Reduction of frontal neocortical grey matter associated with affective aggression in patients with temporal lobe epilepsy: an objective voxel by voxel analysis of automatically segmented MRI

BACKGROUND: Interictal episodes of aggression are often reported in patients with epilepsy. Some have characteristics of what has been referred to as episodic dyscontrol or intermittent explosive disorder (IED). Although structural brain abnormalities are thought to play a part in the pathophysiology of aggression, there are few in vivo studies of structural cerebral changes in patients with epilepsy and aggression. Using quantitative MRI, subtle structural brain abnormalities can be investigated in subgroups of patients with both epilepsy and episodes of affective aggression. METHODS: After automated segmentation of cerebral grey matter from T1 weighted MRI, the objective technique of statistical parametric mapping (SPM) was applied to the analysis of 35 control subjects, 24 patients with temporal lobe epilepsy (TLE) with a history of repeated, interictal episodes of aggression, and 24 patients with TLE without episodes of aggression. Both TLE patient groups were compared with each other and with the control subjects on a voxel by voxel basis for increases and decreases of grey matter. RESULTS: The patients with TLE with aggressive episodes had a decrease of grey matter, most markedly in the left frontal lobe, compared with the control group and with patients with TLE without aggressive episodes. CONCLUSION: These findings suggest that a reduction of frontal neocortical grey matter might underly the pathophysiology of aggression in TLE. These voxel by voxel comparisons can guide further in vivo studies into aggression.     

Verbal learning and forgetting in patients with temporal lobe epilepsy

Studies comparing non-surgical patients with left or right temporal lobe epilepsy (TLE) have shown irregular differences in verbal learning and memory. We assessed the performance of unoperated patients with epileptogenic temporal lobe lesions or cryptogenic TLE using a selective reminding procedure for the learning of a word list, and five delayed trials for the recall of learned words. On the selective reminding procedure, patients with left TLE were found to be more impaired than those with right TLE and controls, in agreement with the role of the left temporal lobe in verbal learning. The patients with right TLE were more impaired than the controls, possibly due to the semantic organization of the word list The rate of forgetting learned words was similar in the patient and control groups, suggesting that patients with left TLE can normally retain and/or retrieve stored items. These data support the hypothesis that distinct functional systems subserve learning and memory. Comparisons of the patient subgroups with epileptogenic lesions (hippocampal sclerosis or low-grade glioma) and those with cryptogenic TLE did not reveal any significant difference in learning or in memory, suggesting that epileptiform activity could affect verbal performance as a detectable temporal lesion.     

Alertness network in patients with temporal lobe epilepsy: a fMRI study

Patients with temporal lobe epilepsy (TLE) often suffer from cognitive deficits. However, it remains elusive whether the performance of TLE patients in the attentional networks test (ANT) is impaired. Functional magnetic resonance imaging (fMRI) can accurately reflect the hemodynamics and functional activities in certain regions of the brain. In the current study, we aimed to investigate the characteristics and neural mechanisms of the functions of the alertness network in patients with TLE using the ANT and fMRI. A total of 12 patients with TLE and 8 healthy controls underwent the ANT behavioral tests and subsequent block-design fMRI scanning. The results showed that the response times of the alertness network had no significant difference between the TLE group and the healthy control group. The fMRI data showed that the activation of the cerebellum, right occipital lobe, right frontal and brainstem was significantly weaker in TLE patients than in healthy control. Our data indicate that despite neuropsychological test performance is normal; the alerting network is deficient in the TLE patients. The decreased activation of brain regions of right occipital lobe, cerebellum, right frontal lobe, brain stem and temporal lobe may be the neural basis of altering network impairment in TEL patients.     

Embryonic stem cell-derived neural precursor grafts for treatment of temporal lobe epilepsy

Complex partial seizures arising from mesial temporal lobe structures are a defining feature of mesial temporal lobe epilepsy (TLE). For many TLE patients, there is an initial traumatic head injury that is the precipitating cause of epilepsy. Severe TLE can be associated with neuropathological changes, including hippocampal sclerosis, neurodegeneration in the dentate gyrus, and extensive reorganization of hippocampal circuits. Learning disabilities and psychiatric conditions may also occur in patients with severe TLE for whom conventional anti-epileptic drugs are ineffective. Novel treatments are needed to limit or repair neuronal damage, particularly to hippocampus and related limbic regions in severe TLE and to suppress temporal lobe seizures. A promising therapeutic strategy may be to restore inhibition of dentate gyrus granule neurons by means of cell grafts of embryonic stem cell-derived GABAergic neuron precursors. “Proof-of-concept” studies show that human and mouse embryonic stem cell-derived neural precursors can survive, migrate, and integrate into the brains of rodents in different experimental models of TLE. In addition, studies have shown that hippocampal grafts of cell lines engineered to release GABA or other anticonvulsant molecules can suppress seizures. Furthermore, transplants of fetal GABAergic progenitors from the mouse or human brain have also been shown to suppress the development of seizures. Here, we review these relevant studies and highlight areas of future research directed toward producing embryonic stem cell-derived GABAergic interneurons for cell-based therapies for treating TLE.     

A study of the relationship between metabolism using 1H-MRS and function using several neuropsychological tests in temporal lobe epilepsy.

Several investigators have reported on the relationship between metabolism, using magnetic resonance spectroscopy (MRS), and function, using neuropsychological tests in temporal lobe epilepsy (TLE) patients, but the opinions regarding the results remain in contention. The aim of this study is to examine the relationship between metabolism, using proton MRS ((1)H-MRS), and function using several neuropsychological tests in the temporal lobes of TLE patients. We studied 29 TLE patients at our hospital using(1)H-MRS and neuropsychological tests. We used a clinical 1.5 T MR unit. We conducted five neuropsychological tests to examine the function of the left or right temporal lobe. There were significant correlations between the N-acetylaspartate/creatine + phosphocreatine (NAA/Cr) ratios and the scores of almost all of the neuropsychological tests for the temporal lobe function ipsilateral to the spike focus. However, in two Wechsler Memory Scale-Revised (WMS-R) subtests we found no significant correlation in the ipsilateral side. These findings suggest that the NAA/Cr ratios, which reflect neural metabolism, are closely related to function in the temporal lobes of TLE patients. The disparity between the results in two subtests of WMS-R show that several tests may be necessary in order to assess temporal lobe function.     

Neuromagnetic recordings in temporal lobe epilepsy.

The introduction of whole-head magnetoencephalography (MEG) systems facilitating simultaneous recording from the entire brain surface has established MEG as a clinically feasible method for the evaluation of patients with temporal lobe epilepsy (TLE). In mesial TLE, two types of MEG spike dipoles could be identified: an anterior vertical and an anterior horizontal dipole. Dipole orientations can be used to attribute spike activity to temporal lobe subcompartments. Whereas the anterior vertical dipole is compatible with epileptic activity in the mediobasal temporal lobe, the anterior horizontal dipole can be explained by epileptic activity of the temporal tip cortex. In nonlesional TLE, medial and lateral vertical dipoles were found which could distinguish between medial and lateral temporal seizure onset zones as evidenced from invasive recordings. In lesional TLE, MEG could clarify the spatial relationship of the structural lesion to the irritative zone. Evaluation of patients with persistent seizures after epilepsy surgery may represent another clinical important application of MEG because magnetic fields are less influenced than electric fields by the prior operation. Simultaneous MEG and invasive EEG recordings indicate that epileptic activity restricted to mesial temporal structures cannot reliably be detected on MEG and that an extended cortical area of at least 6 to 8 cm2 involving also the basal temporal lobe is necessary to produce a reproducible MEG signal. In lateral neocortical TLE MEG seems to be more sensitive than scalp-EEG which further underlines the potential role of MEG for the study of nonlesional TLE. Whole-head MEG therefore can be regarded as a valuable and clinically relevant noninvasive method for the evaluation of patients with TLE.     

Increased apolipoprotein E ϵ4 in epilepsy with senile plaques

Inheritance of the apolipoprotein E (ApoE) ?4 allele is a risk factor for Alzheimer's disease (AD) and is associated with increased deposition of β-amyloid (Aβ) in AD, Down's syndrome, and normal aging. Aβ deposition in the form of senile plaques (SPs) has recently been described in patients with temporal lobe epilepsy (TLE). We studied the relationship between ApoE ?4 genotype and the deposition of Aβ in temporal lobe tissue from patients who underwent temporal lobectomy for intractable epilepsy. TLE patients with SPs had a 70% ApoE ?4 carrier frequency compared with a 27% carrier frequency among age-matched TLE controls without SPs. Our data suggest that the association between ApoE ?4 and intracerebral Aβ accumulation is not unique to the elderly or to those with dementia, and may be a feature of conditions in which there is both an ApoE ?4 allele and over-production of Aβ precursor protein, and, presumably, Aβ.     

Diffusion tensor imaging in temporal lobe epilepsy

Although mesial temporal sclerosis (MTS) has long been recognized in association with temporal lobe epilepsy (TLE), there is a growing body of literature suggesting structural abnormalities extending beyond the temporal lobe in patients with TLE. Diffusion tensor imaging (DTI) is a novel imaging technique that provides insight into the structural integrity of cerebral white matter. DTI studies have demonstrated extensive bilateral white matter abnormalities in TLE that extend far beyond the temporal lobe, even in patients with unilateral MTS. The relationship between white matter abnormalities, seizures, and comorbidity in TLE remains unclear.     

Temporal lobe epilepsy caused by choroid plexus papilloma in the temporal horn

Choroid plexus papilloma (CPP) arising in the temporal horn is rare in adult population, and to the best of our knowledge, there has been no report of such a case with temporal lobe epilepsy (TLE). The authors describe a unique case of a 27-year-old woman who was diagnosed as TLE and was found to have a CPP in the temporal horn. Choroid plexus papilloma of the temporal horn, even though rare, can be found in adult population and be causally related to temporal lobe epilepsy.     

Molecular profiling of temporal lobe epilepsy: comparison of data from human tissue samples and animal models

The advent of gene chip technology and the era of functional genomics have initially been accompanied by huge anticipations to quickly unravel the molecular pathogenesis of multifactorial diseases. Expectations have, today, given way to some concerns about this non-hypothesis driven approach. However, the careful and controlled application of expression microarrays in concert with refined bioinformatic tools may provide novel insights in major disorders particularly of highly complex organs such as the central nervous system (CNS). Epilepsies are among the most frequent CNS disorders affecting approximately 1.5% of the population worldwide. In temporal lobe epilepsy (TLE), the seizure origin typically involves the hippocampal formation, a structure located in the mesial temporal lobe. Many TLE patients develop pharmacoresistance, i.e. seizures can no more be controlled by antiepileptic drugs. In order to achieve seizure control, surgical removal of the epileptogenic focus has been established as successful therapeutic strategy. Hippocampal biopsy tissue of pharmacoresistant TLE patients represents an excellent substrate to analyze molecular mechanisms related to structural and cellular reorganization in epilepsy. The complexity of alterations in TLE hippocampi suggests numerous genes and signaling cascades to be involved in the pathogenesis. By microarrays, genome wide expression profiles can be constituted from TLE tissues. However, hippocampi of pharmacoresistant TLE patients represent an advanced stage of the disease. Early stages of epilepsy development are not available for functional genome analysis in humans. Animal models of TLE appear particularly helpful to study molecular mechanisms of highly dynamic processes such as the development of hyperexcitability and pharmacoresistance. In this review, we summarize recent data of gene expression profiles in human and experimental TLE and discuss the relevance of novel tools for bioinformatic analysis and data mining.     

Lamotrigine improves aggression in patients with temporal lobe epilepsy

Aggression in patients with temporal lobe epilepsy (TLE) may have phenomenological and neurobiological heterogeneity. In the present study, we targeted patients with TLE who showed aggression and evaluated the effects of lamotrigine on this symptom using the Buss-Perry Aggression Questionnaire (BAQ), which is based on a four-factor model that includes Physical Aggression, Verbal Aggression, Anger, and Hostility. As compared with the healthy control subjects (n=115), patients with TLE (n=21) had significantly higher BAQ Total, Physical Aggression, Anger, and Hostility scores. Ten weeks after initiation of lamotrigine, the BAQ Total and Anger scores of the patients with TLE were significantly improved. However, the patients with TLE in this study did not exhibit depressive symptoms. Our results suggest that lamotrigine mitigates aggression, especially anger, which represents the emotional factor of aggression in the BAQ.     

Temporal lobe epilepsy with sensory aura: interictal glucose hypometabolism

Patients with mesial temporal lobe epilepsy (mTLE) exhibit marked depressions of the regional cerebral glucose metabolism (rCMRGlu) in the mesiotemporal region. We hypothesised that patients with temporal lobe epilepsy (TLE) who have a bilateral somatosensory or acoustic ( = temporolateral/SII-) aura can be differentiated from mTLE by rCMRGlu depressions primarily involving temporo-perisylvian locations. We therefore used this ictal semiology as a clinical criterion to define a subgroup of such patients and measured the rCMRGlu in 16 patients with TLE as evident from interictal and ictal EEG-video monitoring. Clinically, they presented with medically refractory complex partial seizures and were subjected to presurgical evaluation. The pattern of the interictal rCMRGlu in the TLE patients was different from that observed in patients with mTLE and showed significant depressions ipsilateral to the epileptic focus in mesial temporal and lateral temporal regions but spared the thalamus. The neocortical metabolic depressions were spatially more extended in right than in left TLE patients. Magnetic resonance images (MRI) were either normal (n = 5) or revealed unilateral or bilateral hippocampal atrophy/sclerosis (n = 7), or temporal or extratemporal focal cortical dysplasia (n = 4). The selected TLE patients presented here comprise a heterogeneous group showing most pronounced metabolic depressions in the lateral temporal cortex. Thus, our data suggest that non-invasive metabolic imaging can assist in identifying the neocortical symptomatogenic zone in putative temporo-perisylvian lobe epilepsy.     

颞叶癫患者的头颅磁共振显像异常表现分析

目的对颞叶癫(TLE)患者头颅磁共振成像(MRI)异常表现进行分析,为临床诊治TLE提供参考。方法对56例TLE患者的头颅MRI异常表现进行分析总结。结果 56例TLE患者头颅MRI主要表现为海马硬化、颞叶软化灶、颞叶肿瘤、颞叶皮质萎缩等。其中,颞叶肿瘤类型多样,主要为少突胶质瘤、星形细胞瘤、脑膜瘤。结论 TLE患者头颅MRI异常表现复杂多样,正确掌握其特点有助于TLE的诊治。     

Neuronal Complexity Loss in Interictal EEG Recorded with Foramen Ovale Electrodes Predicts Side of Primary Epileptogenic Area in Temporal Lobe Epilepsy: A Replication Study

Summary: Purpose: To investigate whether a correct lateralization of the primary epileptogenic area by means of neuronal complexity loss analysis can be obtained from interictal EEG recordings using semi-invasive foramen ovale electrodes. In a previous study with recordings from intrahippocampal depth and subdural strip electrodes it was shown that the dynamics of the primary epileptogenic area can be characterized by an increased loss of neuronal complexity in patients with unilateral temporal lobe epilepsy (TLE).
Methods: Neuronal complexity loss analysis was applied. This analysis method is derived from the theory of nonlinear dynamics and provides a topological diagnosis even in cases where no actual seizure activity can be recorded. We examined interictal EEG recorded intracranially from multipolar foramen ovale electrodes in 19 patients with unilateral TLE undergoing presurgical evaluation.
Results: The primary epileptogenic area was correctly lateralized in 16 of the 19 investigated patients. The misclassification of the side of seizure onset in three patients might be attributed to the larger distance between the foramen ovale electrodes and the mesial temporal structures as compared to intrahippocampal depth electrodes.
Conclusions: Our results confirm the previous findings and provide further evidence for the usefulness of nonlinear time-series analysis for the characterization of the spatiotemporal dynamics of the primary epileptogenic area in mesial temporal lobe epilepsy.     

Lesion side matters — An fMRI study on the association between neural correlates of watching dynamic fearful faces and their evaluation in patients with temporal lobe epilepsy

Most studies assessing facial affect recognition in patients with TLE reported emotional disturbances in patients with TLE. Results from the few fMRI studies assessing neural correlates of affective face processing in patients with TLE are divergent. Some, but not all, found asymmetrical mesiotemporal activations, i.e., stronger activations within the hemisphere contralateral to seizure onset. Little is known about the association between neural correlates of affect processing and subjective evaluation of the stimuli presented. Therefore, we investigated the neural correlates of processing dynamic fearful faces in 37 patients with mesial temporal lobe epilepsy (TLE; 18 with left-sided TLE (lTLE), 19 with right-sided TLE (rTLE)) and 20 healthy subjects. We additionally assessed individual ratings of the fear intensity and arousal perception of the fMRI stimuli and correlated these data with the activations induced by the fearful face paradigm and activation lateralization within the mesiotemporal structures (in terms of individual lateralization indices, LIs). In healthy subjects, whole-brain analysis showed bilateral activations within a widespread network of mesial and lateral temporal, occipital, and frontal areas. The patient groups activated different parts of this network. In patients with lTLE, we found predominantly right-sided activations within the mesial and lateral temporal cortices and the superior frontal gyrus. In patients with rTLE, we observed bilateral activations in the posterior regions of the lateral temporal lobe and within the occipital cortex. Mesiotemporal region-of-interest analysis showed bilateral symmetric activations associated with watching fearful faces in healthy subjects. According to the region of interest and LI analyses, in the patients with lTLE, mesiotemporal activations were lateralized to the right hemisphere. In the patients with rTLE, we found left-sided mesiotemporal activations. In patients with lTLE, fear ratings were comparable to those of healthy subjects and were correlated with relatively stronger activations in the right compared to the left amygdala. Patients with rTLE showed significantly reduced fear ratings compared to healthy subjects, and we did not find associations with amygdala lateralization. Although we found stronger activations within the contralateral mesial temporal lobe in the majority of all patients, our results suggest that only in the event of left-sided mesiotemporal damage is the right mesial temporal lobe able to preserve intact facial fear recognition. In the event of right-sided mesiotemporal damage, fear recognition is disturbed. This underlines the hypothesis that the right amygdala is biologically predisposed to processing fear, and its function cannot be fully compensated in the event of right-sided mesiotemporal damage.     

Lack of association between a GABA receptor 1 gene polymorphism and temporal lobe epilepsy

PURPOSE: Recently a coding nonsynonymous single-nucleotide polymorphism (SNP; G1465A) in the GABBR1 gene was reported to be associated with the incidence and severity of temporal lobe epilepsy (TLE). To clarify the role of this polymorphism in TLE, we attempted to replicate this study. METHODS: We genotyped 188 unrelated patients with TLE (110 women, 78 men) and 259 controls of middle European descent by a restriction-length polymerase chain reaction (PCR) assay. RESULTS: Only two (0.5%) patients and none of the controls exhibited the heterozygous A/G genotype, which was previously reported to be overrepresented among patients as compared with controls. CONCLUSIONS: Although our study was sufficiently powered, we could not replicate the original association. Potential reasons for this failure could lie in subtle genetic differences between the studied populations or differences in the TLE phenotypes.     

When should a resection sparing mesial structures be considered for temporal lobe epilepsy?

Anteromesial temporal lobectomy (AMTL) is an effective and safe treatment for refractory temporal lobe epilepsy (TLE) caused by hippocampal sclerosis (HS). It is possible that modifications to this procedure could offer improved seizure control or a reduction in functional consequences in some patients. Reviewed here is the issue of when it might be appropriate to perform a resection for TLE that spares the mesial structures, particularly the hippocampus and parahippocampal gyrus. This issue is particularly important for dominant hemipshere TLE and for patients without obvious HS, as these are the patients at greatest risk for verbal memory decline following AMTL. Current evidence suggests that mesial structure-sparing resections may be worth consideration for two types of patients: those with temporal lobe foreign tissue lesions outside the mesial structures, and those with temporal lobe hypometabolism on fluorodeoxyglucose positron emission tomography but a normal MRI. Patients with dual pathology (i.e., HS plus another epileptogenic lesion) are unlikely to benefit from a resection that spares the mesial temporal lobe. There is little evidence to state whether resections of this kind are worthwhile for cryptogenic TLE, or for mesial TLE with preserved memory function. There is a clear need to move beyond the field's present focus on the hippocampus and investigate new approaches to TLE that may minimize the risks of functional consequences in patients without HS.     

The Frontal Lobes,Epilepsy, and Behavior

The frontal lobes have been overshadowed by the temporal lobes in the vast literature addressing the neurobehavioral and psychological perspectives of epilepsy. The purpose of this review is to summarize contemporary anatomicobehavioral correlations and to highlight the frontal lobe contributions to the neurology, neuropsychology, and neuropsychiatry of epilepsy, in general, and to temporal lobe epilepsy (TLE) and frontal lobe epilepsy (FLE), in particular. Much evidence has accumulated suggesting that focal epileptogenic tissue may have effects on distant neural systems. Data supporting the case that the frontal regions are preferentially affected in TLE are presented. Emphasis is placed on the results of numerous functional imaging studies demonstrating correlations between frontal hypoperfusion and cognitive or mood impairments in patients with TLE.     

Genetics of temporal lobe epilepsy

The most common partial epilepsy, temporal lobe epilepsy (TLE) consists of a heterogeneous group of seizure disorders originating in the temporal lobe. TLE had been thought to develop as a result of acquired structural problems in the temporal lobe. During the past two decades, there has been growing evidence of the important influence of genetic factors, and familial and non-lesional TLE have been increasingly described. Here, we focus on the genetics of TLE and review related genes which have been studied recently. Although its molecular mechanisms are still poorly understood, TLE genetics is a fertile field, awaiting more research.     

Distribution of regional gray matter abnormalities in a pediatric population with temporal lobe epilepsy and correlation with neuropsychological performance

OBJECTIVE: The goals of the work described here were to determine if hippocampal and extrahippocampal atrophy in children with temporal lobe epilepsy (TLE) follows a pattern similar to that in adult patients, and to assess the clinical and neuropsychological relevance of regional brain atrophy in pediatric TLE. METHODS: Children with symptomatic TLE (n=14: 9 with mesial TLE due to hippocampal atrophy and 5 with TLE due to neocortical lesions), healthy children (n=14), and 9 adults with mesial temporal lobe epilepsy (MTLE) were compared using voxel-based morphometry (VBM) of brain magnetic resonance imaging (MRI). The children underwent a comprehensive neuropsychological battery. RESULTS: Children with MTLE with unilateral hippocampal atrophy (n=9) exhibited a significant reduction in gray matter in the hippocampus ipsilateral to the seizure origin and significant atrophy in the ipsilateral cingulate gyrus and contralateral middle frontal lobe. Children with TLE (n=14) exhibited a significant reduction in the gray matter of the ipsilateral hippocampus and parahippocampal gyrus. There was a correlation between gray matter volume in children with TLE and scores on several neuropsychological tests. Atrophy in pediatric patients with MTLE was less extensive than that in adults, and involved the hippocampi and the frontal cortex. CONCLUSIONS: Similar to adult MTLE, pediatric MTLE is associated with hippocampal and extrahippocampal cell loss. However, children display less intense quantifiable gray matter atrophy, which affects predominantly frontal lobe areas. There was a significant association between volume of gray matter in medial temporal and frontal regions and scores on neuropsychological tests. In childhood, TLE and the concomitant cognitive/behavior disturbances are the result of a damaged neural network.