Limbic Status Epilepticus Research Articles

Interictal aggression in rats with chronic seizures after an early life episode of status epilepticus.

In spite of anecdotal reports describing an association between chronic epilepsy and interictal aggressiveness, and of a few studies suggesting that such an association is common in temporal lobe epilepsy, this concept has not been generally accepted by epileptologists. In the course of studies of the long-term consequences of limbic status epilepticus (SE) in juvenile rats, we noticed that experimental animals, unlike littermate controls, could not be housed together because of severe fighting. We now report a study of interictal aggression in those rats. Long-term behavioral consequences of lithium/pilocarpine SE were studied 3 months after SE had been induced with lithium and pilocarpine in male Wistar rats at age 28 days. Chronic spontaneous seizures developed in 100% of animals. We tested rats for territorial aggression under the resident-intruder paradigm. We measured the number of episodes of dominance (mounting, pinning), and agonistic behavior (attacks, boxing, and biting). Untreated lithium/pilocarpine SE induced a large increase in aggressive behavior, which involved all aspects of aggression in the intruder paradigm when tested 3 months after SE. The experimental rats were dominant toward the controls, as residents or as intruders, and showed episodes of biting and boxing rarely displayed by controls. They also displayed increased aggressiveness compared to controls when tested against each other. This robust model offers an opportunity to better understand the complex relationship between seizures, epilepsy, and aggression, and the role of age, SE versus recurrent spontaneous seizures, and focal neuronal injury in the long-term behavioral effects of SE.

Chronic limbic epilepsy models for therapy discovery: Protocols to improve efficiency.

There have been recommendations to improve therapy discovery for epilepsy by incorporating chronic epilepsy models into the preclinical process, but unpredictable seizures and difficulties in maintaining drug levels over prolonged periods have been obstacles to using these animals. We report new protocols in which drugs are administered through a new chronic gastric tube to rats with higher seizure frequencies to minimize these obstacles. Adult rats with spontaneous limbic seizures following an episode of limbic status epilepticus induced by electrical hippocampal stimulation were monitored with long-term video- electroencephalography (EEG). Animals with a predetermined baseline seizure frequency received an intragastric tube for drug administration. Carbamazepine, levetiracetam, phenobarbital, and phenytoin were tested with either an acute protocol (an increasing single dose every other day for a maximum of three doses) or with a chronic protocol (multiple administrations of one dose for a week). Drug levels were obtained to correlate the effect with the level. With the acute protocol, all four drugs induced a clear dose-related response. Similar dose-related responses were seen following the week-long dosing protocol for carbamazepine, phenobarbital, and phenytoin, and these responses were associated with drug levels that were in the human therapeutic range. The response to chronic levetiracetam was much less robust. The gastric tube route of administration was well tolerated over a number of months. Using rats with stable, higher seizure frequencies made it possible to identify the potential of a drug to suppress seizures in a realistic model of epilepsy with drug levels that are similar to those of human therapeutic levels. The acute protocol provided a full dose response in 1 week. The chronic administration protocol further differentiated drugs that may be effective long term. The gastric tube facilitates a less stressful, humane, and consistent administration of multiple doses.

Deletion of the Na-K-2Cl cotransporter NKCC1 results in a more severe epileptic phenotype in the intrahippocampal kainate mouse model of temporal lobe epilepsy

Increased neuronal expression of the Na-K-2Cl cotransporter NKCC1 has been implicated in the generation of seizures and epilepsy. However, conclusions from studies on the NKCC1-specific inhibitor, bumetanide, are equivocal, which is a consequence of the multiple potential cellular targets and poor brain penetration of this drug. Here, we used Nkcc1 knockout (KO) and wildtype (WT) littermate control mice to study the ictogenic and epileptogenic effects of intrahippocampal injection of kainate. Kainate (0.23 μg in 50 nl) induced limbic status epilepticus (SE) in both KO and WT mice with similar incidence, latency to SE onset, and SE duration, but the number of intermittent generalized convulsive seizures during SE was significantly higher in Nkcc1 KO mice, indicating increased SE severity. Following SE, spontaneous recurrent seizures (SRS) were recorded by continuous (24/7) video/EEG monitoring at 0-1, 4-5, and 12-13 weeks after kainate, using depth electrodes in the ipsilateral hippocampus. Latency to onset of electrographic SRS and the incidence of electrographic SRS were similar in WT and KO mice. However, the frequency of electrographic seizures was lower whereas the frequency of electroclinical seizures was higher in Nkcc1 KO mice, indicating a facilitated progression from electrographic to electroclinical seizures during chronic epilepsy, and a more severe epileptic phenotype, in the absence of NKCC1. The present findings suggest that NKCC1 is dispensable for the induction, progression and manifestation of epilepsy, and they do not support the widely held notion that inhibition of NKCC1 in the brain is a useful strategy for preventing or modifying epilepsy.

Recurrent limbic seizures do not cause hippocampal neuronal loss: A prolonged laboratory study

PurposeIt remains controversial whether neuronal damage and synaptic reorganization found in some forms of epilepsy are the result of an initial injury and potentially contributory to the epileptic condition or are the cumulative affect of repeated seizures. A number of reports of human and animal pathology suggest that at least some neuronal loss precedes the onset of seizures, but there is debate over whether there is further damage over time from intermittent seizures. In support of this latter hypothesis are MRI studies in people that show reduced hippocampal volumes and cortical thickness with longer durations of the disease. In this study we addressed the question of neuronal loss from intermittent seizures using kindled rats (no initial injury) and rats with limbic epilepsy (initial injury). MethodsSupragranular mossy fiber sprouting, hippocampal neuronal densities, and subfield area measurements were determined in rats with chronic limbic epilepsy (CLE) that developed following an episode of limbic status epilepticus (n = 25), in kindled rats (n = 15), and in age matched controls (n = 20). To determine whether age or seizure frequency played a role in the changes, CLE and kindled rats were further classified by seizure frequency (low/high) and the duration of the seizure disorder (young/old). ResultsOverall there was no evidence for progressive neuronal loss from recurrent seizures. Compared with control and kindled rats, CLE animals showed increased mossy fiber sprouting, decreased neuronal numbers in multiple regions and regional atrophy. In CLE, but not kindled rats: 1) Higher seizure frequency was associated with greater mossy fiber sprouting and granule cell dispersion; and 2) greater age with seizures was associated with decreased hilar densities, and increased hilar areas. There was no evidence for progressive neuronal loss, even with more than 1000 seizures. ConclusionThese findings suggest that the neuronal loss associated with limbic epilepsy precedes the onset of the seizures and is not a consequence of recurrent seizures. However, intermittent seizures do cause other structural changes in the brain, the functional consequences of which are unclear.

Effects of Prolonged Seizures on Basal Forebrain Cholinergic Neurons: Evidence and Potential Clinical Relevance.

Seizures originating from limbic structures, especially when prolonged for several minutes/hours up to status epilepticus (SE), can cause specific neurodegenerative phenomena in limbic and subcortical structures. The cholinergic nuclei belonging to the basal forebrain (BF) (namely, medial septal nucleus (MSN), diagonal band of Broca (DBB), and nucleus basalis of Meynert (NBM)) belong to the limbic system, while playing a pivotal role in cognition and sleep-waking cycle. Given the strong interconnections linking these limbic nuclei with limbic cortical structures, a persistent effect of SE originating from limbic structures on cBF morphology is plausible. Nonetheless, only a few experimental studies have addressed this issue. In this review, we describe available data and discuss their significance in the scenario of seizure-induced brain damage. In detail, the manuscript moves from a recent study in a model of focally induced limbic SE, in which the pure effects of seizure spreading through the natural anatomical pathways towards thecholinergic nuclei of BF weretracked by neuronal degeneration. In this experimental setting, a loss of cholinergic neurons was measured in all BF nuclei, to various extents depending on the specific nucleus. These findings are discussed in the light of the effects on the very same nuclei following SE induced by systemic injections of kainate or pilocarpine. The various effects including discrepancies among different studies are discussed. Potential implications for human diseases are included.

Degeneration of cholinergic basal forebrain nuclei after focally evoked status epilepticus

Status epilepticus (SE) of limbic onset might cause degenerative phenomena in different brain structures, and may be associated with chronic cognitive and EEG effects. In the present study SE was evoked focally by microinfusing picomolar doses of cyclothiazide+bicuculline into the anterior extent of the piriform cortex (APC) in rats, the so-called area tempestas, an approach which allows to evaluate selectively the effects of seizure spreading through the natural anatomical circuitries up to secondary generalization. In the brain of rats submitted to SE we analyzed neuronal density, occurrence of degenerative phenomena (by Fluoro-Jade B-FJB- staining) and expression of heat shock protein-70 (HSP-70) in the piriform cortex, the hippocampus and ventromedial thalamus. We further analyzed in detail, the loss of cholinergic neurons, and the presence of FJB- and HSP-70 positive neurons in basal forebrain cholinergic areas, i.e. the medial septal nucleus (MSN, Ch1), the diagonal band of Broca (DBB, Ch2 and Ch3) and the Nucleus basalis of Meynert (NBM, Ch4). In fact, these nuclei are strictly connected with limbic structures, and play a key pivotal role in different cognitive functions and vigilance. Although recent studies begun to investigate these nuclei in experimental epilepsy and in persons with epilepsy, conflicting results were obtained so far. We showed that after severe and long-lasting, focally induced limbic SE there is a significant cell loss within all of the abovementioned cholinergic nuclei ipsi- and contra-laterally to the infusion site. In parallel, these nuclei show also FJB and heat shock protein-70 expression. Those effects vary depending on the single nucleus assessed and on the severity of the SE seizure score. We also showed the occurrence of cell loss and degenerative phenomena in limbic cortex, hippocampus and limbic thalamic areas. These novel findings show direct evidence of SE-induced neuronal damage which is solely due to seizure activity ruling out potential confounding effects produced by systemic pro-convulsant neurotoxins. A damage to basal forebrain cholinergic nuclei, which may underlie cognitive alterations, is documented for the first time in a model of SE triggered focally.

Enhanced AMPA receptor-mediated neurotransmission on CA1 pyramidal neurons during status epilepticus

Status epilepticus (SE) is a common neurological emergency that results from the failure of the mechanisms responsible for seizure termination or the initiation of mechanisms that lead to abnormally prolonged seizures. Although the failure of inhibitory mechanisms during SE is well understood, the seizure-initiating mechanisms are poorly understood. We tested whether hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission was enhanced during SE and assessed the underlying molecular mechanism. In animals in self-sustaining limbic SE the amplitudes of the miniature, spontaneous, and AMPA-evoked excitatory currents recorded from the CA1 pyramidal neurons were larger than those recorded in the controls. The evoked EPSCs rectified inwardly. In these animals, the surface expression of GluA1 subunit-containing AMPARs was increased in the CA1 pyramidal neurons. The phosphorylation of the GluA1 subunit on S831 and S845 residues was reduced in animals in SE. In contrast, the GluA1 subunit surface expression and AMPAR-mediated neurotransmission of dentate granule cells (DGCs) was not altered. Treating animals in SE with the NMDAR antagonist MK-801 or with diazaepam blocked the increased surface expression of the GluA1 subunits. NMDAR blockade also prevented the dephosphorylation of the S845 residue but not that of S831. Targeting NMDARs and AMPARs may provide novel strategies to treat benzodiazepine-refractory SE.

Accelerated cognitive decline in a rodent model for temporal lobe epilepsy.

Cognitive impairment is frequently observed in patients with temporal lobe epilepsy. It is hypothesized that cumulative seizure exposure causes accelerated cognitive decline in patients with epilepsy. We investigated the influence of seizure frequency on cognitive decline in a rodent model for temporal lobe epilepsy. Neurobehavioral assessment was performed before and after surgery, after the induction of self-sustaining limbic status epilepticus (SSLSE), and in the chronic phase in which rats experienced recurrent seizures. Furthermore, we assessed potential confounders of memory performance. Rats showed a deficit in spatial working memory after the induction of the SSLSE, which endured in the chronic phase. A progressive decline in recognition memory developed in SSLSE rats. Confounding factors were absent. Seizure frequency and also the severity of the status epilepticus were not correlated with the severity of cognitive deficits. The effect of the seizure frequency on cognitive comorbidity in epilepsy has long been debated, possibly because of confounders such as antiepileptic medication and the heterogeneity of epileptic etiologies. In an animal model of temporal lobe epilepsy, we showed that a decrease in spatial working memory does not relate to the seizure frequency. This suggests for other mechanisms are responsible for memory decline and potentially a common pathophysiology of cognitive deterioration and the occurrence and development of epileptic seizures. Identifying this common denominator will allow development of more targeted interventions treating cognitive decline in patients with epilepsy. The treatment of interictal symptoms will increase the quality of life of many patients with epilepsy.

On-demand pulsatile intracerebral delivery of carisbamate with closed-loop direct neurostimulation therapy in an electrically induced self-sustained focal-onset epilepsy rat model.

The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemispheric limbic epileptic circuit using closed-loop direct neurostimulation therapy in tandem with "on-demand'" convection-enhanced intracerebral delivery of the antiepileptic drug (AED) carisbamate. A rat model of electrically induced self-sustained focal-onset epilepsy was employed. A 16-contact depth-recording microelectrode was implanted bilaterally in the dentate gyrus (DG) of the hippocampus of Fischer 344 rats. The right microelectrode array included an integrated microcatheter for drug delivery at the distal tip. Bihemispheric spontaneous self-sustained limbic status epilepticus (SSLSE) was induced in freely moving rats using a 90-minute stimulation paradigm delivered to the right medial perforant white matter pathway. Immediately following SSLSE induction, closed-loop right PP stimulation therapy concurrent with on-demand nanoboluses of the AED [(14)C]-carisbamate (n = 4), or on-demand [(14)C]-carisbamate alone (n = 4), was introduced for a mean of 10 hours. In addition, 2 reference groups received either closed-loop stimulation therapy alone (n = 4) or stimulation therapy with saline vehicle only (n = 4). All animals were sacrificed after completing the specified therapy regimen. In situ [(14)C]-autoradiography was used to determine AED distribution. Closed-loop direct stimulation therapy delivered unilaterally in the right PP aborted ictal runs detected in either ipsi- or contralateral hippocampi. Freely moving rats receiving closed-loop direct stimulation therapy with ondemand intracerebral carisbamate delivery experienced a significant reduction in seizure frequency (p < 0.001) and minimized seizure frequency variability during the final 50% of the therapy/recording session compared with closed-loop stimulation therapy alone. Unilateral closed-loop direct stimulation therapy delivered to afferent hippocampal white matter pathways concurrent with on-demand ipsilateral intracerebral delivery of nano-bolused carisbamate can rapidly decrease the frequency of electrographic seizures in an active bihemispheric epileptic network. Additionally, direct pulsatile delivery of carisbamate can stabilize seizure frequency variability compared with direct stimulation therapy alone.

Electroencephalographic and fluorodeoxyglucose-positron emission tomography correlates in anti-N-methyl-d-aspartate receptor autoimmune encephalitis

ImportanceAnti-N-methyl-d-aspartate receptor (anti-NMDAR) autoimmune encephalitis is an increasingly recognized cause of limbic encephalitis (LE). Prolonged LE and limbic status epilepticus (LSE) share many features. The ability to distinguish between the two is crucial in directing appropriate therapy because of the potential iatrogenesis associated with immunosuppression and anesthetic-induced coma.ObservationsA 34-year-old woman with recurrent LE developed behavioral changes, global aphasia, and repetitive focal and generalized tonic–clonic seizures. Because asymmetric rhythmic delta patterns recurred on electroencephalography (EEG) despite treatment with nonsedating antiepileptic drugs followed by anesthetic-induced coma, an investigation to distinguish LSE from LE was undertaken. Implanted limbic/temporal lobe depth electrodes revealed no epileptiform activity. Brain single-photon emission computerized tomography (SPECT) showed no hyperperfusion, and brain fluorodeoxyglucose-positron emission tomography (FDG-PET) showed hypermetabolism in the left frontal, temporal, and parietal cortices. Anti-N-methyl-d-aspartate receptor autoimmune encephalitis was diagnosed based detection of anti-NMDAR antibody in the cerebrospinal fluid (CSF). With chronic immunosuppression, the resolution of brain FDG-PET abnormalities paralleled clinical improvement.Conclusions and relevanceThis case of anti-NMDAR autoimmune encephalitis illustrates the challenges of distinguishing prolonged LE from LSE. We discuss the parallels between these two conditions and propose a management paradigm to optimize evaluation and treatment.

The intrahippocampal kainate model of temporal lobe epilepsy revisited: Epileptogenesis, behavioral and cognitive alterations, pharmacological response, and hippoccampal damage in epileptic rats

Systemic or intracerebral (e.g., intrahippocampal or intraamygdalar) administration of kainate, a potent neurotoxic analog of glutamate, is widely used to induce status epilepticus (SE) and subsequent development of epilepsy in rats. However, in apparent contrast to systemic administration, following intracerebral injection the proportion of rats that have been observed to generate spontaneous recurrent seizures (SRS) and the frequency of the SRS are comparatively low. More recently, it has been shown that these problems can be resolved by injecting kainate into the dorsal hippocampus of awake rats, thus avoiding the insult-modifying effects of anesthesia, which had often been used for intracerebral injection of this convulsant in previous studies. For further characterization of this model, we injected kainate (0.4 μg) unilaterally into the CA3 of the posterior hippocampus in awake rats, which induced limbic SE (ranging from 4 to 20 h) in all rats without mortality. Repeated video-EEG monitoring (24h/day, 7 days/week) for periods of 1-2.5 weeks from 1 to 8 months after SE demonstrated that 91% of the rats developed epilepsy, and that seizure frequency significantly increased over the course of the disease. Epilepsy was associated with increased behavioral excitability and impaired learning and memory in a water maze, most likely as a result of hippocampal pathology, which was characterized by extensive neuronal loss in CA3 and dentate hilus and dispersion of granule cells in the ipsilateral hippocampus. A drug trial with phenobarbital showed that all epileptic rats used in this trial responded to treatment with suppression of SRS. The data substantiate that intrahippocampal kainate injection in awake rats offers an excellent model of human temporal lobe epilepsy and indicate that this model may have particular advantages for studying mechanisms of injury-induced epilepsy and comorbidities as targets for antiepileptic and antiepileptogenic therapies.

The Anticonvulsant and Neuroprotective Effects of Baicalin on Pilocarpine-Induced Epileptic Model in Rats

Baicalin, a flavonoid compound purified from plant Scutellaria baicalensis Georgi, has been reported to possess a wide variety of pharmacological properties including anti-oxidative, anti-apoptotic and neuroprotective properties. Oxidative stress can dramatically alter neuronal function and has been linked to status epilepticus (SE). However, the neuroprotective effect of baicalin on epilepsy is unclear. In this study we investigated whether Baicalin could exert anticonvulsant and neuroprotective effects in the pilocarpine-induced epileptic model in rats. To this end, we recorded the latency to first limbic seizure and SE and observed the incidence of SE and mortality. The changes of oxidative stress were measured 24 h after pilocarpine-induced SE. Nissl staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and Fluoro-Jade B staining were performed to detect the neuronal loss, apoptosis and degeneration in hippocampus 72 h after pilocarpine-induced seizure. Pretreatment with baicalin significantly delayed the onset of the first limbic seizures and SE, reduced the mortality rate, and attenuated the changes in the levels of lipid peroxidation, nitrite content and reduced glutathione in the hippocampus of pilocarpine-treated rats. Furthermore, we also found that baicalin attenuated the neuronal cell loss, apoptosis, and degeneration caused by pilocarpine-induced seizures in rat hippocampus. Collectively, these results indicated remarkable anticonvulsant and neuroprotective effects of baicalin and should encourage further studies to investigate baicalin as an adjuvant in epilepsy both to prevent seizures and to protect against seizure induced brain injury.

Beta adrenergic blockade prevents cardiac dysfunction following status epilepticus in rats

Status epilepticus (SE) can result in temporary cardiac dysfunction in patients, characterized by reduced ejection fraction, decreased ventricular contractility, and alterations in electrical activity of the heart. Although reversible, the cardiac effects of seizures are acutely life threatening, and may contribute to the delayed mortality following SE. The precise mechanisms mediating acute cardiac dysfunctions are not known. These studies evaluated effects of self-sustaining limbic SE in rats on cardiac performance 24h following seizures, and determined if sympathetic nervous system activation during seizures contributed to cardiac dysfunction. Rats subjected to SE received either vehicle (saline) or the B1 adrenergic antagonist atenolol (AT) prior to and during 90 min of seizure activity. Control rats were similarly treated, except they did not undergo seizures. Twenty-four hours after SE, animals were anesthetized and catheterized for measurement of cardiac performance variables. Animals undergoing SE demonstrated significantly reduced cardiac output, decreased ventricular contractility and relaxation, increased blood pressure, and prolonged QT interval. However, heart rate was not altered. Treatment with AT prevented all changes in cardiac performance due to SE, and attenuated the increase in QT interval. These data demonstrate that SE in the rat results in cardiac dysfunction 24h following seizures, mediated by the sympathetic nervous system.

Acute down‐regulation of adenosine A1 receptor activity in status epilepticus

Status epilepticus (SE) remains a potentially devastating condition that quickly becomes refractory to antiepileptic drug treatment and arises as a result of a failure of the brain's endogenous antiepileptic mechanisms. Understanding these mechanisms and how they are disrupted in SE is necessary in order to identify novel therapeutic approaches. Adenosine is considered an endogenous anticonvulsant. Extracellular concentrations increase coinciding with seizure termination; activation of A(1) receptors (A(1)Rs) reduces seizure-induced damage and epileptiform activity. The present study examines the effectiveness of focal drug delivery in a model of limbic SE that closely resembles the human condition and describes, for the first time, alterations in A(1)R signaling during prolonged seizures that may contribute to the progression from self-terminating seizures to self-sustaining SE (SSSE). We developed a rat perforant path stimulation model in which 50% of rats develop SSSE and tested whether modulation of A(1)Rs influenced SSSE development when drugs were infused to the dentate gyrus. We further determined the ability of A(1)Rs to modulate perforant path to granule cell transmission in hippocampal slices taken from sham-operated control and post-SE animals. Adenosine (3 μM) and the A(1)R-selective agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; 10 μM) reduced the severity of SSSE as measured by spike count, electroencephalography power and behavioral seizure score. In addition, CCPA suppressed the progression to SSSE. Surprisingly, the A(1)R-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 μm) had no effect on the severity of or progression to SSSE, suggesting a lack of intrinsic A(1)R activation. Immunohistochemistry revealed no alterations in total A(1)R expression. However, we observed a marked down-regulation of A(1)R modulation of neurotransmission in vitro, indicating acute A(1)R desensitization. These findings indicate that A(1)R activation can prevent the progression to SE and suggest that reduced A(1)R signaling promotes the transition of seizures to SSSE.

Neuroanatomical substrates for recurrent epileptic limbic seizures

Epilepsy is a neurological disorder characterized by the recurrence of spontaneous, unprovoked epileptic seizures. Mesial temporal lobe epilepsy (more briefly, MTLE) is a very common form of epilepsy which is featured by the occurrence of focal limbic seizures, and associated to a specific neuropathological alteration, the so-called Ammon’s horn sclerosis, whose main features are a selective loss of the CA1 and CA3/4 section of the Ammon’s horn (CA, from Latin Cornu Ammonis, abbreviated as CA), a selective cell loss of inhibitory interneurons in the hilus of the dentate gyrus (DG), and the abnormal sprouting of granule cells mossy fibers (the so called mossy fiber sprouting, MFS). The onset of spontaneous seizures (SRS) is the hallmark of a good model of epilepsy. For temporal lobe epilepsy (TLE), the most used models consist in administering systemically chemoconvulsants inducing limbic status epilepticus (i.e. seizures lasting for more than 30’, SE) and evaluating the occurrence of SRS. However, in these models, the widespread involvement of different structures which complicates the interpretation of experimental findings: limbic seizures and status epilepticus (SE) can be triggered by focal infusion of chemoconvulsants within anterior piriform cortex (abbreviated as APC) This brain region is densely innervated by noradrenergic fibers arising from the locus coeruleus (LC), and we recently showed that a lesion of LC (induced by a selective neurotoxin, DSP-4, i.p.), induces SE. LC plays a critical role in modulating several models of seizures, and it plays a critical role in plastic mechanisms and neuroprotection in the brain. Thus, we compared the group DSP-4+bicuculline and cyclothiazide+bicuculline, to evaluate whether the focal SE evoked from the APC is capable of inducing SRS and AHS, and whether LC plays a significant role in this phenomena. We found that: the loss of LC induced: (i)a higher incidence of SRS; (ii) cell loss in the hippocampal DG hilus and CA3 (iii)the loss of parvalbumin-positive neurons. In conclusion, our study confirms that focal induction of SE from the APC represents a good model of TLE, and that NE released from the fibers originating from the LC plays a significant role both in the hippocampal damage occurring after SE, and in the incidence of SRS.

Epileptic Focus Stimulation and Seizure Control in the Rat Model of Kainic Acid-Induced Limbic Seizures

The inhibitory effects of deep brain stimulation (DBS) were investigated in a rat model of kainic acid (KA)-induced limbic status epilepticus. Wistar rats were injected with 1.0 microg KA into the left amygdala after stereotactic implantation of a guide cannula and electrodes. Bipolar rectangular pulses of 0.1 msec duration and 0.1-0.3 mA amplitude were applied intermittently to the left amygdala (10 Hz or 130 Hz), left ventral hippocampus (10 Hz), and left dorsomedial thalamus (130 Hz). Seizure frequency was evaluated by video electroencephalography monitoring and compared to control animals that did not receive DBS. All rats developed limbic status epilepticus 60-90 minutes after KA injection. Seizure frequency was significantly reduced by 10 Hz stimulation of the amygdala and by 130 Hz stimulation of the dorsomedial thalamus. No significant effects were observed with other types of stimulation. Seizure behaviors or duration of seizure were not changed significantly by DBS treatment. DBS of an epileptic focus may attenuate KA-induced limbic seizures, depending on the stimulation sites and parameters.

The pilocarpine model of epilepsy: what have we learned?

The systemic administration of a potent muscarinic agonist pilocarpine in rats promotes sequential behavioral and electrographic changes that can be divided into 3 distinct periods: (a) an acute period that built up progressively into a limbic status epilepticus and that lasts 24 h, (b) a silent period with a progressive normalization of EEG and behavior which varies from 4 to 44 days, and (c) a chronic period with spontaneous recurrent seizures (SRSs). The main features of the SRSs observed during the long-term period resemble those of human complex partial seizures and recurs 2-3 times per week per animal. Therefore, the pilocarpine model of epilepsy is a valuable tool not only to study the pathogenesis of temporal lobe epilepsy in human condition, but also to evaluate potential antiepileptogenic drugs. This review concentrates on data from pilocarpine model of epilepsy.

Seizure susceptibility and the brain regional sensitivity to oxidative stress in male and female rats in the lithium-pilocarpine model of temporal lobe epilepsy

Several studies have shown the existence of sex differences in the sensitivity to various convulsants in animals and to the development of some epilepsy types in humans. The purpose of this study was to investigate whether there are sex differences in seizure susceptibility and sensitivity of different brain regions to oxidative stress in rats with status epilepticus (SE) induced by lithium-pilocarpine administration, that provides a common experimental model of temporal lobe epilepsy (TLE) in humans. Latencies to isolated full limbic seizures or SE onset as well as the number of the animals presenting full limbic seizures, SE or full limbic seizures that progressed to SE were recorded for 2 h after pilocarpine administration. Number of animals which survived 24 h after SE onset was also monitored. Levels of lipid peroxidation as well as the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the piriform and entorhinal cortices, temporal neocortex, thalamus, and hippocampus in rats of both sexes, at 24 h after SE onset were determined. Results of our study showed that males developed full limbic seizures and SE more rapidly and in greater number than females. Levels of lipid peroxidation in all brain regions examined, the SOD activities in the piriform and entorhinal cortices, and temporal neocortex as well as the GSH-Px activities in the piriform and entorhinal cortices, and thalamus were significantly higher in rats with SE in comparison to the values of mentioned biochemical parameters in rats of the control groups. Lipid peroxidation level in the temporal neocortex as well as the GSH-Px activity in the hippocampus in male rats were significantly higher in comparison to the values registered in females. With the exception of the thalamus, where SOD activity in male rats with SE was significantly higher in relation to the respective control group and also to females with SE, sex differences in the response of other brain regions investigated to oxidative stress were not obtained, at 24 h after SE.

Psychopathologie in der Epileptologie

The observation of positive and negative seizure symptoms in the context of focal epileptic seizures represents a window to the brain, in particular if the localisation of the epileptic discharge can be accurately and reliably determined. The epileptic local dysfunction which gives rise to the aura of an epileptic patient represents a bridge between neurology and psychiatry because it can be viewed as short-lived (or in the case of aura continua or dyscognitive limbic status epilepticus as an extended) ictal psychosis. Of particular interest are complex epileptic hallucinations due to discharges in the limbic system because they are frequently associated with changes in the emotional and affective sphere as well as with mood changes. Epileptic de novo hallucinations often cannot be adequately described by patients because there exist no such phenomena in the real outer world. In the context of presurgical evaluation of possible candidates of epilepsy surgery direct recording and electrical stimulation of the brain have provided fascinating insights. Nowadays the invasive EEG methods are complemented by new and non-invasive functional imaging techniques, such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and refined EEG mapping (such as LORETA or related techniques). EEG has the unsurpassable advantage of its excellent time resolution. In addition, focal or regional transitory inactivation of brain structures is possible and indicated in certain patients, as is the case in the so-called temporal lobe amobarbital memory test to predict postoperative memory outcome in patients in whom a selective therapeutic removal of amygdala and hippocampus is planned. Finally, important insights and impulses for modern brain research have emerged from the analysis of the sequels of therapeutic epilepsy surgeries, such as the so-called split-brain symptomatology observed as a consequence of total corpus callosum section. In this article we comment on some aspects of consciousness and awareness. We concentrate on the epileptic aura and epileptic hallucinations and illustrate some electroclinical findings. Aura continua and dyscognitive limbic status epilepticus as ictal phenomena and the interictal behavioural syndrome of temporal lobe epilepsy are referred to. Because auras most often represent memory flashbacks, some memory subsystems and their main brain substrates and the selective inactivation of medial temporal lobe structures by injection of amobarbital into the territory of the anterior choroidal artery are introduced and briefly discussed.

Inflammation Exacerbates Seizure‐induced Injury in the Immature Brain

We examined the hypothesis that the introduction of an inflammatory agent would augment status epilepticus (SE)-induced neuronal injury in the developing rat brain in the absence of an increase in body temperature. Postnatal day 7 (P7) and P14 rat pups were injected with an exogenous provocative agent of inflammation, lipopolysaccharide (LPS), 2 h prior to limbic SE induced by either lithium-pilocarpine (LiPC) or kainic acid. Core temperature was recorded during the SE and neuronal injury was assessed 24 h later using profile cell counts in defined areas of the hippocampus. While LPS by itself did not produce any discernible cell injury at either age, it exacerbated hippocampal damage induced by seizures. In the LiPC model, this effect was highly selective for the CA1 subfield, and there was no concomitant rise in body temperature. Our findings show that inflammation increases the vulnerability of immature hippocampus to seizure-induced neuronal injury and suggest that inflammation might be an important factor aggravating the long-term outcomes of seizures occurring early in life.