FC was found among the DS patients between left hippocampus seed and left putamen?p=0.04?,left precuneus?p=0.001?and right precentral gyrus?p<0.001?in compared with NC patients.In compared with DS,decraesed FC were found among DR?p=0.018?and NC?p<0.001?patients between right hippocampus seed and right precentral gyru.3.The FC between left hippocampus seed and left thalamus-putamen was found to be negatively correlated with duration?r=-0.437,p=0.02?.4.ROC curve indicated that the sensitivity to drug resistant IGE-GTCS of FC between left hippocampus seed and left thalamus-putamen is 100%and the specificity is 89.5%,and the critical FC=0.30.Part3.1.Atrophy of hippocampus and hippocampal subfields were found among the DS and DR patients in compared with NC subjects,and the significant changes were in the left.The trend of hippocampal volumetry were DR<DS<NC.2.In compared with NC subjects,atrophy of left hippocampus?p=0.011?,left CA2₃?p=0.034?,CA4_DG?p=0.020?,presubiculum?p=0.048?and subiculum?p=0.018?were found among the DR patients,while decreased volumes of left hippocampus?p=0.044?,left CA4_DG?p=0.049?and left presubiculum?p=0.048?were detected in the DS group.No significant differences of hippocampal volumetric changes were found between the DR and DS patients.Conclusion:1.Decreasing trend of NAA/Cr in bilateral hippocampi were found among DR patients with no statistical significance probably indicated slight loss of hippocampal neuron.2.Decreased FC of bilateral hippocampi were found among DR patients while an increased FC was found among the DS patients,indicating the functional compensatory of DS patients and dysfunction of DR patients.The ROC curve suggested that the FC btween left hippocampus seed and left thalamus-putamen could be the sensitive and specified indicator of DR patients.3.Atrophy of bilateral hippocampi and hippocampal subfields were found among the DR patients,indicating a hippocamapal structural damage.In summary,the pathological role of hippocampus in IGE-GTCS,especially in DR patients,could be the irreversible neuronal loss and proliferation of gliocytes within the hippocampus after repeating GTCS result to integrity between hippocampus and global network,and the exceeded compensation of the network eventually lead to drug resistance.Therefore the reduced FC between hippocampus and global network could be a reliable imaging marker in drug resistance prediction.