Hippocampal N-acetylaspartate in neocortical epilepsy and mesial temporal lobe epilepsy

Previous magnetic resonance spectroscopy (MRS) studies have shown that N?acetylaspartate (NAA) is reduced not only in the ipsilateral but also in the contralateral hippocampus of many patients with mesial temporal lobe epilepsy (mTLE). The reason for the contralateral damage is not clear. To test whether the hippocampus is also damaged if the focus is outside the hippocampus, we have measured patients with neocortical epilepsy (NE). Therefore, the goals of this study were to determine if hippocampal NAA is reduced in NE and if hippocampal NAA discriminates NE from mTLE. MRS imaging (MRSI) studies were performed on 10 NE patients and compared with MRSI results in 23 unilateral mTLE patients and 16 controls. The results show that, in contrast to mTLE, NAA was not reduced in the hippocampus of NE patients, neither ipsilateral nor contralateral to the seizure focus. These results suggest that repeated seizures do not cause secondary damage to the hippocampus. The absence of spectroscopic differences in NE may help to distinguish NE from mTLE.     

Regional neocortical thinning in mesial temporal lobe epilepsy

PURPOSE: To determine the nature and extent of regional cortical thinning in patients with mesial temporal lobe epilepsy (MTLE). METHODS: High-resolution volumetric MRIs were obtained on 21 patients with MTLE and 21 controls. Mean cortical thickness was measured within regions of interest and point-by-point across the neocortex using cortical reconstruction and parcellation software. RESULTS: Bilateral thinning was observed within frontal and lateral temporal regions in MTLE patients relative to controls. The most striking finding was bilateral cortical thinning in the precentral gyrus and immediately adjacent paracentral region and pars opercularis of the inferior frontal gyrus, extending to the orbital region. Within the temporal lobe, bilateral thinning was observed in Heschl's gyrus only. Ipsilateral only thinning was observed in the superior and middle temporal gyri, as well as in the medial orbital cortex. Greater asymmetries in cortical thickness were observed in medial temporal cortex in patients relative to controls. Individual subject analyses revealed that this asymmetry reflected significant ipsilateral thinning of medial temporal cortex in 33% of patients, whereas it reflected ipsilateral thickening in 20% of MTLEs. DISCUSSION: Patients with MTLE show widespread, bilateral pathology in neocortical regions that is not appreciated on standard imaging. Future studies are needed that elucidate the clinical implications of neocortical thinning in MTLE.     

Characterization of neocortical and hippocampal synaptosomes from temporal lobe epilepsy patients

To investigate epilepsy-associated changes in the presynaptic terminal, we isolated and characterized synaptosomes from biopsies resected during surgical treatment of drug-resistant temporal lobe epilepsy (TLE) patients. Our main findings are: (1) The yield of synaptosomal protein from biopsies of epilepsy patients was about 25% of that from rat brain. Synaptosomal preparations were essentially free of glial contaminations. (2) Synaptosomes from TLE patients and naive rat brain, quickly responded to K(+)-depolarization with a 70% increase in intrasynaptosomal Ca(2+) ([Ca(2+)](i)), and a 40% increase in B-50/GAP-43 phosphorylation. (3) Neocortical and hippocampal synaptosomes from TLE patients contained 20-50% of the glutamate and gamma-aminobutyric acid (GABA) contents of rat cortical synaptosomes. (4) Although the absolute amount of glutamate and GABA released under basal conditions from neocortical synaptosomes of TLE patients was lower than from rat synaptosomes, basal release expressed as percentage of total content was higher (16.4% and 17.3%, respectively) than in rat (11.5% and 9. 9%, respectively). (5) Depolarization-induced glutamate and GABA release from neocortical synaptosomes from TLE patients was smaller than from rat synaptosomes (3.9% and 13.0% vs. 21.9% and 25.0%, respectively). (6) Analysis of breakdown of glial fibrillary acid protein (GFAP) indicates that resection time (anoxic period during the operation) is a critical parameter for the quality of the synaptosomes. We conclude that highly pure and viable synaptosomes can be isolated even from highly sclerotic human epileptic tissue. Our data show that in studies on human synaptosomes it is of critical importance to distinguish methodological (i.e., resection time) from pathology-related abnormalities.     

Differences between mesial and neocortical magnetic-resonance-imaging-negative temporal lobe epilepsy

ObjectiveThe aim of this study was to assess clinical and electrophysiological differences within a group of patients with magnetic-resonance-imaging-negative temporal lobe epilepsy (MRI-negative TLE) according to seizure onset zone (SOZ) localization in invasive EEG (IEEG).MethodsAccording to SOZ localization in IEEG, 20 patients with MRI-negative TLE were divided into either having mesial SOZ–mesial MRI-negative TLE or neocortical SOZ–neocortical MRI-negative TLE. We evaluated for differences between these groups in demographic data, localization of interictal epileptiform discharges (IEDs), and the ictal onset pattern in semiinvasive EEG and in ictal semiology.ResultsThirteen of the 20 patients (65%) had mesial MRI-negative TLE and 7 of the 20 patients (35%) had neocortical MRI-negative TLE. The differences between mesial MRI-negative TLE and neocortical MRI-negative TLE were identified in the distribution of IEDs and in the ictal onset pattern in semiinvasive EEG. The patients with neocortical MRI-negative TLE tended to have more IEDs localized outside the anterotemporal region (p = 0.031) and more seizures without clear lateralization of ictal activity (p = 0.044). No other differences regarding demographic data, seizure semiology, surgical outcome, or histopathological findings were found.ConclusionsAccording to the localization of the SOZ, MRI-negative TLE had two subgroups: mesial MRI-negative TLE and neocortical MRI-negative TLE. The groups could be partially distinguished by an analysis of their noninvasive data (distribution of IEDs and lateralization of ictal activity). This differentiation might have an impact on the surgical approach.     

Neuropathological features of mesial temporal sclerosis: Histochemical studies of surgically resected specimens from patients with temporal lobe epilepsy

Mesial temporal sclerosis (MTS) is the most common pathological finding in temporal lobe epilepsy (TLE), but the relationship between MTS and hyperexcitability has not been defined. The neuropathological findings of MTS on the basis of our histochemical investigations using surgically resected specimens from patients with intractable TLE will be reviewed and discussed. Various sclerotic changes including neuronal loss and astrogliosis were observed not only in the hippocampus but also in the other mesial temporal structures such as the amygdala and entorhinal cortex. Moreover, aberrant residual pyramidal neurons were recognized, which showed morphological abnormalities; abnormal distribution of zinc, γ-aminobutyric acid-A receptor and glutamate decarboxy-lase; and disorganization of the granule cell layer (dispersion and bilaminar distribution). Increases in density of the corpora amylacea and peripheral type benzodiazepine receptor binding corresponded with glial proliferation. Histochemical studies demonstrated the association of mossy fiber sprouting with synaptic reorg-anization and changes of several chemically defined inter-neuron systems in the dentate gyrus. Quantitative analysis using in vitro autoradiography showed that neurotrans-mitter receptor bindings related to neuronal excitation (AMPA and NMDA receptor) and inhibition (central type benzodiazepine receptor) were reduced differently as a function of neuronal loss in MTS. These cytochemical changes associated with neurotransmitters and their receptors in the sclerotic hippocampus may constitute the pathological background of epileptogenesis in TLE.     

Memory in patients with drug-responsive mesial temporal lobe epilepsy and hippocampal sclerosis

PURPOSE: Mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) is the most common of the antiepileptic drug (AED)-resistant seizure syndromes that are remediable mostly with surgery, although a small group of patients have benign prognosis with fewer seizures. Material-specific memory impairment is an important feature in these patients and may be related to both the structural abnormality and the frequent seizures. In this study, we investigated the relation between memory deficit and HS by taking seizure frequency into account. METHODS: The patients were evaluated according to a standard protocol and divided into two groups, considering their response to AEDs: the good-responder group (GRg, n = 18) and the pharmacoresistant group (PRg, n = 95). They were administered a neuropsychological test battery that included verbal and nonverbal memory tests, compared with each other and with a normal control group (n = 29). The responder group was evaluated by the same battery once again (mean, 23 months; SD, 8.25; range, 14-38 months). RESULTS: Both GR and PR patient groups had poorer memory than the normal controls in all memory tests (p < 0.05). However, the comparison of GRg with PRg revealed that only the digit-span test was significantly worse in PRg (p = 0.0061), and no difference was found in any other memory scores. The reevaluation of the GRg showed no significant difference between the first and second evaluation. CONCLUSIONS: We concluded that the memory impairment in patients with MTLE-HS was permanent and might be related to the direct effect of HS itself. Therefore patients with good response to AEDs can be used as a model for investigating the memory problems in patients with MTLE-HS.     

Biogenic amines in the human neocortex in patients with neocortical and mesial temporal lobe epilepsy: identification with in situ microvoltammetry

Biogenic amines in well defined subtypes of human temporal lobe epilepsy (TLE) have not been well characterized. Specimens from five patients with neocortical TLE (NTLE) and nine with mesial TLE (MTLE) were immediately placed in Ringer's lactate; stearate indicator microelectrodes were placed in temporal gray matter, Ag/AgCl reference microelectrodes and auxiliary microelectrodes were placed 3-7 mm contralaterally to the indicator microelectrode. Dopamine (DA), ascorbic acid (AA), norepinephrine (NE) and serotonin (5-HT) were identified by their characteristic oxidative potentials in vitro. Four of five patients with NTLE had NE depletion in temporal neocortex while eight of nine patients with MTLE had high concentrations of NE (chi-square P<0.01). Significant concentrations of DA were present in the temporal lobes of three of five NTLE patients but in only one of the nine MTLE patients (chi-square P<0.05). 5-HT was present in the neocortex of both NTLE and MTLE patients in similar concentrations. AA was found in the neocortex of one NTLE patient. These data support an association between NE depletion and NTLE. The relative NE deficiency along with the consistent presence of DA in NTLE patients suggest an impairment in the catecholamine pathway. The presence of AA, a co-factor in NE synthesis, in the neocortex of one NTLE patient may also be related since AA is a cofactor in NE synthesis.     

In vivo hippocampal glucose metabolism in mesial temporal lobe epilepsy

BACKGROUND: The appearance of decreased 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) uptake in the mesial temporal region in temporal lobe epilepsy may simply reflect loss of gray matter due to hippocampal atrophy. Increased partial volume effects due to atrophic hippocampi may further increase appearance of hypometabolism. METHODS: The authors used a combination of MRI-PET coregistration, with MRI-based gray matter segmentation, and partial volume correction to improve the examination of hippocampal specific glucose uptake in FDG PET. The goal was to determine 1) if relative mesial temporal hypometabolism is an artifact of gray matter (hippocampal) atrophy, 2) whether hippocampal metabolism correlates with atrophy evaluated on MRI, and 3) if MRI-based partial volume correction influences measurement of hippocampal metabolic-volume relationships, including epilepsy lateralization. RESULTS: Findings showed that ipsilateral hippocampi of mesial temporal lobe epilepsy (MTLE) are relatively hypometabolic per unit of gray matter volume, and that hippocampal metabolism directly correlates with hippocampal volume. Specifically, partial volume corrected hippocampal metabolism correlated strongly (r = 0.613, p < 0.001) with hippocampal volume. Without partial volume correction, a weaker, but still significant, correlation was present (r = 0.482, p < 0.001). Degree of asymmetry was consistently greater and provided higher sensitivity of lateralization with partial volume vs non-partial volume corrected metabolic measurements. CONCLUSIONS: Although, decreased metabolism may occur in the absence of neuronal cell loss, hippocampal atrophy and presumed degree of neuronal cell loss appears to be a primary factor involved in the cause of decreased metabolism in epileptogenic hippocampi. Partial volume correction is recommended for optimal interpretation of hippocampal structure and function relationships.     

Hypertrophy of hippocampal end folium neurons in patients with mesial temporal lobe epilepsy

Hypertrophic and dysmorphic neurons have been identified in the hippocampal end folium of patients with mesial temporal lobe epilepsy (mTLE). No data are available regarding the correlation between these cellular alterations and the severity of hippocampal sclerosis (HS), and the significance of this phenomenon has been unclear. We evaluated both the perikaryon and nuclear areas of residual neurons in the hippocampal end folium of 47 patients with mTLE, seven with lesional neocortical temporal lobe epilepsy (LTLE), and 10 controls without seizure episodes. According to the severity of neuron loss in the end folium, we defined mTLE cases showing slight (<10%) or no, moderate (10–50%) and severe (>50%) loss as groups A, B and C, respectively. We also performed immunohistochemistry with antibodies against heat shock protein 70 and the phosphorylated epitope of neurofilament. In both mTLE and LTLE cases, the perikaryon and nuclear areas of the end folium neurons were significantly greater than those in the controls (P < 0.0001), and those in mTLE were significantly greater than those in LTLE. There were no differences in areas between groups A and B, but the areas in group C were significantly greater than those of both groups A and B. Neurons with large, bizarre morphology were labeled with both antibodies. Neuronal hypertrophy is evident in patients with epilepsy, and appears to advance gradually as the hippocampal sclerosis becomes more severe. This alteration may be a consequence of cellular stress incurred by neurons.     

Seizure outcome and hippocampal atrophy in familial mesial temporal lobe epilepsy

OBJECTIVE: To describe the clinical, genetic and MR characteristics of patients with familial mesial temporal lobe epilepsy (MTLE). DESIGN/METHODS: The familial occurrence of MTLE was identified by a systematic search of family history of seizures in patients followed in the authors' epilepsy clinic. All probands and, whenever possible, other affected family members underwent EEG and MR investigations. RESULTS: Twenty-two unrelated families with at least two individuals with MTLE were identified by clinical and EEG findings. Ninety-eight individuals with history of seizures were evaluated. Sixty-eight patients fulfilled the diagnostic criteria for MTLE. MRI was performed in 84 patients, and showed hippocampal atrophy with increased T2 signal in 48 (57%). The distribution of hippocampal atrophy according to the seizure outcome groups was 6 of 13 patients (46%) with seizure remission, 16 of 31 (51%) with good seizure control under medication, and all 16 patients with refractory MTLE. Hippocampal atrophy was found also in patients that did not fulfill the criteria for MTLE: 3 of 10 (30%) patients with febrile seizure alone, 6 of 10 (60%) patients with recurrent generalized tonic-clonic seizures, and 1 of 4 (25%) patients with a single partial seizure. CONCLUSION: Familial MTLE is a clinically heterogeneous syndrome. Hippocampal atrophy was observed in 57% of patients, including those with benign course or seizure remission, indicating that the relationship between hippocampal atrophy and severity of epilepsy might be more complex than previously suspected. In addition, these findings indicate the presence of a strong genetic component determining the development of mesial temporal sclerosis in these families.     

Neuronal apoptosis in the resected sclerotic hippocampus in patients with mesial temporal lobe epilepsy.

To further confirm at the molecular level that neuronal apoptosis occurs in mesial temporal sclerosis (MTS), the main substrate of mesial temporal lobe epilepsy (MTLE), 24 resected sclerotic hippocampi from 24 patients with drug-resistant MTLE associated with MTS were studied microscopically, electronmicroscopically and immunohistochemically, with detection of expression of apoptosis-associated genes including bcl-2, p53, bax, fas and caspase-3. Early apoptosis changes were found morphologically in hippocampi from three patients with MTLE using transmission electron microscopy. Positive immunostained neurons for bcl-2, p53, fas and caspase-3 were found in the sclerotic hippocampi of 19/24, 14/24, 22/24 and 20/24 patients respectively, which was statistically different from controls. Correlative analysis showed the expression of p53, fas and caspase-3 were positively correlated with seizure frequency. Apoptosis may contribute to MTS, and seizures may induce apoptosis, and thus contribute to neuronal loss in MTS.     

Periodic epileptiform discharges in mesial temporal lobe epilepsy with hippocampal sclerosis

PurposePeriodic epileptiform discharges (PEDs) are an uncommon, abnormal EEG pattern seen usually in patients with acute diseases and less frequently in chronic conditions, such as mesial temporal lobe epilepsy (mTLE). Evaluate the clinical histories, neuroimaging findings, and serial electrophysiological studies prior to the appearance of PEDs in patients with mTLE secondary to hippocampal sclerosis (HS).MethodsWe searched 19, 375 EEGs (2006–2012) for the presence of PEDs secondary to mTLE due to HS.Results12 patients were included. The patients with PEDs had a high prevalence of psychiatric comorbilities, including major depression (50%), interictal psychosis (16%) and dementia (8%). All of the patients had intractable epilepsy with similar clinical findings. We observed a sequential neurophysiological worsening of the EEG patterns prior to the appearance of PEDs. Five patients with PEDs underwent epilepsy surgery and four were seizure free at follow-up 15 (±9) months.ConclusionsPEDs are rare in patients with mTLE and HS and their presence in these cases could reflect clinical severity and neurophysiologic worsening, clinically manifested by intractable epilepsy and severe psychiatric comorbidities. The presence of PEDs in EEGs of patients with mTLE, however, was not associated with poor postsurgical seizure-freedom.     

Surgical outcome of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis

Seizure outcome in mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) that was evaluated according to a noninvasive protocol was assessed in 165 patients and reported using both Engel's and ILAE classifications. The mean postoperative follow-up was 5.0 +/- 2.7 years. At the end of first year, 77.1% of patients were in Engel-I, and 52.7% were in ILAE-I. Antiepileptic drugs (AEDs) were discontinued in 41 patients (42.7%), all remained seizure-free for >or= 2 years that could be accepted as "cure." Thirty-six patients had recurrences, 19 had running-down phenomena. Anterior temporal lobectomy (ATL) was performed in 27 patients with a better outcome when compared to patients operated by selective anterior hippocampectomy. Clinical risk factors for better and worse outcome, which show some similarity in different reports, seem to veil the main reason, which is the accurate delineation of epileptogenic zone considering the presence of different subgroups and underlying developmental pathologies.     

耐药性颞叶内侧癫痫发作前期海马脑电特征分析

目的 观察耐药性颞叶内侧癫痫患者发作前期海马电极脑电活动特点,为判断和切除癫痫病灶提供神经电生理学依据.方法 对16例非侵入性手段难以明确病灶的耐药性颞叶内侧癫痫患者进行双侧海马电极监测,患者停用抗癫痫药在非麻醉状态下监测48～72 h,分析癫痫发作前期海马电极脑电图资料,探讨耐药性颞叶内侧癫痫发作前期海马电极脑电活动特点.结果 16例发作间期记录到背景活动基础上出现局限于某几个电极点的阵发性高幅慢波1例、发作性快波节律1例、棘波或棘尖慢复合波14例,视为异常脑电活动;经过48～ 72 h监测,10例监测到33次临床癫痫发作,发作起始期海马电极均可记录到清晰可辨的癫痫样脑电波形.结论 颞叶内侧癫痫临床发作起始期海马电极癫痫样放电清晰可辨,部位局限,易于确定癫痫性活动起源部位.对于非侵入性手段难以判断癫痫样放电起源的颞叶内侧癫痫可采用脑立体定向技术植入海马深部电极进行脑电监测.     

Metabolic profiles and correlation with surgical outcomes in mesial versus neocortical temporal lobe epilepsy

Aims

Differentiating mesial temporal lobe epilepsy (MTLE) and neocortical temporal lobe epilepsy (NTLE) remains challenging. Our study characterized the metabolic profiles between MTLE and NTLE and their correlation with surgical prognosis using ¹⁸F-FDG-PET.

Methods

A total of 137 patients with intractable temporal lobe epilepsy (TLE) and 40 age-matched healthy controls were recruited. Patients were divided into the MTLE group (N = 91) and the NTLE group (N = 46). ¹⁸F-FDG-PET was used to measure the metabolism of regional cerebra, which was analyzed using statistical parametric mapping. The volume of abnormal metabolism in cerebral regions and their relationship with surgical prognosis were calculated for each surgical patient.

Results

The cerebral hypometabolism of MTLE was limited to the ipsilateral temporal and insular lobes (p < 0.001, uncorrected). The NTLE patients showed hypometabolism in the ipsilateral temporal, frontal, and parietal lobes (p < 0.001, uncorrected). The MTLE patients showed extensive hypermetabolism in cerebral regions (p < 0.001, uncorrected). Hypermetabolism in NTLE was limited to the contralateral temporal lobe and cerebellum, ipsilateral frontal lobe, occipital lobe, and bilateral thalamus (p < 0.001, uncorrected). Among patients who underwent resection of epileptic lesions, 51 (67.1%) patients in the MTLE group and 10 (43.5%) in the NTLE group achieved Engel class IA outcome (p = 0.041). The volumes of metabolic increase for the frontal lobe or thalamus in the MTLE group were larger in non-Engel class IA patients than Engel class IA patients (p < 0.05).

Conclusions

The spatial metabolic profile discriminated NTLE from MTLE. Hypermetabolism of the thalamus and frontal lobe in MTLE may facilitate preoperative counseling and surgical planning.     

伴海马硬化的颞叶内侧面癫痫手术治疗临床分析

目的探讨伴海马硬化的颞叶内侧面癫痫患者的临床特点以及手术治疗的疗效。方法回顾性分析47例伴海马硬化的颞叶内侧面癫痫患者的临床资料。其中癫痫全面性强直-阵挛性发作17例,部分性发作继发全面性发作8例,复杂部分性发作22例。结合视频脑电图、MRI检查结果以及临床表现,对其行标准前颞叶切除术。结果患者术后病理诊断均为海马硬化。所有患者均未出现永久性神经功能障碍,无重大并发症。术后Engel分级结果:Ⅰ级占76.6%;Ⅱ级占10.6%;Ⅲ级占8.5%;Ⅳ级占4.3%。结论对于明确诊断颞叶癫痫伴有海马硬化的患者,标准前颞叶切除术(包括大部分海马和杏仁核)的疗效满意。临床应在规范操作的基础上,推广应用此手术方法。     

Prognostic factors in patients with mesial temporal lobe epilepsy

Purpose:   To disclose clinical, electrophysiologic, and neuroradiologic factors correlated to prognosis in patients with mesial temporal lobe epilepsy (MTLE).
Methods:   One hundred thirty-six MTLE patients were studied for family history, clinical characteristics, instrumental data [electroencephalography (EEG), video-EEG, neuroimaging], and outcome. The population was divided into drug-resistant (DR: 108 patients, 79.4%) and non–drug-resistant (NDR: 28 patients, 20.6%) groups; all variables were analyzed in the two groups.
Results:   The comparison between the two groups shows a relation between resistance to therapy and febrile seizures (FS) (DR 43.5% vs. NDR 17.8%, p = 0.008), mesial temporal sclerosis (MTS) (DR 64.8% vs. NDR 32.1%, p = 0.0025), early age at seizure onset (DR 23.1% vs. NDR 3.6% p = 0.0160), and epileptiform interictal abnormalities (DR 89.7% vs. NDR 68%, p = 0.010). FS were more frequent in patients with MTS than in patients without (46.28% vs. 26.3%, p = 0.0199). Sixty-nine patients underwent surgery and 85.3% of them had a good outcome.
Conclusion:   MTLE is a heterogeneous syndrome. Establishing the factors responsible for and associated with drug resistance is important for therapeutic purposes, as prompt diagnosis of drug resistance must lead to early surgical management. This study shows that FS, MTS, early age at seizure onset, and epileptiform interictal abnormalities are negative prognostic factors and that FS are related to MTS.     

Sex differences in patients with mesial temporal lobe epilepsy

Possible sex differences in the pattern of interictalhypometabolism were investigated, and also seizure spread in patients with mesial temporal lobe epilepsy (n=48) and hippocampal sclerosis (MTLE). Male patients (n=21) more often had a frontal lobehypometabolism ipsilateral to the seizure onset (p<0.0001) and aspread of epileptiform activity to this region (p=0.001). By contrast,female patients more often exhibited hypometabolism (p=0.0052) and anictal spread to the contralateral temporal lobe (p=0.0097). Thesefindings suggest sex differences in spatial distribution of braindysfunction in MTLE, perhaps reflecting sexual dimorphism in regionalcerebral connectivity.