Temporal Lobe Epilepsy Patients Research Articles

MRI-Negative Medial Temporal Lobe Epilepsy can Benefit from Stereotactic Radiofrequency Thermocoagulation Applied to the Amygdalohippocampal Complex.

Seizure control (SC) is often poor in cases of magnetic resonance imaging- negative epilepsy after resection surgery. This study aimed to evaluate the therapeutic efficacy of depth-electrode-guided stereotactic radiofrequency thermocoagulation (RFTC) applied to the amygdalohippocampal complex (AHC) for the treatment of patients with MRI-negative medial temporal lobe epilepsy. A total of 62 cases with magnetic resonance imaging-negative medial temporal lobe epilepsy were retrospectively studied after the application of depth-electrode-guided RFTC to the AHC. Single-target coagulations were applied to all patients, and multi-target coagulations were applied to those patients who did not experience significant reductions in discharges after the first target ablation. Bilateral-target coagulations were applied to bilateral medial temporal lobe epilepsy patients, using single target ablation applied to each side. After 24-83 months of follow-up, 32/62 (51.61%) patients became seizure-free, and 35/62 (56.45%) patients reported significant reductions in seizure episodes. The total effective rate was 69.35% (43/62). No significant differences were observed for SC among the single-target, multi-target, and bilateral-target groups. However, a significant difference was observed for the reduction in epileptic discharges after coagulations between those patients who became seizure-free and those who did not. Magnetic resonance imaging-negative medial temporal lobe epilepsy patients can benefit from RFTC applied to the AHC. A significant reduction in epileptic discharges observed during operations after RFTC is applied may predict good SC. RFTC applied to the AHC could be considered a promising method for the treatment of magnetic resonance imaging-negative medial temporal lobe epilepsy patients.

Disruption of Cerebellar-Cerebral Functional Connectivity in Temporal Lobe Epilepsy and the Connection to Language and Cognitive Functions.

ObjectiveTo investigate the changes in the cerebellar-cerebral language network in temporal lobe epilepsy (TLE) patients from the cerebellar perspective, the research analyzes the changes of language and cognitive network in terms of functional connectivity (FC), as well as their efficiency of the reorganization were evaluated basing on relationship between the network metrics and neuropsychological scale scores.Methods30 TLE patients and 30 healthy controls were recruited. Brain activity was evaluated by voxel-mirrored homotopic connectivity analysis (VMHC). Two groups were analyzed and compared in terms of language FC using the following methods: Seed-to-Voxel analysis, pairwise correlations [region of interest(ROI)-to-ROI] and graph theory. Correlation analysis was performed between network properties and neuropsychological score.ResultsCompared with healthy participants, VMHC values in the Cerebellum Anterior Lobe, Frontal Lobe, Frontal_Sup_R/L, Cingulum_Ant_R/L, and Cingulum_Mid_R/L were decreased in TLE patients. Decreased FC was observed from the Cerebelum_10_R to the left inferior frontal gyrus, from the Cerebelum_6_R to the left Lingual Gyrus, from the Cerebelum_4_5_R to left Lingual Gyrus, left Cuneal Cortex and Precuneous Cortex, from the Cerebelum_3_R to Brain-Stem, and from the Cerebelum_Crus1_L to Cerebelum_6_R in TLE patients. The FC was enhanced between bilateral Cingulum_Mid and angular gyrus and frontoparietal insular cranium, between Frontal_Sup_Med L and left/right superior temporal gyrus (pSTG l/r), while it was decreased between left middle temporal gyrus and pSTG l/r. Compared with controls, the Betweenness Centrality (BC) of the right superior marginal gyrus (SMG), Temporal_Pole_Mid_R and Temporal_Mid_L as well as the Degree Centrality (DC) and Nodal Efficiency (NE) of the right SMG were lower in TLE patients. Further analysis showed that decreased VMHC in bilateral Cerebellum Anterior Lobe was positively correlated with the Boston Naming Test score in TLE patients, but it was negatively correlated with the Verbal Fluency Test score. The NE and DC of SMG_R were both negatively correlated with visual perception score in Montreal Cognitive Assessment.ConclusionOur results suggest that presence of abnormalities in the static functional connectivity and the language and cognitive network of TLE patients. Cerebellum potentially represents an intervention target for delaying or improving language and cognitive deficits in patients with TLE.

The Degree Centrality and Functional Connectivity in Patients With Temporal Lobe Epilepsy Presenting as Ictal Panic: A Resting State fMRI Study.

ObjectivesIctal panic (IP) can be observed occasionally in patients with temporal lobe epilepsy (TLE). Such descriptions can be found in previous studies, but the mechanism is still not clear and often confused with panic attacks in patients with panic disorder (PD). We try to use imaging methods (resting-state functional magnetic resonance imaging, rs-fMRI) to study the mechanism of this psychiatric comorbidity in patients with TLE.MethodsForty right-onset TLE patients were observed, including 28 patients with TLE but without IP and 12 patients with TLEIP along with 30 gender-age matched healthy controls were included. We collected clinical/physiological/neuropsychological and rs-fMRI data. Degree centrality (DC) and functional connectivity (FC) were calculated. For the DC and FC values, analysis of covariance (ANCOVA) was used to find different areas and t-tests were used to compare differences between the TLEIP, TLE without IP, and healthy control(HC)groups. The relationship between brain abnormalities and patient characteristics was explored by correlation analyses.ResultsNo significant differences in gender and age were found among the three groups, and no significant differences in education level, Montreal Cognitive Assessment (MOCA), Hamilton Depressive Scale (HAMD), Hamilton Anxiety Scale (HAMA), and epilepsy duration (years) between the TLEIP and TLE without IP groups. In addition to fear, other symptoms were observed, including nausea, palpitations, rising epigastric sensation, and dyspnea. There was no correlation between the duration of IP and HAMA. Moreover, all IP durations were <2 min. Compared to the HCs and TLE without IP group, the DC value of the TLEIP group in the left middle temporal gyrus (LMTG) was significantly increased. Compared to the HCs, FC could be found between the LMTG and left inferior temporal gyrus (LITG) in the TLEIP group. In addition, there was FC between the LMTG and cerebellum in the TLEIP group. The difference in the magnitude of FC between the TLEIP vs. HC group was greater than the difference between the TLE vs. HC group.ConclusionsThis study describes brain abnormalities in patients with TLEIP. These results will help to preliminarily understand the mechanism of ictal panic and abnormal functional connection in patients with TLE, and further explore the neuroimaging mechanism of ictal panic in patients with TLE.

Volumetric analysis of the piriform cortex in temporal lobe epilepsy

The piriform cortex, at the confluence of the temporal and frontal lobes, generates seizures in response to chemical convulsants and electrical stimulation. Resection of more than 50% of the piriform cortex in anterior temporal lobe resection for refractory temporal lobe epilepsy (TLE) was associated with a 16-fold higher chance of seizure freedom. The objectives of the current study were to implement a robust protocol to measure piriform cortex volumes and to quantify the correlation of these volumes with clinical characteristics of TLE. Sixty individuals with unilateral TLE (33 left) and 20 healthy controls had volumetric analysis of left and right piriform cortex and hippocampi. A protocol for segmenting and measuring the volumes of the piriform cortices was implemented, with good inter-rater and test-retest reliability. The right piriform cortex volume was consistently larger than the left piriform cortex in both healthy controls and patients with TLE. In controls, the mean volume of the right piriform cortex was 17.7% larger than the left, and the right piriform cortex extended a mean of 6 mm (Range: −4 to 12) more anteriorly than the left. This asymmetry was also seen in left and right TLE. In TLE patients overall, the piriform cortices were not significantly smaller than in controls. Hippocampal sclerosis was associated with decreased ipsilateral and contralateral piriform cortex volumes. The piriform cortex volumes, both ipsilateral and contralateral to the epileptic temporal lobe, were smaller with a longer duration of epilepsy. There was no significant association between piriform cortex volumes and the frequency of focal seizures with impaired awareness or the number of anti-seizure medications taken. Implementation of robust segmentation will enable consistent neurosurgical resection in anterior temporal lobe surgery for refractory TLE..

Abnormal Ventral Somatomotor Network Homogeneity in Patients With Temporal Lobe Epilepsy.

BackgroundAbnormalities of functional connectivity in the somatomotor network have been thought to play an essential role in the pathophysiology of epilepsy. However, there has been no network homogeneity (NH) study about the ventral somatomotor network (VSN) in patients with temporal lobe epilepsy (TLE). Therefore, we explored the NH of the VSN in TLE patients in this study.MethodsThe sample included 52 patients with left temporal lobe epilepsy, 83 patients with right temporal lobe epilepsy, and 68 healthy controls. The NH method was utilized to analyze the resting-state functional magnetic resonance imaging data.ResultsCompared to the controls, rTLE patients had significantly higher NH in the bilateral postcentral gyrus, and significantly lower NH in the bilateral Rolandic operculum and the right superior temporal gyrus (STG). The NH values of the left postcentral gyrus were significantly higher in lTLE patients than in the healthy controls, and lTLE patients had lower NH in the right Rolandic operculum. The altered NH in the postcentral gyrus was negatively correlated with the illness duration, and the decreased NH in the left Rolandic operculum was negatively correlated with the executive control reaction time (ECRT).ConclusionOur findings suggest that altered NH of the postcentral gyrus, Rolandic operculum and STG might be associated with the pathophysiology of TLE, and thus, highlight the contribution of the VSN to the pathophysiology of TLE.

Combined [18F]FDG-PET with MRI structural patterns in predicting post-surgical seizure outcomes in temporal lobe epilepsy patients.

To integrate the glucose metabolism measured using [18F]FDG PET/CT and anatomical features measured using MRI to forecast the post-surgical seizure outcomes of intractable temporal lobe epilepsy. This retrospective study enrolled 63 patients with drug-resistant temporal lobe epilepsy. Z-transform of the patients' PET images based on comparison with a database of healthy controls, cortical thickness, and quantitative anisotropy (QA) of the diffusion spectrum imaging concordant/non-concordant with cortical resection was adopted to quantify their predictive values for the post-surgical seizure outcomes. The PET hypometabolism region was concordant with the surgical field in 47 of the 63 patients. Forty-two patients were seizure-free post-surgery. The sensitivity and specificity of PET in predicting seizure freedom were 89.4% and 68.8%, respectively. Complete resection of foci with overlapped PET, cortical thickness, and QA abnormalities resulted in Engel I in 27 patients, which was a good predictor of seizure freedom with an odds ratio (OR) of 19.57 (95% CI 2.38-161.25, p = 0.006). Hypometabolism involved in multiple lobes (OR = 7.18, 95% CI 1.02-50.75, p = 0.048) and foci of hypometabolism with QA/cortical thickness abnormalities outside surgical field (OR = 14.72, 95% CI 2.13-101.56, p = 0.006) were two major predictors of Engel III/IV outcomes. ORs of QA to predict Engel I and seizure recurrence were 14.64 (95% CI 2.90-73.80, p = 0.001) and 12.01 (95% CI 2.91-49.65, p = 0.001), respectively. Combined PET and structural pattern is helpful to predict the post-surgical seizure outcomes and worse outcomes of Engel III/IV. This might decrease unnecessary surgical injuries to patients who are potentially not amenable to surgery. • A combined metabolic and structural pattern is helpful to predict the post-surgical seizure outcomes. • Favorable post-surgical seizure outcome was most likely reached in patients whose hypometabolism overlapped with the structural changes. • Hypometabolism in multiple lobes and QA or cortical thickness abnormalities outside the surgical field were predictors of worse seizure outcomes of Engel III/IV.

A resting-state fMRI study of temporal lobe epilepsy using multivariate pattern analysis and Granger causality analysis.

Understanding the pathogenesis of temporal lobe epilepsy (TLE) is essential for its diagnosis and treatment. The study aimed to explore regional homogeneity (ReHo) and changes in effective connectivity (EC) between brain regions in TLE patients, hoping to discover potential abnormalities in certain brain regions in TLE patients. Resting-state functional magnetic resonance data were collected from 23 TLE patients and 32 normal controls (NC). ReHo was used as a feature of multivariate pattern analysis (MVPA) to explore the ability of its alterations in identifying TLE. Based on the results of the MVPA, certain brain regions were selected as seed points to further explore alterations in EC between brain regions using Granger causality analysis. MVPA results showed that the classification accuracy for the TLE and NC groups was 87.27%, and the right posterior cerebellum lobe, right lingual gyrus (LING_R), right cuneus (CUN_R), and left superior temporal gyrus (STG_L) provided significant contributions. Moreover, the EC from STG_L to right fusiform gyrus (FFG_R) and LING_R and the EC from CUN_R to the right occipital superior gyrus (SOG_R) and right occipital middle gyrus (MOG_R) were altered compared to the NC group. The MVPA results indicated that ReHo abnormalities in brain regions may be an important feature in the identification of TLE. The enhanced EC from STG_L to FFG_R and LING_R indicates a shift in language processing to the right hemisphere, and the weakened EC from SOG_R and MOG_R to CUN_R may reveal an underlying mechanism of TLE.

Correlation Between the Functional Connectivity of Basal Forebrain Subregions and Vigilance Dysfunction in Temporal Lobe Epilepsy With and Without Focal to Bilateral Tonic-Clonic Seizure.

PurposePrevious research has shown that subcortical brain regions are related to vigilance in temporal lobe epilepsy (TLE). However, it is unknown whether alterations in the function and structure of basal forebrain (BF) subregions are associated with vigilance impairment in distinct kinds of TLE. We aimed to investigate changes in the structure and function BF subregions in TLE patients with and without focal to bilateral tonic-clonic seizures (FBTCS) and associated clinical features.MethodsA total of 50 TLE patients (25 without and 25 with FBTCS) and 25 healthy controls (HCs) were enrolled in this study. The structural and functional alterations of BF subregions in TLE were investigated using voxel-based morphometry (VBM) and resting-state functional connectivity (rsFC) analysis. Correlation analyses were utilized to investigate correlations between substantially altered imaging characteristics and clinical data from patients.ResultsFBTCS patients had a lower rsFC between Ch1-3 and the bilateral striatum as well as the left cerebellum posterior lobe than non-FBTCS patients. In comparison to non-FBTCS patients, the rsFC between Ch4 and the bilateral amygdala was also lower in FBTCS patients. Compared to HCs, the TLE patients had reduced rsFC between the BF subregions and the cerebellum, striatum, default mode network, frontal lobe, and occipital lobes. In the FBTCS group, the rsFC between the left Ch1-3 and striatum was positive correlated with the vigilance measures. In the non-FBTCS group, the rsFC between the left Ch4 and striatum was significantly negative correlated with the alertness measure.ConclusionThese results extend current understanding of the pathophysiology of impaired vigilance in TLE and imply that the BF subregions may serve as critical nodes for developing and categorizing TLE biomarkers.

P.111 In vivo hippocampal mGluR5 abnormalities predict MTLE post-surgical outcome

Background: PET imaging of [11C]ABP688 shows reduced hippocampal mGluR5 availability in mesial temporal lobe epilepsy (MTLE) patients, however the relation with post-surgical outcomes is unclear. Here, we tested whether [11C]ABP688 binding in hippocampal subfields vulnerable to glutamate excitotoxicity is related to post-surgical outcome. Methods: [11C]ABP688-PET was obtained from 31 unilateral MTLE patients and 30 controls. Hippocampal subfields were automatically segmented into 1) CA1-3, 2) CA4/dentate gyrus (DG), 3) Subiculum and manually corrected. Partial volume corrected [11C]ABP688 non-displaceable binding potential (BPND) was calculated in the subfields and compared between seizure-free and non-seizure-free patients. Results: [11C]ABP688 BPND was significantly reduced in ipsilateral CA1-3 &amp; CA4/DG (p&lt;0.001) compared to controls. No difference was seen in Subiculum. Ipsilateral CA1-3 [11C]ABP688 BPND was lower in seizure-free (p=0.012; Engel Ia, n=13) vs non-seizure- free (Engel Ic-III, n=10) patients, and this effect was independent of subfield volume. In a subset of patients with [18F]FDG-PET, CA1-3 [11C]ABP688 BPND was significantly lower in seizure-free patients (p=0.03), while no difference was found for [18F]FDG uptake. Conclusions: Reduced CA1-3 mGluR5 availability was associated with post-surgical seizure-freedom independent of atrophy and hypometabolism. Thus, [11C]ABP688-PET may offer a potential biomarker for surgical outcomes and may be particularly relevant for pre-surgical workup in MRI- and [18F]FDG-negative MTLE patients.

Higher phase-amplitude coupling between ripple and slow oscillations indicates the distribution of epileptogenicity in temporal lobe epilepsy with hippocampal sclerosis

Objective: We assessed the diagnostic utility of the occurrence rate of high-frequency oscillations and modulation index (MI) from intraoperative electrocorticography (ioECoG) in determining the extent of epileptogenicity in mesial temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS).Methods: We enrolled 17 patients who underwent selective amygdalohippocampectomy (SelAH) for TLE due to HS. We analyzed the occurrence rate of ripples (80–200 Hz) and fast ripples (200–300 Hz); and MI between ripples and 3–4 Hz (MIRipples/3–4 Hz) and fast ripples and 3–4 Hz (MIFRs/3–4 Hz) from the amygdala, hippocampus, and lateral temporal lobe (LTL) pre-SelAH and the LTL post-SelAH, and subsequently categorized the patients into good and poor seizure outcome groups. We compared the occurrence rates and MIs over each region of interest between both groups. Receiver operating characteristic analysis was used to identify the most optimal indicator to predict poor surgical outcomes.Results: In the poor seizure outcome group, an increase in the occurrence rate of ripples was seen in the hippocampus and LTL pre-SelAH and the LTL post-SelAH. The MIRipples/3–4 Hz from the LTL pre-SelAH was the most indicative factor of poor outcome.Conclusions: High occurrence rate of ripples and MIRipples/3–4 Hz from the LTL showed wide epileptogenicity in TLE patients with poor seizure outcomes after SelAH. Our data suggest that the analysis of the occurrence rate of HFOs and MIHFOs/3–4 Hz from ioECoG, especially from the LTL, can indicate the distribution of epileptogenicity in TLE with HS.

Correlation between fluorodeoxyglucose positron emission tomography brain hypometabolism and posttraumatic stress disorder symptoms in temporal lobe epilepsy.

The relationship between posttraumatic stress disorder (PTSD) and focal epilepsy is poorly understood. It has been hypothesized that there is a complex and reciprocal potential reinforcement of the symptoms of each condition. In this study, we investigated whether there are PTSD‐specific brain changes in temporal lobe epilepsy (TLE). Brain fluorodeoxyglucose positron emission tomography (PET) metabolism was compared between controls and two groups of TLE patients: one group of 15 patients fulfilling the criteria for a potential diagnosis of PTSD (TLE‐PTSD+), another group of 24 patients without a diagnosis of PTSD (TLE‐PTSD‐), and a group of 30 healthy control participants. We compared the differences in brain PET metabolism among these three groups, and we studied their correlations with interictal and peri‐ictal scales of PTSD symptoms. TLE‐PTSD+ patients showed more significant hypometabolism involving right temporal and right orbitofrontal cortex in comparison to TLE‐PTSD‐ patients and healthy subjects. Moreover, degree of reduced metabolism in these brain areas correlated with interictal and peri‐ictal PTSD questionnaire scores. PTSD in temporal epilepsy is associated with specific changes in neural networks, affecting limbic and paralimbic structures. This illustrates the close intertwining of epileptogenic and psychogenic processes in these patients.

Expression profile of synaptic vesicle glycoprotein 2A, B, and C paralogues in temporal neocortex tissue from patients with temporal lobe epilepsy (TLE)

Synaptic vesicle glycoprotein-2 (SV2) is a family of proteins consisting of SV2A, SV2B, and SV2C. This protein family has attracted attention in recent years after SV2A was shown to be an epileptic drug target and a perhaps a biomarker of synaptic density. So far, the anatomical localization of these proteins in the rodent and human brain have been reported, but co-expression of SV2 genes on a cellular level, their expressions in the human brain, comparison to radioligand binding, any possible regulation in epilepsy are not known. We have here analyzed the expression of SV2 genes in neuronal subtypes in the temporal neocortex in selected specimens by using single nucleus-RNA sequencing, and performed quantitative PCR in populations of temporal lobe epilepsy (TLE) patients and healthy controls. [3H]-UCB-J autoradiography was performed to analyze the correlation between the mRNA transcript and binding capacity to SV2A. Our data showed that the SV2A transcript is expressed in all glutamatergic and GABAergic cortical subtypes, while SV2B expression is restricted to only the glutamatergic neurons and SV2C has very limited expression in a small subgroup of GABAergic interneurons. The level of [3H]-UCB-J binding and the concentration of SV2A mRNA is strongly correlated in each patient, and the expression is lower in the TLE patients. There is no relationship between SV2A expression and age, sex, seizure frequency, duration of epilepsy, or whether patients were recently treated with levetiracetam or not. Collectively, these findings point out a neuronal subtype-specific distribution of the expression of the three SV2 genes, and the lower levels of both radioligand binding and expression further emphasize the significance of these proteins in this disease.

Automated temporal lobe epilepsy and psychogenic nonepileptic seizure patient discrimination from multichannel EEG recordings using DWT based analysis

Psychogenic nonepileptic seizure (PNES) and epileptic seizure resemble each other, behaviorally. This similarity causes misdiagnosis of PNES and epilepsy patients, thus patients suffering from PNES may be treated with antiepileptic drugs which can have various side effects. Furthermore, seizure is diagnosed after time consuming examination of electroencephalography (EEG) recordings realized by the expert. In this study, automated temporal lobe epilepsy (TLE) patient, PNES patient and healthy subject discrimination method from EEG signals is proposed in order to eliminate the misdiagnosis and long inspection time of EEG recordings. Also, this study provides automated approach for TLE interictal and ictal epoch classification, and TLE, PNES and healthy epoch classification. For this purpose, subbands of EEG signals are determined from discrete wavelet transform (DWT), then classification is performed using ensemble classifiers fed with energy feature extracted from the subbands. Experiments are conducted by trying two approaches for TLE, PNES and healthy epoch classification and patient discrimination. Results show that in the TLE, PNES and healthy epoch classification the highest accuracy of 97.2%, sensitivity of 97.9% and specificity of 98.1% were achieved by applying adaptive boosting method, and the highest accuracy of 87.1%, sensitivity of 86.0% and specificity of 93.6% were attained using random under sampling (RUS) boosting method in the TLE patient, PNES patients and the healthy subject discrimination.

Cortical remodeling before and after successful temporal lobe epilepsy surgery.

To explore dynamic alterations of cortical thickness before and after successful anterior temporal lobectomy (ATL) in patients with unilateral mesial temporal lobe epilepsy (mTLE). High-resolution T1-weighted MRI was obtained in 28 mTLE patients who achieved seizure freedom for at least 24months after ATL and 29 healthy controls. Patients were scanned at five timepoints, including before surgery, 3, 6, 12 and 24months after surgery. Preoperative cortical thickness of mTLE patients were compared with healthy controls. Dynamic alterations of cortical thickness before and after surgery were compared among five scans using linear mixed models. Patients with mTLE showed cortical thinning pre-surgically in ipsilateral entorhinal cortex, parahippocampal gyrus, inferior parietal cortex, lateral occipital cortex; contralateral pericalcarine cortex (PCC); and bilateral caudal middle frontal gyrus (cMFG), paracentral lobule, precentral gyrus (PCG), superior parietal cortex. Cortical thickening was observed in contralateral rostral anterior cingulate cortex (rACC). Patients showed postsurgical cortical thinning in ipsilateral temporal lobe, fusiform gyrus, caudal anterior cingulate cortex, lingual gyrus, and insula. Ipsilateral cMFG, PCC, and contralateral PCG showed significant cortical thickening after surgery. In addition, contralateral rACC showed cortical thickening at 3 months follow-up, however, with obvious cortical thinning at 24months follow-up. Mesial temporal lobe epilepsy patients showed widespread cortical thinning before and after anterior temporal lobectomy. Progressive cortical thinning mainly existed in neighboring regions of resection. Postoperative cortical thickening may indicate cortical remodeling after successful surgery.

Altered Adult Neurogenesis and Cognition in Mesial Temporal Lobe Epilepsy Patients

Epilepsy is a syndromic disorder in which neuronal hyperactivity causes seizures, cognitive impairment, and neuropsychiatric comorbidities. Aberrant neurogenesis plays a critical role in the initiation and progression of epilepsy in rodent hippocampus, yet it is unknown whether this also holds true in humans.

Serotonin transporter in the temporal lobe, hippocampus and amygdala in SUDEP.

Several lines of evidence link deficient serotonin function and SUDEP. Chronic treatment with serotonin reuptake inhibitors (SRIs) reduces ictal central apnoea, a risk factor for SUDEP. Reduced medullary serotonergic neurones, modulators of respiration in response to hypercapnia, were reported in a SUDEP post‐mortem series. The amygdala and hippocampus have high serotonergic innervation and are functionally implicated in seizure‐related respiratory dysregulation. We explored serotonergic networks in mesial temporal lobe structures in a surgical and post‐mortem epilepsy series in relation to SUDEP risk. We stratified 75 temporal lobe epilepsy patients with hippocampal sclerosis (TLE/HS) into high (N = 16), medium (N = 11) and low risk (N = 48) groups for SUDEP based on generalised seizure frequency. We also included the amygdala in 35 post‐mortem cases, including SUDEP (N = 17), epilepsy controls (N = 10) and non‐epilepsy controls (N = 8). The immunohistochemistry labelling index (LI) and axonal length (AL) of serotonin transporter (SERT)‐positive axons were quantified in 13 regions of interest with image analysis. SERT LI was highest in amygdala and subiculum regions. In the surgical series, higher SERT LI was observed in high risk than low risk cases in the dentate gyrus, CA1 and subiculum (p < 0.05). In the post‐mortem cases higher SERT LI and AL was observed in the basal and accessory basal nuclei of the amygdala and peri‐amygdala cortex in SUDEP compared to epilepsy controls (p < 0.05). Patients on SRI showed higher SERT in the dentate gyrus (p < 0.005) and CA4 (p < 0.05) but there was no difference in patients with or without a psychiatric history. Higher SERT in hippocampal subfields in TLE/HS cases with SUDEP risk factors and higher amygdala SERT in post‐mortem SUDEP cases than epilepsy controls supports a role for altered serotonergic networks involving limbic regions in SUDEP. This may be of functional relevance through reduced 5‐HT availability.

A Novel Pathway Phenotype of Temporal Lobe Epilepsy and Comorbid Psychiatric Disorders: Results of Precision Nomothetic Medicine.

No precision medicine models of temporal lobe epilepsy (TLE) and associated mental comorbidities have been developed to date. This observational study aimed to develop a precision nomothetic, data-driven comorbid TLE model with endophenotype classes and pathway phenotypes that may have prognostic and therapeutical implications. We recruited forty healthy controls and 108 TLE patients for this research and assessed TLE and psychopathology (PP) features as well as oxidative stress (OSTOX, e.g., malondialdehyde or MDA, lipid hydroperoxides, and advanced oxidation protein products) and antioxidant (paraoxonase 1 or PON1 status, -SH groups, and total radical trapping potential or TRAP) biomarkers. A large part (57.2%) of the variance in a latent vector (LV) extracted from the above TLE and PP features was explained by these OSTOX and antioxidant biomarkers. The PON1 Q192R genetic variant showed indirect effects on this LV, which were completely mediated by PON1 activity and MDA. Factor analysis showed that a common core could be extracted from TLE, PP, OSTOX and antioxidant scores, indicating that these features are manifestations of a common underlying construct, i.e., a novel pathway phenotype of TLE. Based on the latter, we constructed a new phenotype class that is characterized by increased severity of TLE, PP and OSTOX features and lowered antioxidant defenses. A large part of the variance in episode frequency was explained by increased MDA, lowered antioxidant, and nitric oxide metabolite levels. In conclusion, (a) PP symptoms belong to the TLE phenome, and the signal increased severity; and (b) cumulative effects of aldehyde formation and lowered antioxidants determine epileptogenic kindling.

Aerobic glycolysis imaging of epileptic foci during the inter-ictal period.

SummaryBackgroundIn drug-resistant epilepsy, surgical resection of the epileptic focus can end seizures. However, success is dependent on the ability to identify foci locations and, unfortunately, current methods like electrophysiology and positron emission tomography can give contradictory results. During seizures, glucose is metabolized at epileptic foci through aerobic glycolysis, which can be imaged through the oxygen-glucose index (OGI) biomarker. However, inter-ictal (between seizures) OGI changes have not been studied, which has limited its application.Methods18 healthy controls and 24 inter-ictal, temporal lobe epilepsy patients underwent simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) scans. We used [18F]fluorodeoxyglucose-PET (FDG-PET) to detect cerebral glucose metabolism, and calibrated functional MRI to acquire relative oxygen consumption. With these data, we calculated relative OGI maps.FindingsWhile bilaterally symmetrical in healthy controls, we observed, in patients during the inter-ictal period, higher OGI ipsilateral to the epileptic focus than contralateral. While traditional FDG-PET results and temporal lobe OGI results usually both agreed with invasive electrophysiology, in cases where FDG-PET disagreed with electrophysiology, temporal lobe OGI agreed with electrophysiology, and vice-versa.InterpretationAs either our novel epilepsy biomarker or traditional approaches located foci in every case, our work provides promising insights into metabolic changes in epilepsy. Our method allows single-session OGI measurement which can be useful in other diseases.FundingThis work was supported by ShanghaiTech University, the Shanghai Municipal Government, the National Natural Science Foundation of China Grant (No. 81950410637) and Shanghai Municipal Key Clinical Specialty (No. shslczdzk03403). F. H. and P. H. were supported by USA National Institute of Health grants (R01 NS-100106, R01 MH-067528).Z. W. was supported by the Key-Area Research and Development Program of Guangdong Province (2019B030335001), National Natural Science Foundation of China (No. 82151303), and National Key R&D Program of China (No. 2021ZD0204002).

Deep learning resting state functional magnetic resonance imaging lateralization of temporal lobe epilepsy.

Localization of focal epilepsy is critical for surgical treatment of refractory seizures. There remains a great need for noninvasive techniques to localize seizures for surgical decision-making. We investigate the use of deep learning using resting state functional magnetic resonance imaging (RS-fMRI) to identify the hemisphere of seizure onset in temporal lobe epilepsy (TLE) patients. A total of 2132 healthy controls and 32 preoperative TLE patients were studied. All participants underwent structural MRI and RS-fMRI. Healthy control data were used to generate training samples for a three-dimensional convolutional neural network (3DCNN). RS-fMRI was synthetically altered in randomly lateralized regions in the healthy control participants. The model was then trained to classify the hemisphere containing synthetic noise. Finally, the model was tested on TLE patients to assess its performance for detecting biological seizure onset zones, and gradient-weighted class activation mapping (Grad-CAM) identified the strongest predictive regions. The 3DCNN classified healthy control hemispheres known to contain synthetic noise with 96% accuracy, and TLE hemispheres clinically identified to be seizure onset zones with 90.6% accuracy. Grad-CAM identified a range of temporal, frontal, parietal, and subcortical regions that were strong anatomical predictors of the seizure onset zone, and the resting state networks that colocalized with Grad-CAM results included default mode, medial temporal, and dorsal attention networks. Lastly, in an analysis of a subset of patients with postsurgical outcomes, the 3DCNN leveraged a more focal set of regions to achieve classification in patients with Engel Class >I compared to Engel Class I. Noninvasive techniques capable of localizing the seizure onset zone could improve presurgical planning in patients with intractable epilepsy. We have demonstrated the ability of deep learning to identify the correct hemisphere of the seizure onset zone in TLE patients using RS-fMRI with high accuracy. This approach represents a novel technique of seizure lateralization that could improve preoperative surgical planning.

Diagnostic value of MRI in the presurgical evaluation of patients with epilepsy: influence of field strength and sequence selection: a systematic review and meta-analysis from the E-PILEPSY Consortium.

MRI is a cornerstone in presurgical evaluation of epilepsy. Despite guidelines, clinical practice varies. In light of the E-PILEPSY pilot reference network, we conducted a systematic review and meta-analysis on the diagnostic value of MRI in the presurgical evaluation of epilepsy patients. We included original research articles on diagnostic value of higher MRI field strength and guideline-recommended and additional MRI sequences in detecting an epileptogenic lesion in adult or paediatric epilepsy surgery candidates. Lesion detection rate was used as a metric in meta-analysis. Eighteen studies were included for MRI field strength and 25 for MRI sequences, none were free from bias. In patients with normal MRI at lower-field strength, 3T improved lesion detection rate by 18% and 7T by 23%. Field strengths higher than 1.5T did not have higher lesion detection rates in patients with hippocampal sclerosis (HS). The lesion detection rate of epilepsy-specific MRI protocols was 83% for temporal lobe epilepsy (TLE) patients. Dedicated MRI protocols and evaluation by an experienced epilepsy neuroradiologist increased lesion detection. For HS, 3DT1, T2, and FLAIR each had a lesion detection rate at around 90%. Apparent diffusion coefficient indices had a lateralizing value of 33% for TLE. DTI fractional anisotropy and mean diffusivity had a localizing value of 8% and 34%. A dedicated MRI protocol and expert evaluation benefits lesion detection rate in epilepsy surgery candidates. If patients remain MRI negative, imaging at higher-field strength may reveal lesions. In HS, apparent diffusion coefficient indices may aid lateralization and localization more than increasing field strength. DTI can add further diagnostic information. For other additional sequences, the quality and number of studies is insufficient to draw solid conclusions. Our findings may be used as evidence base for developing new high-quality MRI studies and clinical guidelines.