Etiology Of Temporal Lobe Epilepsy Research Articles

Fibroblast growth factor 13 is involved in the pathogenesis of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults, with pathological mechanisms remaining to be fully elucidated. Fibroblast Growth Factor 13 (FGF13) encodes an intracellular protein involved in microtubule stabilization and regulation of voltage-gated sodium channels (VGSCs) function. FGF13 mutation has been identified in patients with inherent seizure, suggesting a potential association between FGF13 and the etiology of TLE. Here, we set to explore the pathological role of FGF13 in the etiology of TLE. We found that the expression of FGF13 was increased in the cortical lesions and CA1 region of sclerotic hippocampus and correlated with the seizure frequency in TLE patients. Also, Fgf13 expression was increased in the hippocampus of chronic TLE mice generated by kainic acid (KA) injection. Furthermore, Fgf13 knockdown or overexpression was respectively found to attenuate or potentiate the effects of KA on axonal length, somatic area and the VGSCs-mediated current in the hippocampal neurons. Taken together, these findings suggest that FGF13 is involved in the pathogenesis of TLE by modulating microtubule activity and neuronal excitability.

TNFα-Driven Astrocyte Purinergic Signaling during Epileptogenesis

The etiology of temporal lobe epilepsy is unclear, but proinflammatory molecules and disturbed neuron-glia communications are emerging as potential causers. A recent study (Nikolic et al. Glia 2018; https://doi.org/10.1002/glia.23519) revealed that pathologically elevated tumor necrosis factor α contributes to epileptogenesis, by boosting hyperexcitation through an autocrine mechanism involving purinergic signaling, astrocyte glutamate release, and modulation of neuronal transmitter release.

Altered mitochondrial acetylation profiles in a kainic acid model of temporal lobe epilepsy

Impaired bioenergetics and oxidative damage in the mitochondria are implicated in the etiology of temporal lobe epilepsy, and hyperacetylation of mitochondrial proteins has recently emerged as a critical negative regulator of mitochondrial functions. However, the roles of mitochondrial acetylation and activity of the primary mitochondrial deacetylase, SIRT3, have not been explored in acquired epilepsy. We investigated changes in mitochondrial acetylation and SIRT3 activity in the development of chronic epilepsy in the kainic acid rat model of TLE. Hippocampal measurements were made at 48 h, 1 week and 12 weeks corresponding to the acute, latent and chronic stages of epileptogenesis. Assessment of hippocampal bioenergetics demonstrated a ≥ 27% decrease in the ATP/ADP ratio at all phases of epileptogenesis (p < 0.05), whereas cellular NAD+ levels were decreased by ≥ 41% in the acute and latent time points (p < 0.05), but not in chronically epileptic rats. In spontaneously epileptic rats, we found decreased protein expression of SIRT3 and a 60% increase in global mitochondrial acetylation, as well as enhanced acetylation of the known SIRT3 substrates MnSOD, Ndufa9 of Complex I and IDH2 (all p < 0.05), suggesting SIRT3 dysfunction in chronic epilepsy. Mass spectrometry-based acetylomics investigation of hippocampal mitochondria demonstrated a 79% increase in unique acetylated proteins from rats in the chronic phase vs. controls. Pathway analysis identified numerous mitochondrial bioenergetic pathways affected by mitochondrial acetylation. These results suggest SIRT3 dysfunction and aberrant protein acetylation may contribute to mitochondrial dysfunction in chronic epilepsy.

Protocol for intraoperative assessment of the human cerebrovascular glycocalyx

IntroductionAdequate functioning of the blood–brain barrier (BBB) is important for brain homoeostasis and normal neuronal function. Disruption of the BBB has been described in several neurological diseases. Recent reports suggest...

Spotlight on the October 27 Issue

#### Notable in Neurology This issue features an article investigating systemic thrombolysis in acute ischemic stroke patients with unruptured intracranial aneurysms and another on predicting an underrecognized etiology of temporal lobe epilepsy: temporal anteroinferior encephalocele. A review article focuses on chronic traumatic encephalopathy in athletes. ### Age-specific association of migraine with cryptogenic TIA and stroke: Population-based study In patients with TIA and ischemic stroke, migraine was more commonly associated with cryptogenic events than with events of known etiology, particularly at older ages. Migraine is accepted as a risk factor for “young” stroke, but these findings suggest a causal relationship between migraine …

Mitochondrial respiration deficits driven by reactive oxygen species in experimental temporal lobe epilepsy

Metabolic alterations have been implicated in the etiology of temporal lobe epilepsy (TLE), but whether or not they have a functional impact on cellular energy producing pathways (glycolysis and/or oxidative phosphorylation) is unknown. The goal of this study was to determine if alterations in cellular bioenergetics occur using real-time analysis of mitochondrial oxygen consumption and glycolytic rates in an animal model of TLE. We hypothesized that increased steady-state levels of reactive oxygen species (ROS) initiated by epileptogenic injury result in impaired mitochondrial respiration. We established methodology for assessment of bioenergetic parameters in isolated synaptosomes from the hippocampus of Sprague–Dawley rats at various times in the kainate (KA) model of TLE. Deficits in indices of mitochondrial respiration were observed at time points corresponding with the acute and chronic phases of epileptogenesis. We asked if mitochondrial bioenergetic dysfunction occurred as a result of increased mitochondrial ROS and if it could be attenuated in the KA model by pharmacologically scavenging ROS. Increased steady-state ROS in mice with forebrain-specific conditional deletion of manganese superoxide dismutase (Sod2fl/flNEXCre/Cre) in mice resulted in profound deficits in mitochondrial oxygen consumption. Pharmacological scavenging of ROS with a catalytic antioxidant restored mitochondrial respiration deficits in the KA model of TLE. Together, these results demonstrate that mitochondrial respiration deficits occur in experimental TLE and ROS mechanistically contribute to these deficits. Furthermore, this study provides novel methodology for assessing cellular metabolism during the entire time course of disease development.

Post-Translational Oxidative Modification and Inactivation of Mitochondrial Complex I in Epileptogenesis

Mitochondrial oxidative stress and damage have been implicated in the etiology of temporal lobe epilepsy, but whether or not they have a functional impact on mitochondrial processes during epilepsy development (epileptogenesis) is unknown. One consequence of increased steady-state mitochondrial reactive oxygen species levels is protein post-translational modification (PTM). We hypothesize that complex I (CI), a protein complex of the mitochondrial electron transport chain, is a target for oxidant-induced PTMs, such as carbonylation, leading to impaired function during epileptogenesis. The goal of this study was to determine whether oxidative modifications occur and what impact they have on CI enzymatic activity in the rat hippocampus in response to kainate (KA)-induced epileptogenesis. Rats were injected with a single high dose of KA or vehicle and evidence for CI modifications was measured during the acute, latent, and chronic stages of epilepsy. Mitochondrial-specific carbonylation was increased acutely (48 h) and chronically (6 week), coincident with decreased CI activity. Mass spectrometry analysis of immunocaptured CI identified specific metal catalyzed carbonylation to Arg76 within the 75 kDa subunit concomitant with inhibition of CI activity during epileptogenesis. Computational-based molecular modeling studies revealed that Arg76 is in close proximity to the active site of CI and carbonylation of the residue is predicted to induce substantial structural alterations to the protein complex. These data provide evidence for the occurrence of a specific and irreversible oxidative modification of an important mitochondrial enzyme complex critical for cellular bioenergetics during the process of epileptogenesis.

Genetics of Temporal Lobe Epilepsy: A Review

Temporal lobe epilepsy (TLE) is usually regarded as a polygenic and complex disorder. To understand its genetic component, numerous linkage analyses of familial forms and association studies of cases versus controls have been conducted since the middle of the nineties. The present paper lists genetic findings for TLE from the initial segregation analysis to the most recent results published in May 2011. To date, no genes have been clearly related to TLE despite many efforts to do so. However, it is vital to continue replication studies and collaborative attempts to find significant results and thus determine which gene variant combination plays a definitive role in the aetiology of TLE.

Association study of functional polymorphisms in serotonin transporter gene with temporal lobe epilepsy in Han Chinese population

Serotoninergic dysfunction was reported to be involved in aetiology of temporal lobe epilepsy (TLE). Serotonin (5-HT) is actively cleared from synaptic cleft by serotonin transporter (5-HTT). We investigated the association between three common polymorphisms of 5-HTT gene, which may influence gene expression or function, and risk for TLE. Three hundred and thirty-four patients with TLE and four hundred and eighty-seven non-epileptic control subjects from Han Chinese origin were enrolled for the present study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping. 10-repeat allele frequency of 17 bp variable number of tandem repeats in the second intron (5-HTTVNTR) was moderately higher in patients with TLE than in controls (9.1% vs. 6.1%, P=0.0187, OR=1.55, 95%CI=1.07-2.26). Our study suggested 10-repeat allele of 5-HTTVNTR may be associated with TLE susceptibility.

Epilepsia del lóbulo temporal. Clasificación etiológica en 61 pacientes en edad pediátrica

There are very few studies on the aetiology of temporal lobe epilepsy (TLE) in childhood. The purpose of the present study is to analyse the data of 61 children diagnosed with TLE, in order to describe the aetiology of TLE in children seen in a neuropaedriatic clinic. We also discuss the currently proposed classification. A retrospective analysis was carried out on patients diagnosed with TLE. Patients consisted of 61 children less than 15 years old. Patients were classified into three groups: Group 1 (symptomatic temporal lobe epilepsy) consisted of 25 patients (40.98 %) with any temporal lesion on neuroimaging (tumours, malformations or infections) or significant history; Group 2 (Mesial temporal sclerosis) consisted of 17 patients (27.86 %), a history of simple and complex febrile seizure were common in this group; and Group 3 (Cryptogenic epilepsy) consisted of 19 patients (31.15 %) with no abnormalities on neuroimaging or significant history. To our knowledge, this is the largest paediatric series of childhood new-onset TLE assessed only by MRI in the literature. We have modified the previous aetiological classification in order to make the groups more realistic.

Relevance of seizure-induced neurogenesis in animal models of epilepsy to the etiology of temporal lobe epilepsy.

Seizure induction in laboratory animals is followed by many changes in structure and function, and one of these is an increase in neurogenesis-the birth of new neurons. This phenomenon may be relevant to temporal lobe epilepsy (TLE), because one of the regions of the brain where seizure-induced neurogenesis is most robust is the dentate gyrus-an area of the brain that has been implicated in the pathophysiology of TLE. Although initial studies predicted that neurogenesis in the dentate gyrus would be important to normal functions, such as learning and memory, the new neurons that are born after seizures may not necessarily promote normal function. There appears to be a complex functional and structural relationship between the new dentate gyrus neurons and preexisting cells, both in the animal models of TLE and in tissue resected from patients with intractable TLE. These studies provide new insights into the mechanisms of TLE, and suggest novel strategies for intervention that could be used to prevent or treat TLE.

Sub-classification of temporal lobe epilepsy and clinical and etiological characteristics thereof

To study the sub-classification of temporal lobe epilepsy (TLE) and clinical and etiological characteristics thereof. The clinical data of 190 patients with TLE, aged 1.5 approximately 67, were analyzed. The sub-classification was based on clinical manifestations and electroencephalographic recording. The etiology of TLE was mainly concluded from both clinical history and neuroimaging. 172 patients were subclassified as with mesial temporal lobe epilepsy (MTLE), of which 62.2% had auras such as epigastric abnormal sensation and 67.4% had automatism, especially oroalimentary automatism. The electroencephalography recording of the MTLE patients showed interictal epileptic paroxysm discharges over the anterior or mid-anterior temporal areas. The main etiological factors related to MTLE were hippocampal sclerosis, intracranial infection, tumor, cerebrovascular disease, and trauma. Ten patients were subclassified as with lateral temporal lobe epilepsy (LTLE), all presenting auras such as acoust. The electroencephalography recording showed interictal epileptic paroxysm discharges over the posterior or mid-posterior temporal areas. The main etiological factors were trauma, tumor, and atrophy in the LTLE group. Eight patients were unable to be sub-classified. Electroencephalography is the main base for classification of TLE. Subclassification of TLE is important in the selection of treatment strategies.

A Kv4.2 truncation mutation in a patient with temporal lobe epilepsy

Temporal lobe epilepsy (TLE) has a multifactorial etiology involving developmental, environmental, and genetic components. Here, we report a voltage-gated potassium channel gene mutation found in a TLE patient, namely a Kv4.2 truncation mutation. Kv4.2 channels, encoded by the KCND2 gene, mediate A currents in the brain. The identified mutation corresponds to an N587fsX1 amino acid change, predicted to produce a truncated Kv4.2 protein lacking the last 44 amino acids in the carboxyl terminal. Electrophysiological analysis indicates attenuated K+ current density in cells expressing this Kv4.2-N587fsX1 mutant channel, which is consistent with a model of aberrant neuronal excitability characteristic of TLE. Our observations, together with other lines of evidence, raise the intriguing possibility of a role for KCND2 in the etiology of TLE.

Temporal lobe epilepsy in children: etiology in a cohort with new-onset seizures.

The aim of this study was to characterize the incidence and etiology of temporal lobe epilepsy (TLE) in a community-based cohort of children with new-onset disease. A community-based cohort of 30 children with TLE was studied. The patients had new-onset disease before age 14 years between 1995 and 1999. They underwent clinical, EEG, and magnetic resonance imaging investigations. The patients could be divided in three main groups according to likely etiology, as suggested by Harvey et al. (Neurology 1997;49:960-8). Group 1 consisted of eight (26.7%) children with malformations or long-standing, nonprogressive tumors (developmental TLE). Arachnoid cysts were found in three, dual pathology [cortical dysplasia and hippocampal sclerosis (HS)] in one, and focal cortical dysplasia with glioproliferative changes in one patient. Dysembryoplastic neuroepithelial tumor was responsible for the epilepsy in one, and ganglioglioma, in two children. Group 2 consisted of seven (23.3%) children with a significant antecedent and/or HS. Five children had a significant illness or event before the onset of TLE, including perinatal hypoxic-ischemic encephalopathy in one, encephalitis in one, traumatic brain injury in two, and complex febrile seizures in one. HS was found in the patients with traumatic brain injury and complex febrile seizures in the history in addition to two children without known antecedents. Group 3 comprised 15 (50%) children with no abnormality on neuroimaging and no significant antecedents (cryptogenic TLE). Etiologic differences between children with new-onset TLE may have prognostic implications: children with TLE and significant antecedents/HS are expected to have the greatest risk of continued seizures and psychological problems.

Chronic changes in synaptic responses of entorhinal and hippocampal neurons after amino-oxyacetic acid (AOAA)-induced entorhinal cortical neuron loss.

Chronic changes in synaptic responses of entorhinal and hippocampal neurons after amino-oxyacetic acid (AOAA)-induced entorhinal neuron loss. J. Neurophysiol. 80: 3031-3046, 1998. Synaptic responses of entorhinal cortical and hippocampal neurons were examined in vivo and in vitro, 1 mo to 1.5 yr after a unilateral entorhinal lesion caused by a focal injection of amino-oxyacetic acid (AOAA). It has been shown previously that injection of AOAA into the medial entorhinal cortex produces cell loss in layer III preferentially. Although behavioral seizures stopped approximately 2 h after AOAA treatment, abnormal evoked responses were recorded as long as 1.5 yr later in the entorhinal cortex and hippocampus. In the majority of slices from AOAA-treated rats, responses recorded in the superficial layers of the medial entorhinal cortex to white matter, presubiculum, or parasubiculum stimulation were abnormal. Extracellularly recorded responses to white matter stimulation were prolonged and repetitive in the superficial layers. Intracellular recordings showed that residual principal cells in superficial layers produced prolonged, repetitive excitatory postsynaptic potentials (EPSPs) and discharges in response to white matter stimulation compared with brief EPSPs and a single discharge in controls. Responses of deep layer neurons of AOAA-treated rats did not differ from controls in their initial synaptic response. However, in a some of these neurons, additional periods of excitatory activity occurred after a delay. Abnormal responses were recorded from slices ipsilateral as well as contralateral to the lesioned hemisphere. Recordings from the entorhinal cortex in vivo were abnormal also, as demonstrated by prolonged and repetitive responses to stimulation of the area CA1/subiculum border. Evoked responses of hippocampal neurons, recorded in vitro or in vivo, demonstrated abnormalities in selected pathways, such as responses of CA3 neurons to hilar stimulation in vitro. There was a deficit in the duration of potentiation of CA1 population spikes in response to repetitive CA3 stimulation in AOAA-treated rats. Theta activity was reduced in amplitude in area CA1 and the dentate gyrus of AOAA-treated rats, although evoked responses to angular bundle stimulation could not be distinguished from controls. The results demonstrate that a preferential lesion of layer III of the entorhinal cortex produces a long-lasting change in evoked and spontaneous activity in parts of the entorhinal cortex and hippocampus. Given the similarity of the lesion produced by AOAA and entorhinal lesions in temporal lobe epileptics, these data support the hypothesis that preferential damage to the entorhinal cortex contributes to long-lasting changes in excitability, which could be relevant to the etiology of temporal lobe epilepsy.

Cholinomimetics produce seizures and brain damage in rats.

Microinjections of the cholinergic agonists, carbachol and bethanechol, either into the amygdala or into the dorsal hippocampus produced sustained limbic seizures and brain damage in rats. Systemic administration of pilocarpine in rats resulted in a sequence of convulsive disorders and widespread brain damage as well. Scopolamine prevented the development of convulsive activity and brain damage produced by cholinomimetics. These results suggest that the excessive stimulation of cholinergic muscarinic receptors can lead to limbic seizures and brain damage. It is postulated that muscarinic cholinergic mechanisms are linked to the etiology of temporal lobe epilepsy and epileptic brain damage.