Mitochondrial dysfunction in epilepsy

Mitochondrial dysfunction has been identified as one potential cause of epileptic seizures. Impaired mitochondrial function has been reported for the seizure focus of patients with temporal lobe epilepsy and Ammon's horn sclerosis and of adult and immature animal models of epilepsy. Since mitochondrial oxidative phosphorylation provides the major source of ATP in neurons and mitochondria participate in cellular Ca(2+) homeostasis and generation of reactive oxygen species, their dysfunction strongly affects neuronal excitability and synaptic transmission. Therefore, mitochondrial dysfunction is proposed to be highly relevant for seizure generation. Additionally, mitochondrial dysfunction is known to trigger neuronal cell death, which is a prominent feature of therapy-resistant epilepsy. For this reason mitochondria have to be considered as promising targets for neuroprotective strategies in epilepsy.     

Whole mitochondrial DNA variations in hippocampal surgical specimens and blood samples with high-throughput sequencing: A case of mesial temporal lobe epilepsy with hippocampal sclerosis

Introduction

Hippocampal sclerosis is the most common lesion in patients with mesial temporal lobe epilepsy. Recently, there has been growing evidence on the involvement of mitochondria also in sporadic forms of epilepsy. In addition, it has been increasingly argued that mitochondrial dysfunction has an important role in epileptogenesis and seizure generation in temporal lobe epilepsy. Although mtDNA polymorphisms have been identified as potential risk factors for neurological diseases, the link between homoplasmy and heteroplasmy within tissues is not clear. We investigated whether mitochondrial DNA (mtDNA) polymorphisms are involved in a case report of a patient with mesial temporal lobe epilepsy-hippocampal sclerosis (MTLE-HS).

Design

We report the whole genome mtDNA deep sequencing results and clinical features of a 36-year-old woman with MTLE-HS. We used pyrosequencing technology to sequence a whole mitochondrial genome isolated from six different regions of her brain and blood. To assess the possible role of mitochondrial DNA variations in affected tissues, we compared all specimens from different regions of the hippocampus and blood.

Results

In total, 35 homoplasmic and 18 heteroplasmic variations have been detected in 6 different regions of the hippocampus and in blood samples. While the samples did not display any difference in homoplasmic variations, it has been shown that hippocampus regions contain more heteroplasmic variations than blood. The number of heteroplasmic variations was highest in the CA2 region of the brain and accumulated in ND2, ND4 and ND5 genes. Also, dentate and subiculum regions of the hippocampus had similar heteroplasmic variation profiles.

Discussion

We present a new rare example of parallel mutation at 16223 position. Our case suggests that defects in mitochondrial function might be underlying the pathogenesis of seizures in temporal lobe epilepsy.     

Endocrine abnormalities in human temporal lobe epilepsy

Patients with temporal lobe epilepsy secrete ACTH at higher rates and in greater amounts than normal subjects. Temporal lobectomy restores ACTH secretion to normal amounts and rates. The ACTH secretion in temporal lobe epilepsy is independent of anticonvulsant drug effect and seizure frequency. Electrical stimulation of medial temporal lobe structures in patients with temporal lobe epilepsy affected ACTH secretion in a manner consistent with the hypothesis that ACTH secretion is regulated by tonic inhibition. A defect in the excitatory and/or inhibitory components of this regulatory process appears to exist in temporal lobe epilepsy.     

癫痫与海马结构的改变

癫痫作为一种严重危害人类健康的常见病、多发病，其致病机理至今尚未阐明。30—60％的患者药物治疗无效，称“难治性癫痫”。随着现代医学的发展，外科手术的开展对于癫痫患者治疗也没有满意的效果。这就对于我们探求癫痫患者病灶的起源有了更深层次的要求。大量动物实验表明，海马作为中枢神经系统的重要结构不仅同学习、记忆、情绪等密切相关，还同癫痫的发生发展有着重要的联系。本文就大脑可塑性与癫痫的关系进行综述。     

Persistent impairment of mitochondrial and tissue redox status during lithium-pilocarpine-induced epileptogenesis

Mitochondrial dysfunction and oxidative stress are known to occur following acute seizure activity but their contribution during epileptogenesis is largely unknown. The goal of this study was to determine the extent of mitochondrial oxidative stress, changes to redox status, and mitochondrial DNA (mtDNA) damage during epileptogenesis in the lithium-pilocarpine model of temporal lobe epilepsy. Mitochondrial oxidative stress, changes in tissue and mitochondrial redox status, and mtDNA damage were assessed in the hippocampus and neocortex of Sprague-Dawley rats at time points (24h to 3months) following lithium-pilocarpine administration. A time-dependent increase in mitochondrial hydrogen peroxide (H(2)O(2)) production coincident with increased mtDNA lesion frequency in the hippocampus was observed during epileptogenesis. Acute increases (24-48h) in H(2)O(2) production and mtDNA lesion frequency were dependent on the severity of convulsive seizure activity during initial status epilepticus. Tissue levels of GSH, GSH/GSSG, coenzyme A (CoASH), and CoASH/CoASSG were persistently impaired at all measured time points throughout epileptogenesis, that is, acutely (24-48h), during the 'latent period' (48h to 7days), and chronic epilepsy (21days to 3months). Together with our previous work, these results demonstrate the model independence of mitochondrial oxidative stress, genomic instability, and persistent impairment of mitochondrial specific redox status during epileptogenesis. Lasting impairment of mitochondrial and tissue redox status during the latent period, in addition to the acute and chronic phases of epileptogenesis, suggests that redox-dependent processes may contribute to the progression of epileptogenesis in experimental temporal lobe epilepsy.     

Mitochondrial dysfunction and oxidative stress: a contributing link to acquired epilepsy?

Mitochondrial dysfunction and oxidative stress contribute to several neurologic disorders and have recently been implicated in acquired epilepsies such as temporal lobe epilepsy (TLE). Acquired epilepsy is typically initiated by a brain injury followed by a "latent period" whereby molecular, biochemical and other cellular alterations occur in the brain leading to chronic epilepsy. Mitochondrial dysfunction and oxidative stress are emerging as factors that not only occur acutely as a result of precipitating injuries such as status epilepticus (SE), but may also contribute to epileptogenesis and chronic epilepsy. Mitochondria are the primary site of reactive oxygen species (ROS) making them uniquely vulnerable to oxidative damage that may affect neuronal excitability and seizure susceptibility. This mini-review provides an overview of evidence suggesting the role of mitochondrial dysfunction and oxidative stress as acute consequences of injuries that are known to incite chronic epilepsy and their involvement in the chronic stages of acquired epilepsy.     

Clinical Aspects of Temporal Lobe Epilepsy

Temporal lobe epilepsy appears to be of increasing concern to psychiatrists, pediatricians and lawyers as an explanation for some aspects of behavior. There is a high incidence of structural abnormality associated with temporal lobe epilepsy, the most common being mesial temporal sclerosis. Depth electrode studies have shown that the most common focus for the clinical seizure is in the hippocampus or hippocampal gyrus. The first line of treatment continues to be attempt at control with anticonvulsant agents. Surgical treatment can be offered, in many instances, when drug therapy has failed.     

Functional Connectivity Estimated from Intracranial EEG Predicts Surgical Outcome in Intractable Temporal Lobe Epilepsy

This project aimed to determine if a correlation-based measure of functional connectivity can identify epileptogenic zones from intracranial EEG signals, as well as to investigate the prognostic significance of such a measure on seizure outcome following temporal lobe lobectomy. To this end, we retrospectively analyzed 23 adult patients with intractable temporal lobe epilepsy (TLE) who underwent an invasive stereo-EEG (SEEG) evaluation between January 2009 year and January 2012. A follow-up of at least one year was required. The primary outcome measure was complete seizure-freedom at last follow-up. Functional connectivity between two areas in the temporal lobe that were sampled by two SEEG electrode contacts was defined as Pearson’s correlation coefficient of interictal activity between those areas. SEEG signals were filtered between 5 and 50 Hz prior to computing this correlation. The mean and standard deviation of the off diagonal elements in the connectivity matrix were also calculated. Analysis of the mean and standard deviation of the functional connections for each patient reveals that 90% of the patients who had weak and homogenous connections were seizure free one year after temporal lobectomy, whereas 85% of the patients who had stronger and more heterogeneous connections within the temporal lobe had recurrence of seizures. This suggests that temporal lobectomy is ineffective in preventing seizure recurrence for patients in whom the temporal lobe is characterized by weakly connected, homogenous networks. This pilot study shows promising potential of a simple measure of functional brain connectivity to identify epileptogenicity and predict the outcome of epilepsy surgery.     

Mossy cells of the dentate gyrus: Drivers or inhibitors of epileptic seizures?

Mossy cells (MCs) are glutamatergic cells of the dentate gyrus with an important role in temporal lobe epilepsy. Under physiological conditions MCs can control both network excitations via direct synapses to granule cells and inhibition via connections to GABAergic interneurons innervating granule cells. In temporal lobe epilepsy mossy cell loss is one of the major hallmarks, but whether the surviving MCs drive or inhibit seizure initiation and generalization is still a debate. The aim of the present review is to summarize the latest findings on the role of mossy cells in healthy and overexcited hippocampus.     

Extraction of reproducible seizure patterns based on EEG scalp correlations

The objective of this work is to identify similarities in the spatio-temporal dynamics of epileptic seizures, record with scalp EEG. A comprehensive method is proposed and applied in EEG of the patients who suffer from temporal lobe epilepsy. The method is based on the computation of the time-varying degree of non linear correlation between scalp electrodes at seizure onset and during seizure spread, determined by a nonlinear regression analysis. The quantification and coding of these similarity relations allow the comparison between two epileptic networks. Results show that reproducible patterns may be extracted from different seizures of the same patient and confirm the existence of different subtypes of temporal lobe epilepsy.     

Electrographic Waveform Structure Predicts Laminar Focus Location in a Model of Temporal Lobe Seizures In Vitro

Temporal lobe epilepsy is the most common form of partial-onset epilepsy and accounts for the majority of adult epilepsy cases in most countries. A critical role for the hippocampus (and to some extent amygdala) in the pathology of these epilepsies is clear, with selective removal of these regions almost as effective as temporal lobectomy in reducing subsequent seizure risk. However, there is debate about whether hippocampus is ‘victim’ or ‘perpetrator’: The structure is ideally placed to ‘broadcast’ epileptiform activity to a great many other brain regions, but removal often leaves epileptiform events still occurring in cortex, particularly in adjacent areas, and recruitment of the hippocampus into seizure-like activity has been shown to be difficult in clinically-relevant models. Using a very simple model of acute epileptiform activity with known, single primary pathology (GABA_A Receptor partial blockade), we track the onset and propagation of epileptiform events in hippocampus, parahippocampal areas and neocortex. In this model the hippocampus acts as a potential seizure focus for the majority of observed events. Events with hippocampal focus were far more readily propagated throughout parahippocampal areas and into neocortex than vice versa. The electrographic signature of events of hippocampal origin was significantly different to those of primary neocortical origin – a consequence of differential laminar activation. These data confirm the critical role of the hippocampus in epileptiform activity generation in the temporal lobe and suggest the morphology of non-invasive electrical recording of neocortical interictal events may be useful in confirming this role.     

Which clinical and experimental data link temporal lobe epilepsy with depression?

The association of temporal lobe epilepsy with depression and other neuropsychiatric disorders has been known since the early beginnings of neurology and psychiatry. However, only recently have in vivo and ex vivo techniques such as Positron Emission Tomography, Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy in combination with refined animal models and behavioral tests made it possible to identify an emerging pattern of common pathophysiological mechanisms. We now have growing evidence that in both disorders altered interaction of serotonergic and noradrenergic neurons with glutamatergic systems is associated with abnormal neuronal circuits and hyperexcitability. Neuronal hyperexcitability can possibly evoke seizure activity as well as disturbed emotions. Moreover, decreased synaptic levels of neurotransmitters and high glucocorticoid levels influence intracellular signaling pathways such as cAMP, causing disturbances of brain-derived and other neurotrophic factors. These may be associated with hippocampal atrophy seen on Magnetic Resonance Imaging and memory impairment as well as altered fear processing and transient hypertrophy of the amygdala. Positron Emission Tomography studies additionally suggest hypometabolism of glucose in temporal and frontal lobes. Last, but not least, in temporal lobe epilepsy and depression astrocytes play a role that reaches far beyond their involvement in hippocampal sclerosis and ultimately, therapeutic regulation of glial-neuronal interactions may be a target for future research. All these mechanisms are strongly intertwined and probably bidirectional such that the structural and functional alterations from one disease increase the risk for developing the other. This review provides an integrative update of the most relevant experimental and clinical data on temporal lobe epilepsy and its association with depression.     

GABA neurons in seizure disorders: A review of immunocytochemical studies

Immunocytochemical studies have identified alterations in GABA neurons in several models of seizure disorders. However, the changes have varied among different epilepsy models, and these variations presumably reflect the diversity of mechanisms that can lead to seizure disorders. In models of cortical focal epilepsy, there is strong evidence fordecreases in the number of GABAergic elements, and the changes closely parallel the time course of seizure development. By contrast, in some genetic models of epilepsy,increases in the number of immunocytochemically-detectable neurons have been observed in selected brain regions. In several models of temporal lobe epilepsy, there presently is little immunocytochemical evidence for alterations of GABA neurons within the hippocampal formation despite physiological demonstrations of decreased GABA-mediated inhibition in this region. However, it remains possible that certain types of GABA neurons could be differentially affected in some seizure disorders while other types are preserved. Thus, distinguishing between different classes of GABA neurons and determining their functional roles represent major challenges for future studies of GABA neurons in seizure disorders.Special issue dedicated to Dr. Eugene Roberts.     

Effect of commissurotomy on complex partial epilepsy in patients without a resectable seizure focus

Twenty-five patients in a series of 51 undergoing partial or complete section of the corpus callosum for the treatment of intractable epilepsy experienced complex partial seizures among their seizure types preoperatively. Ten of these 25 patients have experienced no further complex partial seizures. Reduction in severity of seizures has been found in 11 of the 15 patients still experiencing this seizure type, and 3 have had greater than 80% frequency reduction. These findings are consistent with the electrophysiologic observations of Lieb on the relative unimportance of the hippocampal commissure in man and the behavioral observations of Quesney on unilateral versus bilateral temporal lobe seizure activity.     

Use of chromosome substitution strains to identify seizure susceptibility loci in mice

Seizure susceptibility varies among inbred mouse strains. Chromosome substitution strains (CSS), in which a single chromosome from one inbred strain (donor) has been transferred onto a second strain (host) by repeated backcrossing, may be used to identify quantitative trait loci (QTLs) that contribute to seizure susceptibility. QTLs for susceptibility to pilocarpine-induced seizures, a model of temporal lobe epilepsy, have not been reported, and CSS have not previously been used to localize seizure susceptibility genes. We report QTLs identified using a B6 (host) × A/J (donor) CSS panel to localize genes involved in susceptibility to pilocarpine-induced seizures. Three hundred fifty-five adult male CSS mice, 58 B6, and 39 A/J were tested for susceptibility to pilocarpine-induced seizures. Highest stage reached and latency to each stage were recorded for all mice. B6 mice were resistant to seizures and slower to reach stages compared to A/J mice. The CSS for Chromosomes 10 and 18 progressed to the most severe stages, diverging dramatically from the B6 phenotype. Latencies to stages were also significantly shorter for CSS10 and CSS18 mice. CSS mapping suggests seizure susceptibility loci on mouse Chromosomes 10 and 18. This approach provides a framework for identifying potentially novel homologous candidate genes for human temporal lobe epilepsy.     

Wnt/β‐catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid‐induced epilepsy

Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis with massive neuronal loss and severe gliosis. Aberrant neurogenesis has been shown in the epileptogenesis process of temporal lobe epilepsy. However, the molecular mechanisms underlying aberrant neurogenesis remain unclear. The roles of Wnt signalling cascade have been well established in neurogenesis during multiple aspects. Here, we used kainic acid‐induced rat epilepsy model to investigate whether Wnt/β‐catenin signalling pathway is involved in the aberrant neurogenesis in temporal lobe epilepsy. Immunostaining and western blotting results showed that the expression levels of β‐catenin, Wnt3a, and cyclin D1, the key regulators in Wnt signalling pathway, were up‐regulated during acute epilepsy induced by the injection of kainic acids, indicating that Wnt signalling pathway was activated in kainic acid‐induced temporal lobe epilepsy. Moreover, BrdU labelling results showed that blockade of the Wnt signalling by knocking down β‐catenin attenuated aberrant neurogenesis induced by kainic acids injection. Altogether, Wnt/β‐catenin signalling pathway mediated hippocampal neurogenesis during epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis. Aberrant neurogenesis has been shown to involve in the epileptogenesis process of temporal lobe epilepsy. In the present study, we discovered that Wnt3a/β‐catenin signalling pathway serves as a link between aberrant neurogenesis and underlying remodelling in the hippocampus, leading to temporal lobe epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy.     

Neurosurgical management of epilepsy: a personal perspective in 1983

The therapeutic goal in the neurosurgical treatment of medically intractable epilepsy is complete seizure control, for both biologic and psychosocial reasons. Cortical resections are more likely to accomplish this than other surgical alternatives for epilepsy. Although abnormalities on new imaging techniques (CT, positron emission scanning) aid in identifying the epileptic focus, interictal epileptiform EEG changes remain the main indicator of focal origin of the seizures. Where this is equivocal, direct brain recording of spontaneous seizures with subdural electrodes is of value in identifying the side and lobe of seizure onset. The cortical resection is then tailored by the extent of the interictal electrocorticographic abnormalities and functional identification of essential areas such as those for language, using an electrical stimulation mapping technique, under local anesthesia. With this approach, half of the patients with temporal lobe foci are seizure-free since the time of operation, over two-thirds become so with time, and over three-quarters have at least very major reductions in seizure frequency.     

Characterization of synchronization in interacting groups of oscillators: application to seizures

We investigate the emergence of synchronization in two groups of oscillators; one group acts as a synchronization source, and the other as the target. Based on phase model simulations, we construct a synchrony index (SI): a combination of intra- and intergroup synchronies. The SI characterizes the extent of induced synchrony in the population. We demonstrate the usefulness of the measure in a test case of mesial temporal lobe epilepsy: the SI can be readily calculated from standard electroencephalographic measurements. We show that the synchrony index has a statistically significant increased value for the ictal periods and that the epileptic focus can be located by identifying the most synchronous pairs of electrodes during the initial part of ictal period of the seizure. We also show that it is possible in this pilot case to differentiate clinical and subclinical seizures based on the dynamical features of the synchronization. The synchronization index was found to be a useful quantity for the characterization of “pathological hypersynchronization” within a well-characterized patient with mesial temporal lobe epilepsy and thus has potential medical value in seizure detection, localizing ability, and association with later surgical outcome.     

Mitophagy in Refractory Temporal Lobe Epilepsy Patients with Hippocampal Sclerosis

This study aimed to determine if there is an association between mitophagy and refractory temporal lobe epilepsy (rTLE) with hippocampal sclerosis. During epilepsy surgery, we collected tissue samples from the hippocampi and temporal lobe cortexes of rTLE patients with hippocampal sclerosis (as diagnosed by a pathologist). Transmission electron microscopy (TEM) was used to study the ultrastructural features of the tissue. To probe for mitophagy, we used fluorescent immunolabeling to determine if mitochondrial and autophagosomal markers colocalized. Fourteen samples were examined. TEM results showed that early autophagosomes were present and mitochondria were impaired to different degrees in hippocampi. Immunofluorescent labeling showed colocalization of the autophagosome marker LC3B with the mitochondrial marker TOMM20 in hippocampi and temporal lobe cortexes, indicating the presence of mitophagy. Mitochondrial and autophagosomal marker colocalization was lower in hippocampus than in temporal lobe cortex (P < 0.001). Accumulation of autophagosomes and mitophagy activation are implicated in rTLE with hippocampal sclerosis. Aberrant accumulation of damaged mitochondria, especially in the hippocampus, can be attributed to defects in mitophagy, which may participate in epileptogenesis.     

Epileptic seizures may begin hours in advance of clinical onset: a report of five patients

Mechanisms underlying seizure generation are traditionally thought to act over seconds to minutes before clinical seizure onset. We analyzed continuous 3- to 14-day intracranial EEG recordings from five patients with mesial temporal lobe epilepsy obtained during evaluation for epilepsy surgery. We found localized quantitative EEG changes identifying prolonged bursts of complex epileptiform discharges that became more prevalent 7 hr before seizures and highly localized subclinical seizure-like activity that became more frequent 2 hr prior to seizure onset. Accumulated energy increased in the 50 min before seizure onset, compared to baseline. These observations, from a small number of patients, suggest that epileptic seizures may begin as a cascade of electrophysiological events that evolve over hours and that quantitative measures of preseizure electrical activity could possibly be used to predict seizures far in advance of clinical onset.