Showing papers on "Epileptogenesis published in 2003"

The biology of epilepsy genes

Abstract: Mutations in over 70 genes now define biological pathways leading to epilepsy, an episodic dysrhythmia of the cerebral cortex marked by abnormal network synchronization. Some of the inherited errors destabilize neuronal signaling by inflicting primary disorders of membrane excitability and synaptic transmission, whereas others do so indirectly by perturbing critical control points that balance the developmental assembly of inhibitory and excitatory circuits. The genetic diversity is now sufficient to discern short- and long-range functional convergence of epileptogenic molecular pathways, reducing the broad spectrum of primary molecular defects to a few common processes regulating cortical synchronization. Synaptic inhibition appears to be the most frequent target; however, each gene mutation retains unique phenotypic features. This review selects exemplary members of several gene families to illustrate principal categories of the disease and trace the biological pathways to epileptogenesis in the developing brain.

Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model.

Abstract: Excessive astrocytosis in cortical tubers in tuberous sclerosis complex (TSC) suggests that astrocytes may be important for epileptogenesis in TSC. We previously demonstrated that astrocyte-specific Tsc1 gene inactivation in mice (Tsc1 cKO mice) results in progressive epilepsy. Here, we report that glutamate transporter expression and function is impaired in Tsc1 cKO astrocytes. Tsc1 cKO mice exhibit decreased GLT-1 and GLAST protein expression. Electrophysiological assays demonstrate a functional decrease in glutamate transport currents of Tsc1 cKO astrocytes in hippocampal slices and astrocyte cultures. These findings suggest that Tsc1 inactivation in astrocytes causes dysfunctional glutamate homeostasis, leading to seizure development in TSC. Ann Neurol 2003

Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures

Abstract: Seizures induced by fever (febrile seizures) are the most frequent seizures affecting infants and children; however, their impact on the developing hippocampal formation is not completely understood. Such understanding is highly important because of the potential relationship of prolonged febrile seizures to temporal lobe epilepsy. Using an immature rat model, we have previously demonstrated that prolonged experimental febrile seizures render the hippocampus hyperexcitable throughout life. Here we examined whether (1) neuronal loss, (2) altered neurogenesis, or (3) mossy fiber sprouting, all implicated in epileptogenesis in both animal models and humans, were involved in the generation of a pro-epileptic, hyperexcitable hippocampus by these seizures. The results demonstrated that prolonged experimental febrile seizures did not result in appreciable loss of any vulnerable hippocampal cell population, though causing strikingly enhanced sensitivity to hippocampal excitants later in life. In addition, experimental febrile seizures on postnatal day 10 did not enhance proliferation of granule cells, whereas seizures generated by kainic acid during the same developmental age increased neurogenesis in the immature hippocampus. However, prolonged febrile seizures resulted in long-term axonal reorganization in the immature hippocampal formation: Mossy fiber densities in granule cell- and molecular layers were significantly increased by 3 months (but not 10 days) after the seizures. Thus, the data indicate that prolonged febrile seizures influence connectivity of the immature hippocampus long-term, and this process requires neither significant neuronal loss nor altered neurogenesis. In addition, the temporal course of the augmented mossy fiber invasion of the granule cell and molecular layers suggests that it is a consequence, rather than the cause, of the hyperexcitable hippocampal network resulting from these seizures.

Correlated stage- and subfield-associated hippocampal gene expression patterns in experimental and human temporal lobe epilepsy.

Abstract: Epileptic activity evokes profound alterations of hippocampal organization and function. Genomic responses may reflect immediate consequences of excitatory stimulation as well as sustained molecular processes related to neuronal plasticity and structural remodeling. Using oligonucleotide microarrays with 8799 sequences, we determined subregional gene expression profiles in rats subjected to pilocarpine-induced epilepsy (U34A arrays, Affymetrix, Santa Clara, CA, USA; P < 0.05, twofold change, n = 3 per stage). Patterns of gene expression corresponded to distinct stages of epilepsy development. The highest number of differentially expressed genes (dentate gyrus, approx. 400 genes and CA1, approx. 700 genes) was observed 3 days after status epilepticus. The majority of up-regulated genes was associated with mechanisms of cellular stress and injury - 14 days after status epilepticus, numerous transcription factors and genes linked to cytoskeletal and synaptic reorganization were differentially expressed and, in the stage of chronic spontaneous seizures, distinct changes were observed in the transcription of genes involved in various neurotransmission pathways and between animals with low vs. high seizure frequency. A number of genes (n = 18) differentially expressed during the chronic epileptic stage showed corresponding expression patterns in hippocampal subfields of patients with pharmacoresistant temporal lobe epilepsy (n = 5 temporal lobe epilepsy patients; U133A microarrays, Affymetrix; covering 22284 human sequences). These data provide novel insights into the molecular mechanisms of epileptogenesis and seizure-associated cellular and structural remodeling of the hippocampus.

Overlapping Microarray Profiles of Dentate Gyrus Gene Expression during Development- and Epilepsy-Associated Neurogenesis and Axon Outgrowth

Abstract: Neurogenesis and axon outgrowth are features shared by normal nervous system development and certain forms of epileptogenesis. This observation has led to the hypothesis that some aspects of normal development and epileptogenesis have common molecular mechanisms. To test this hypothesis, we have used DNA microarray analysis to characterize gene expression in the dentate gyrus and identify genes exhibiting similar patterns of regulation during development and epileptogenesis. Of more than 8000 sequences surveyed, over 600 were regulated during development or epileptogenesis, and 37 of these were either upregulated or downregulated during both processes. In situ hybridization analysis of a subset of these “commonality genes” confirmed the patterns of regulation predicted by the microarray data in most cases and demonstrated various spatial and temporal patterns of commonality gene expression. Of the 25 named commonality genes in which some functional characteristics are known, 11 have been implicated in cell morphology and axon outgrowth or cellular proliferation and fate determination. This enrichment for candidate plasticity-related genes supports the concept that developmental mechanisms contribute to network alterations associated with epileptogenesis and offers a useful strategy for identifying molecules that may play a role in both of these processes.

Involvement of Gap Junctions in the Manifestation and Control of the Duration of Seizures in Rats In Vivo

Abstract: Summary: Purpose: The possible role of gap junctions in the manifestation and control of the duration of seizures was tested on the 4-aminopyridine–induced epilepsy model in rats in vivo, by using electrophysiologic, pharmacologic, and molecular biologic techniques. Methods: In electrophysiologic experiments, the functional states of the gap junctions were manipulated with a specific blocker (carbenoxolone) or opener (trimethylamine) at the already active focus of adult, anesthetized rats, 60 min after the induction of the first seizure, which was repeated spontaneously thereafter. Semiquantitative reverse transcriptase–polymerase chain reaction (RT-PCR) amplification was used to measure the levels of connexin (Cx) 32, 43, and 36 messenger RNAs (mRNAs) prepared from the areas of the already active primary and mirror foci. Results: After repeated seizures, the expression levels of Cx32, Cx43, and Cx36 mRNAs at the epileptic foci were increased significantly. Blockade of the gap junctions with carbenoxolone shortened the duration of seizures and decreased the amplitude of the seizure discharges, whereas their opening with trimethylamine lengthened the duration and increased the amplitude. Secondary epileptogenesis was facilitated when the gap junctions were opened. Conclusions: Our findings support the idea that, in epileptic foci, the gap junctions are involved in the expression of rhythmic ictal discharges and in the control of the duration and propagation of the individual seizures in vivo.

cDNA profiling of epileptogenesis in the rat brain.

Abstract: Symptomatic temporal lobe epilepsy typically develops in three phases: brain insult --> latency period (epileptogenesis) --> recurrent seizures (epilepsy). We hypothesized that remodeling of neuronal circuits underlying epilepsy is associated with altered gene expression during epileptogenesis. Epileptogenesis was induced by electrically triggered status epilepticus (SE) in rats. Animals were continuously monitored with video-EEG, and the hippocampus and temporal lobe were collected either during epileptogenesis (1, 4 and 14 days) or after the first spontaneous seizures (14 days) for cDNA array analysis. Altogether, 282 genes had altered expression, from which 87 were in the hippocampus and 208 in the temporal lobe (overlap in 13). Assessment of hippocampal gene expression during epileptogenesis indicated that 37 genes were altered in the 1-day group, 12 in the 4-day group and 14 in the 14-day epileptogenesis group. There were 42 genes with altered expression in the 14-day epilepsy group. In the temporal lobe, the number of genes with altered expression was 29 in the 1-day group, 155 in the 4-day group, 32 in the 14-day epileptogenesis group and 62 in the 14-day epilepsy group. Products of the altered genes are involved in neuronal plasticity, gliosis, organization of the cytoskeleton or extracellular matrix, cell adhesion, signal transduction, regulation of cell cycle, and metabolism. As most of these genes have not previously been implicated in epileptogenesis or epilepsy, these data open new avenues for understanding the molecular basis of epileptogenesis and provide new targets for rational development of anti-epileptogenic treatments for patients with an elevated risk of epileptogenesis after brain injury.

Generalized epilepsy in hypothalamic hamartoma: Evolution and postoperative resolution

Abstract: Objective: To better understand the epileptogenesis of symptomatic generalized epilepsy in patients with hypothalamic hamartoma and intractable epilepsy, many of whom experience remission of generalized seizures and slow spike-wave discharges following surgery. Methods: The authors documented the evolution of symptomatic generalized epilepsy in 12 of 20 children who underwent transcallosal microsurgical hypothalamic hamartoma resection. In seven patients they recorded intraoperative EEG from the hamartoma and simultaneously from the scalp and frontal cortex before, during, and after resection. Results: Gelastic seizures began on average at 6 months of age (range birth to 3 years); tonic seizures began at 6 years (range 2 months to 9 years). Normal EEG were reported in early childhood; thereafter, abnormalities were progressive. Interictal spike-wave was recorded intraoperatively over the scalp and cortex in six patients, but not from the hypothalamic hamartoma. Hamartoma resection had no immediate effect on cortical spike-wave, but waking spike-wave was absent in seven patients on subsequent postoperative EEG. Tonic seizures ceased in 11 of 12 patients, but 6 of these had postoperative generalized seizures that resolved over 1 to 6 months. Conclusion: Gelastic seizures in hypothalamic hamartoma arise from the hamartoma itself; the interictal spike-wave does not. The evolution of EEG abnormalities, the development of generalized seizures years after onset of gelastic seizures, and the postoperative running down of interictal spike-wave and generalized seizures in these patients may reflect secondary epileptogenesis.

Expression and cell distribution of group I and group II metabotropic glutamate receptor subtypes in Taylor-type focal cortical dysplasia

Abstract: Summary: Purpose: Focal cortical dysplasia (FCD) is known to be a major cause of intractable epilepsy. The cellular mechanism(s) underlying the epileptogenicity of FCD remain largely unknown. Because recent studies indicate that metabotropic glutamate receptor subtypes (mGluRs) play a role in epileptogenesis, we investigated the expression and cellular distribution pattern of mGluRs in FCD specimens. Methods: Immunocytochemical expression of group I and group II mGluR subtypes was investigated in 15 specimens of human FCD obtained during epilepsy surgery. Results: Strong mGluR1α and mGluR5 (group I mGluRs) immunoreactivity (IR) was observed in the majority of FCD specimens in dysplastic as well as in heterotopic neurons. mGluR1α was expressed in a subpopulation of neurons (mainly large dysplastic cells), whereas mGluR5 was represented in a higher percentage of dysplastic neuronal cells. Group II mGluRs (mGluR2/3) IR was observed less frequently than that in group I mGluRs and generally appeared in <10% of the dysplastic neurons. IR for all three mGluR subtypes was observed in balloon cells. mGluR2/3 appeared to be most frequently expressed in glial fibrillary acidic protein (GFAP)-positive balloon cells (glial type), and mGluR1α, in microtubule-associated protein (MAP)2-positive cells (neuronal type). mGluR5 was present in the majority of balloon cells. Occasionally glial mGluR1α IR was observed in bizarre glial cells with di- or multinuclei. Reactive astrocytes were intensively stained, mainly with mGluR5 and mGluR2/3. Conclusions: The cellular distribution of mGluR subtypes, with high expression of mGluR1α and mGluR5 in dysplastic neurons, suggests a possible contribution of group I mGluRs to the intrinsic and high epileptogenicity of dysplastic cortical regions.

Cellular biology of epileptogenesis.

Abstract: Summary The ionic currents that underlie the mechanisms of epileptogenesis have been systematically characterised in different experimental preparations. The recent elucidation of the molecular structures of most membrane channels and receptors has enabled structure–function analyses in both physiological and pathophysiological conditions. The neurophysiological and biomolecular features of epileptogenic mechanisms that putatively account for human epilepsies are summarised in this review. Particular emphasis is given to epilepsies that are associated with genetically determined alterations of ligand-gated and voltage-gated ion channels. Changes in ionic currents that flow through sodium, potassium, and calcium channels can lead to different types of epilepsies. Inherited or acquired changes that alter the function of receptors for acetylcholine, glutamate, and γ-aminobutryic acid are also involved. A better understanding of the role of these epileptogenic mechanisms will promote new advances in the development of selective and targeted antiepileptic drugs.

The anticonvulsant effect of citalopram as an indirect evidence of serotonergic impairment in human epileptogenesis

Abstract: Some evidence would indicate that a serotonergic deficit may be involved in epileptogenesis. A preliminary trial of citalopram, a selective inhibitor of serotonin reuptake, was carried out. Citalopram 20mg/day was given to 11 non-depressed patients with poorly controlled epilepsy as an add on treatment with an open label design for 8–10 months. The median seizure frequency dropped by 55.6% in the whole group, with nine patients improving by at least 50%. No adverse reactions occurred with the exception of mild drowsiness. There were no changes of post-treatment as compared to pre-treatment AED serum concentrations. Although controlled studies are required to confirm the anticonvulsant effect of citalopram, these findings may be regarded as an indirect evidence of serotonergic impairment in human epileptogenesis.

Anticonvulsant pharmacology of voltage-gated Na+ channels in hippocampal neurons of control and chronically epileptic rats.

Abstract: Voltage-gated Na+ channels are a main target of many first-line anticonvulsant drugs and their mechanism of action has been extensively investigated in cell lines and native neurons. Nevertheless, it is unknown whether the efficacy of these drugs might be altered following chronic epileptogenesis. We have, therefore, analysed the effects of phenytoin (100 micro m), lamotrigine (100 micro m) and valproate (600 micro m) on Na+ currents in dissociated rat hippocampal granule neurons in the pilocarpine model of chronic epilepsy. In control animals, all three substances exhibited modest tonic blocking effects on Na+ channels in their resting state. These effects of phenytoin and lamotrigine were reduced (by 77 and 64%) in epileptic compared with control animals. Phenytoin and valproate caused a shift in the voltage dependence of fast inactivation in a hyperpolarizing direction, while all three substances shifted the voltage dependence of activation in a depolarizing direction. The anticonvulsant effects on Na+ channel voltage dependence proved to be similar in control and epileptic animals. The time course of fast recovery from inactivation was potently slowed by lamotrigine and phenytoin in control animals, while valproate had no effect. Interestingly, the effects of phenytoin on fast recovery from inactivation were significantly reduced in chronic epilepsy. Taken together, these results reveal that different anticonvulsant drugs may exert a distinct pattern of effects on native Na+ channels. Furthermore, the reduction of phenytoin and, to a less pronounced extent, lamotrigine effects in chronic epilepsy raises the possibility that reduced pharmacosensitivity of Na+ channels may contribute to the development of drug resistance.

Epilepsy after early-life seizures can be independent of hippocampal injury

Abstract: Prolonged early-life seizures are considered potential risk factors for later epilepsy development, but mediators of this process remain largely unknown. Seizure-induced structural damage in hippocampus, including cell loss and mossy fiber sprouting, is thought to contribute to the hyperexcitability characterizing epilepsy, but a causative role has not been established. To determine whether early-life insults that lead to epilepsy result in similar structural changes, we subjected rat pups to lithium-pilocarpine–induced status epilepticus during postnatal development (day 20) and examined them as adults for the occurrence of spontaneous seizures and alterations in hippocampal morphology. Sixty-seven percent of rats developed spontaneous seizures after status epilepticus, yet only one third of these epileptic animals exhibited visible hippocampal cell loss or mossy fiber spouting in dentate gyrus. Most epileptic rats had no apparent structural alterations in the hippocampus detectable using standard light microscopy methods (profile counts and Timm's staining). These results suggest that hippocampal cell loss and mossy fiber sprouting can occur after early-life status epilepticus but may not be necessary prerequisites for epileptogenesis in the developing brain. Ann Neurol 2003

Antiepileptogenesis, neuroprotection, and disease modification in the treatment of epilepsy: focus on levetiracetam

Abstract: The search for antiepileptic drugs (AEDs) using drug screens that test for the ability to suppress paroxysmal events has primarily resulted in the discovery of AEDs that inhibit neuronal excitability. While profoundly reducing expression of epileptic seizures, current pharmacologic treatments have not been able to completely control seizures in all patients, and can impair normal neuronal excitation underlying cognition. A new approach to drug screening, including the process of epileptogenesis, may yield new classes of drugs that not only suppress seizures but also specifically act to protect against the neurobiological changes that contribute to the development of epilepsy. By preventing or reversing the neuronal circuit reorganizations that produce lowered seizure thresholds following brain insults such as head trauma or status epilepticus, these antiepileptogenic drugs could prevent, or reverse, progressive worsening of the epileptic process. It is likely that antiepileptogenic drugs will have mechanisms of action distinct from traditional AEDs, as the molecular mechanisms underlying epileptogenesis and ictogenesis probably differ. One new AED with potential antiepileptogenic properties is levetiracetam, which was discovered using non-conventional drug screens. It markedly suppresses kindling development at doses devoid of adverse effects, with persistent suppression of kindled seizures even after termination of treatment. Further design and implementation of antiepileptogenic drug screens are needed for the discovery of other novel disease-modifying agents.

Comment on "On the origin of interictal activity in human temporal lobe epilepsy in vitro".

Abstract: For more than a decade, there has been extensive discussion about whether hippocampal sclerosis causes enhanced neuronal excitability as a prerequisite for seizure generation. The disorder known as Ammon’s horn sclerosis (AHS) is characterized by pronounced cell loss and gliosis in various regions of the hippocampal formation, leaving the subiculum generally intact (1, 2). Given the hypothesis that epileptic activity is generated within the hippocampal formation when the CA3 and CA1 regions are damaged or even absent, it is feasible that the adjacent subiculum is uniquely responsible for the generation of limbic seizures. Using multielectrode recordings in hippocampal brain slices of patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis, Cohen et al. (3) detected spontaneous, rhythmic spikes in the subiculum—but rarely in the CA3 or CA1 regions. This activity closely resembled the discharges seen on the electroencephalograms (EEGs) of these patients. Cohen et al. (3) therefore concluded that in patients with AHS, deafferentation of the subiculum initiates an epileptogenic plasticity that includes changes in glutamatergic or -aminobutyric acid (GABA)-ergic signaling. We find that even in nonsclerotic hippocampal tissue, as graded by Wyler (4), the subiculum shows cellular and synaptic changes which suffice to generate an epileptic focus. To elucidate this issue further, we investigated the contribution of subicular cells to interictal activity recorded in EEGs of TLE patients with (AHS, Wyler score W3, W4; n 7) and without hippocampal sclerosis (non-AHS, W0-W2;

Temporal specific patterns of semaphorin gene expression in rat brain after kainic acid-induced status epilepticus.

Abstract: Mossy fiber sprouting and other forms of synaptic reorganization may form the basis for a recurrent excitatory network in epileptic foci. Four major classes of axon guidance molecules--the ephrins, netrins, slits, and semaphorins--provide targeting information to outgrowing axons along predetermined pathways during development. These molecules may also play a role in synaptic reorganization in the adult brain and thereby promote epileptogenesis. We studied semaphorin gene expression, as assessed by in situ hybridization, using riboprobes generated from rat cDNA in an adult model of synaptic reorganization, kainic acid (KA)-induced status epilepticus (SE). Within the first week after KA-induced SE, semaphorin 3C, a class III semaphorin, mRNA content is decreased in the CA1 area of the hippocampus and is increased in the upper layers of cerebral cortex. Another class III semaphorin, semaphorin 3F, is also decreased in CA1 and CA3 of hippocampus within the first week after KA-SE. These changes in gene expression are principally confined to neurons. By contrast, there was little change in the semaphorin 4C mRNA content of CA1 neurons at this time. No changes in expression of semaphorin 3A and 4C genes were detected 28 days after KA-induced SE. Regulation of semaphorin gene expression after KA-induced SE suggests that neurons may regulate the expression of axonal guidance molecules and thereby contribute to synaptic reorganization after injury of the mature brain. The anatomic locale of the altered semaphorin gene expression may serve as a marker for specific networks undergoing synaptic reorganization in the epileptic brain.

Physiology of human cortical neurons adjacent to cavernous malformations and tumors.

Abstract: Summary: Purpose: Focal neocortical seizures can be associated with a number of specific pathologies including supratentorial tumors and cavernous malformations (CMs), both of which are highly epileptogenic. Methods: To begin to address the question of whether these lesions have different mechanisms of epileptogenesis, we used intracellular recordings from neurons adjacent to intracerebral neoplasms and cerebral CMs. Developmental anomalies were not included in this study. Results: Neurons adjacent to CMs had a greater propensity to show large (>5 mV), complex spontaneous synaptic events than did neurons neighboring neoplastic substrates (50 vs. 4.7% of cells and 75 and 8% of patients, respectively; p < 0.004; p < 0.05). Both spontaneous excitatory and inhibitory events were noted. In contrast, in tissue adjacent to tumors, low-amplitude (<3 mV) spontaneous excitatory activity predominated. Neurons neighboring CMs also exhibited more excitable responses to synaptic stimulation, with multiple action potentials riding on prolonged excitatory postsynaptic potentials (EPSPs) being evoked in 71% of these cells, versus 32% of cells from the tumor group; p < 0.05. In studies using hippocampal tissue, we noted a similar pattern of spontaneous activity in tissue adjacent to CMs. Conclusions: These data suggest that CMs may induce seizure activity via a different pathophysiologic mechanism(s) than glial tumors.

Hyperexcitability of intact neurons underlies acute development of trauma‐related electrographic seizures in cats in vivo

Abstract: Cortical trauma can lead to development of electrographic paroxysmal activities. Current views of trauma-induced epileptogenesis suggest that chronic neuronal hyperexcitability and extensive morphological reorganization of the traumatized cortex are required for the generation of electrographic seizures. However, the mechanisms responsible for the initiation of electrographic seizures shortly after cortical injury are poorly understood. Here we show that, in the experimental model of partially deafferented (undercut) cortex, an increase in intrinsic and synaptic excitability of neurons in areas adjacent to the undercut cortex is sufficient for the generation of electrographic paroxysmal activity within few hours after partial cortical deafferentation. Locally increased and spatially restricted neuronal excitability arose from the increased incidence of intrinsically bursting neurons, enhanced intrinsic and synaptic neuronal responsiveness, and slight disinhibition. These mechanisms only operate in neurons located in the vicinity of partially deafferented sites because, after the cortical injury, partially deafferented neurons are mostly silent and hypoexcitable. Our results suggest that trauma-induced electrographic seizures first arise in cortical fields that are closest to the site of injury and such seizures do not require long-term neuronal reorganization.

Neurostimulation for refractory epilepsy

Abstract: Neurostimulation is an emerging treatment for refractory epilepsy. To date the precise mechanism of action remains to be elucidated. Better insight in the mechanism of action may identify seizure types or syndromes that respond to such a treatment and may guide the search for optimal stimulation parameters and finally improve clinical efficacy. In the past ten years some progress has been made through neurophysiological, neuroanatomical, neurochemical and cerebral blood flow studies in patients and animals undergoing vagus nerve stimulation (VNS). Interesting results have been found in VNS-treated patients that underwent evoked potential measurements, cerebrospinal fluid investigation, neuropsychological testing and PET, SPECT and fMRI testing. Desynchronisation of abnormal synchronous epileptic activity is one of the hypotheses on the mode of action that might primarily be responsible for an anti-seizure effect. There is however increasing evidence from research and clinical observation that VNS might establish a true and long-term anti-epileptic effect. It has been shown that VNS influences neurotransmission in the brain and provokes long-term changes in cerebral blood flow in areas crucial for epileptogenesis such as the thalamus and medial temporal lobe structures. Deep brain stimulation (DBS) for epilepsy has regained interest. Central nervous system structures known to play a key role in the epileptogenic network such as the thalamus and subthalamic nucleus have been targeted. Another approach is to target the ictal onset zone such as the medial temporal lobe. At Ghent University Hospital 10 patients have been treated with long-term amygdalohippocampal DBS. Several hypotheses have been raised for the mechanism of action of DBS for refractory seizures. Seizure reduction may be due to a microlesion caused by electrode insertion or by provoking a reversible functional lesion due to the effect of electrical current on hyperexcitable tissue. Neurophysiological techniques such as evoked potentials monitoring and intraoperative single unit potential recordings may guide correct electrode placement, individual DBS titration and elucidation of the mechanims of action of DBS for epilepsy.

Rapid and long-term alterations of hippocampal GABAB receptors in a mouse model of temporal lobe epilepsy.

Abstract: Alterations of γ-aminobutyric acid (GABA) B receptor expression have been reported in human temporal lobe epilepsy (TLE). Here, changes in regional and cellular expression of the GABA B receptor subunits R1 (GBR1) and R2(GBR2) were investigated in a mouse model that replicates major functional and histopathological features of TLE. Adult mice received a single, unilateral injection of kainic acid (KA) into the dorsal hippocampus, and GABA B receptor immunoreactivity was analysed between 1 day and 3 months thereafter. In control mice, GBR1 and GBR2 were distributed uniformly across the dendritic layers of CA1-CA3 and dentate gyrus. In addition, some interneurons were labelled selectively for GBR1. At 1 day post-KA, staining for both GBR1 and GBR2 was profoundly reduced in CA1, CA3c and the hilus, and no interneurons were visible anymore. At later stages, the loss of GABA B receptors persisted in CA1 and CA3, whereas staining increased gradually in dentate gyrus granule cells, which become dispersed in this model. Most strikingly, a subpopulation of strongly labelled interneurons reappeared, mainly in the hilus and CA3 starting at 1 week post-KA. In double-staining experiments, these cells were selectively labelled for neuropeptide Y. The number of GBR1-positive interneurons also increased contralaterally in the hilus. The rapid KA-induced loss of GABA B receptors might contribute to epileptogenesis because of a reduction in both presynaptic control of transmitter release and postsynaptic inhibition. In turn, the long-term increase in GABA B receptors in granule cells and specific subtypes of interneurons may represent a compensatory response to recurrent seizures.

Advances in Understanding the Process of Epileptogenesis Based on Patient Material: What Can the Patient Tell Us?

Abstract: Summary: Many different types of epileptic seizures and epileptic syndromes exist. The process of epileptogenesis and the progressive nature of epilepsy, however, can most easily be investigated in the acquired epilepsies, in which a brain insult presumably gives rise to changes in neuronal systems that ultimately become capable of generating spontaneous ictal events. Invasive in vivo and in vitro research can be carried out in patients with acquired epileptogenic lesions in the course of epilepsy surgery; however, such studies are possible only for those epileptic conditions that can be treated surgically, and can be used only to examine an end stage of the epileptogenic process. Consequently, experimental animal models of human epileptic conditions are still required to study mechanisms by which specific cerebral insults initiate the epileptogenic process and the progression of an epileptic disturbance. Most current parallel human/animal invasive research has been focused on temporal lobe epilepsy, and particularly that form associated with hippocampal sclerosis, the most common human epileptogenic lesion. Studies indicate that epileptogenesis in this condition is initiated by specific types of cell loss and neuronal reorganization, which results not only in enhanced excitation, but also in enhanced inhibition, predisposing to hypersynchronization. Even within this single, well-studied epileptic disorder, evidence is found for more than one type of ictal onset, and individual seizures can demonstrate a transition from one ictal mechanism to another. Recent in vivo and in vitro parallel, reiterative investigations in patients with mesial temporal lobe epilepsy, and in rats with intrahippocampal kainate-induced hippocampal seizures, have revealed the presence of interictal epileptiform events, termed “fast ripples,” which appear to be unique in tissue capable of generating spontaneous seizures. Pursuit of the fundamental mechanisms underlying these abnormalities should elucidate the neurobiologic basis of epileptogenicity in this disorder. Furthermore, if these events are markers for epileptogenicity, they may have clinical value for diagnosis and pharmacologic, as well as surgical, treatment. Further research is needed to determine if these observations are relevant to other types of epilepsies.