脑电图预测痫性发作研究进展

癫痫(epilepsy)是由脑部神经元高度同步化异常放电所致的临床综合征,系神经系统的常见病,困扰着全世界约1%的人群.每次神经元的阵发性放电或短暂的脑功能异常称为痫性发作(seizures).     

Sensitization to noise-mediated induction of seizure susceptibility by MK-801 and phencyclidine

The effect of single administrations of MK-801 (5-methyl-10,11-dihydro-5H-dibenzo[a,d]cylohepten-5,10-imine) or PCP (phencyclidine) on the induction of audiogenic seizure susceptibility by noise in immature rats was examined. Treatments with these non-competitiveN-methyl-D-aspartate (NMDA) receptor antogonist resulted in increases in noise exposure-dependent susceptibility. In neonatally drug-treated rats, seizures during adulthood were found to occur with significantly higher incidence and severity. Furthermore, drug treatments were found to lengthen what is normally a restricted developmental period within which susceptibility can be induced by noise exposure. The 801 exhibited predictable anticonvulsant effects. These data suggests acute PCP or MK-801 exposures may transiently exacerbate risks inherent in certain forms of trauma. The mechanism underlying these effects is unknown although certain inferences are possible and may reveal much about epileptogenesis in this model.     

Analysis of initial slow waves (ISWs) at the seizure onset in patients with drug resistant temporal lobe epilepsy

RATIONALE: The goal of this study is to analyze initial slow waves (ISWs) at seizure onset in patients with refractory temporal lobe epilepsy. ISWs are a specific type of ictal EEG pattern characterized by a slow wave at the seizure onset followed by low voltage fast activity. METHODS: Investigations were carried out on 14 patients from the UCLA hospital (USA) and 10 from the Ghent University Hospital (Belgium) implanted with depth and grid electrodes for localization of the epileptogenic zone. RESULTS: Sixty-one seizures in the UCLA group and 30 seizures in the Ghent group were analyzed. Fourteen UCLA and seven Ghent patients had ISWs at seizure onset. The duration of ISWs varied between 0.3 to 6.0 s and maximum amplitude varied from 0.2 to 1.4 mV. ISWs in three of 14 UCLA patients (30% of seizures) had a consistent positive polarity at the deepest contacts that were located in the amygdala, hippocampus, or entorhinal cortex and reversed polarity outside of these brain areas (ISWs1). ISWs in 11 of 14 UCLA patients (70% of seizures) had negative polarity at the deepest electrodes and their amplitude increased toward the recording contacts located in the white matter or neocortex (ISWs2). All ISWs from the seven Ghent patients were negative in the depth contacts (ISWs2) and positive on grid electrodes at the cortical surface. ISWs1 were associated with EEG spikes at the onset and on increase in amplitude of 10-20 Hz sinusoidal activity. In contrast, ISWs2 were associated with suppression of EEG amplitude, an increase in frequency in the range of 20-50 Hz, and did not have EEG spikes at the onset. Multiunit neuronal activity showed strong synchronization of neuronal discharges during interictal spikes, but multiunit synchronization was not obvious during ISWs2. CONCLUSION: The existence of EEG spikes and phase reversal with ISWs1 indicates this type of seizure may be triggered by hypersynchronous neuronal discharges; however, seizures with ISWs2 at the onset may be triggered by different mechanisms, perhaps nonneuronal.     

癫痫及痫性发作动物模型制作研究进展

癫痫是神经病学研究的重要领域.癫痫动物模型主要用于研究癫痫的发生机制、脑电生理、行为学变化以及筛选新的抗癫痫药物.动物模型可分为痫性发作模型和癫痫模型.人类将癫痫定义为多次自发性反复发作(spontaneous recurrent seizures,SRS),那么诱导出急性痫性发作而没有慢性SRS的模型仅为痫性发作模型.     

Construction of rules for seizure prediction based on approximate entropy

Objective

In this study on the analysis of EEG signals for seizure prediction, we used a combination of statistically relevant theory and nonlinear dynamics to maximize the sensitivity of nonlinear analysis and improved prediction accuracy (PA) and effectiveness.

Methods

First, a physiological reference range of approximate entropy (ApEn) was set up based on normal EEG data. Second, using the concept of global optimization, all EEG electrodes were used in the study regardless of the location of epileptic foci, and the five-electrode group with the strongest synchronization discharge was employed as the optimal electrode group for the next prediction. We set a warning signal when the ApEn values of the data were below the reference range in five electrodes at the same time.

Results

From the overall 142.7-h EEG signal containing 37 seizures from nine epileptics, our PA was 94.59%, the false prediction rate was 0.084/h, and the mean prediction time was 26.64 min.

Conclusion

Combining statistically relevant theory and nonlinear dynamics can significantly improve the sensitivity of the nonlinear analysis in seizure prediction.

Significance

This method may provide a theoretical foundation for the development of a clinical real-time warning system for patients with partial epilepsy.     

Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons

The electrophysiological effects of the non-competitive (NMDA) antagonist (+)-MK801 (MK-801) on nigrostriatal and mesoaccumbal dopaminergic (DA) neurons were evaluated in chloral hydrate-anesthetized rats. MK-801 (0.05–3.2 mg/kg, i.v.) stimulated the firing rates of 14 (74%) of 19 nigrostriatal DA (NSDA) neurons and all 16 mesoaccumbal DA (MADA) neurons tested. Stimulatory effects of the drug were more prominent on MADA neurons. Interspike interval analysis revealed that MK-801 also regularized DA neuronal firing pattern. Acute brain hemitransection between the midbrain and forebrain attenuated the stimulatory effects of MK-801 on firing rate and blocked the effects on firing pattern. Similar to MK-801, hemitransection itself increased NSDA and MADA cell firing rates and regularized firing pattern. Both i.v. and iontophoretic MK-801 blocked the excitatory effects of iontophoretic NMDA but did not effect excitations caused by the non-NMDA glutamatergic receptor agonists quisqualate and kainate. Iontophoretic MK-801 had no effect alone. These results suggest that the excitatory effects of i.v. MK-801 on DA neuronal activity are not due to direct actions on DA neurons. Glutamatergic projections originating anterior to the hemistransection appear to play a role in the effectrs of MK-801 on DA neuronal activity.     

Quantitative assessment of seizure severity for clinical trials: a review of approaches to seizure components

Quantitative assessment of seizure severity has been approached using a variety of systems. This review describes currently available methods and possible new approaches to seizure assessment for clinical trials. A review of the literature on methods of seizure assessments resulted in tabulation of the seizure rating scales known as VA, Chalfont-National Hospital, Liverpool, Hague, and the Occupational Hazard Scale. Seizures have been evaluated by simply counting all events, counting events by type, by clinician ratings, patient ratings, and combinations. Each of the scales has advantages and disadvantages. Most scales share core components: seizure frequency, seizure type, seizure duration, postictal events, postictal duration, automatisms, seizure clusters, known patterns, warnings, tongue biting, incontinence, injuries, and functional impairment. This review revealed a partial consensus about aspects of seizures that are important markers for severity. However, usefulness of the existing scales is limited by lack of data on responsiveness. New approaches are needed to assess changes in seizure severity as a result of an intervention in a clinical trial.     

Acute interactive effects of MK-801 and morphine on cortical EEG and EEG power spectra in rats

The interaction between MK-801 and morphine-induced effects on cortical electroencephalography (EEG) was investigated. Rats were administered one of five MK-801 doses (IP) prior to morphine (IV). MK-801 dose-dependently increased morphine-induced global spectral power, duration of morphine-induced EEG bursts and latency to sleep onset, and decreased morphine-induced mean frequency, mobility, complexity, and edge frequency. MK-801 pretreatment shifted the relative distribution of total power to the left. Significant interaction effects were found for all spectral parameters except peak frequency. A second group of rats was administered MK-801 prior to an increasing cumulative morphine dose. MK-801 increased maximal morphine effects on all spectral parameters except peak frequency. The results are in agreement with those of recent analgesia and in vitro studies in spinal neurons, and support observations of a synergistic interaction between effects of NMDA antagonism and morphine. These data further suggest that the component of cortical EEG that is produced by mu-opioid- and NMDA-receptor interactive effects may be dominated by an inhibitory effect of morphine on NMDA receptor activity.     

A fuzzy rule-based system for epileptic seizure detection in intracranial EEG

ObjectiveWe present a method for automatic detection of seizures in intracranial EEG recordings from patients suffering from medically intractable focal epilepsy.MethodsWe designed a fuzzy rule-based seizure detection system based on knowledge obtained from experts’ reasoning. Temporal, spectral, and complexity features were extracted from IEEG segments, and spatio-temporally integrated using the fuzzy rule-based system for seizure detection. A total of 302.7 h of intracranial EEG recordings from 21 patients having 78 seizures was used for evaluation of the system.ResultsThe system yielded a sensitivity of 98.7%, a false detection rate of 0.27/h, and an average detection latency of 11 s. There was only one missed seizure. Most of false detections were caused by high-amplitude rhythmic activities. The results from the system correlate well with those from expert visual analysis.ConclusionThe fuzzy rule-based seizure detection system enabled us to deal with imprecise boundaries between interictal and ictal IEEG patterns.SignificanceThis system may serve as a good seizure detection tool with high sensitivity and low false detection rate for monitoring long-term IEEG.     

Analysis of chronic seizure onsets after intrahippocampal kainic acid injection in freely moving rats

PURPOSE: The goal of this study was to analyze the transition period between interictal and ictal activity in freely moving rats with recurrent spontaneous seizures after unilateral intrahippocampal kainic acid (KA) injection. METHODS: Pairs of tungsten electrodes (50 microm O/D) were implanted bilaterally under anesthesia at symmetrical points in the dentate gyrus (DG) and CA1 regions of anterior and posterior hippocampi and entorhinal cortex of adult Wistar rats. Stimulating electrodes were placed in the right angular bundle and KA was injected into the right posterior CA3 area of hippocampus after 1 week of baseline EEG recording. Beginning 24 h after injection, electrographic activity was recorded with video monitoring for seizures every day for 8 h/day for 60 days. RESULTS: Seventy percent of seizures started locally in the DG ipsilateral to injection, with an increase in frequency of interictal EEG spikes (hypersynchronous type, HYP), and 26% of seizures started with a decrease of EEG amplitude with parallel increase in frequency (low-voltage fast type, LVF). During HYP seizures, a significant increase was observed in amplitude of beta-gamma range frequencies, ripple frequency, and fast ripple (FR) frequency, whereas during LVF seizure, an increase was noted only in the beta-gamma range. In all cases but one, an EEG wave preceded ripple and FR oscillations. Before seizure onset, the amplitude of DG-evoked responses to single pulses decreased, whereas the amplitude of the response to the second pulse delivered at 30-ms interval increased. CONCLUSIONS: If ripple and FR oscillations indicate the seizure-generating neuronal substrate, these areas must be small and widespread, so that the probability of recording from them directly is very low. The decreased response to electrical stimulation before seizures could indicate a protective inhibitory mechanism that contains or prevents seizure occurrence. The presence of decreased paired-pulse suppression could indicate a network predisposition to follow an external input with a certain frequency.     

Effects of Valproate, Phenytoin, and MK-801 in a Novel Model of Epileptogenesis

Summary: Purpose: We have developed and characterized a novel model of epileptogenesis based on the convulsive actions of flurothyl in mice. The hallmark feature of this model is a reliable change in the type of seizure expressed in response to flurothyl from generalized clonic to generalized tonic seizures. The purpose of our study was to evaluate the effects of chronic administration of valproate (VPA), phenytoin (PHT), and MK-801 on the change in seizure phenotype observed in our model system.
Methods: Male C57BL/6J mice received flurothyl seizures on 8 consecutive days. Two hours after the last generalized seizure, chronic drug or vehicle was administered twice daily at 12-h intervals for 28 days. The drugs evaluated were VPA (250 mg/kg), PHT (30 mg/kg), and MK-801 (0.5 mg/kg). After a 7-day drug washout period, mice were retested with flurothyl.
Results: Among uninjected or vehicle-injected control mice, there was a significant increase in the proportion of animals expressing tonic seizures after the 28-day stimulation-free interval. Chronic administration of VPA or MK-801, but not PHT, blocked the characteristic change in seizure type from clonic to tonic.
Conclusions: The change in seizure phenotype observed after exposure to our paradigm indicates a fundamental reorganization in the propagation of flurothyl-initiated seizures. As in electrical kindling, VPA and MK-801 are effective at blocking or retarding the reorganization, whereas PHT is not. The concordance in pharmacologic profiles between kindling and our model suggests that the processes underlying changes in seizure susceptibility in these two models share mechanisms in common.     

Hyperventilation revisited: physiological effects and efficacy on focal seizure activation in the era of video-EEG monitoring

PURPOSE: Hyperventilation is an activation method that provokes physiological slowing of brain rhythms, interictal discharges, and seizures, especially in generalized idiopathic epilepsies. In this study we assessed its effectiveness in inducing focal seizures during video-EEG monitoring. METHODS: We analyzed the effects of hyperventilation (HV) during video-EEG monitoring (video-EEG) of patients with medically intractable focal epilepsies. We excluded children younger than 10 years, mentally retarded patients, and individuals with frequent seizures. RESULTS: We analyzed 97 patients; 24 had positive seizure activation (PSA), and 73 had negative seizure activation (NSA). No differences were found between groups regarding sex, age, age at epilepsy onset, duration of epilepsy, frequency of seizures, and etiology. Temporal lobe epilepsies were significantly more activated than frontal lobe epilepsies. Spontaneous and activated seizures did not differ in terms of their clinical characteristics, and the activation did not affect the performance of ictal single-photon emission computed tomography (SPECT). CONCLUSIONS: HV is a safe and effective method of seizure activation during monitoring. It does not modify any of the characteristics of the seizures and allows the obtaining of valuable ictal SPECTs. This observation is clinically relevant and suggests the effectiveness and the potential of HV in shortening the presurgical evaluation, especially of temporal lobe epilepsy patients, consequently reducing its costs and increasing the number of candidates for epilepsy surgery.     

Chelatable zinc modulates excitability and seizure duration in the amygdala rapid kindling model

Zinc is present in high concentration in many structures of the limbic circuitry, however the role of zinc as a neuromodulator in such synapses is still uncertain. In this work, we verified the effects of zinc chelation in an animal model of epileptogenesis induced by amygdala rapid kindling.

The basolateral amygdala was electrically stimulated ten times per day for 2 days. A single stimulus was applied on the third day. Stimulated animals received injections of PBS or the zinc chelator diethildythiocarbamate acid (DEDTC) before each stimulus series. Animals were monitored with video-EEG and were perfused 3 h after the last stimulus for subsequent neo-Timm and Fluoro-Jade B analysis.

Zinc chelation decreased the duration of both behavioral seizures and electrical after-discharges, and also decreased the EEG spikes frequency, without changing the progression of behavioral seizure severity. These results indicate that the zinc ion may have a facilitatory role during kindling progression.     

Vagus nerve stimulation elevates seizure threshold in the kindling model

Purpose: Vagus nerve stimulation (VNS) provides partial relief of medically refractory partial seizures in a subset of patients. The optimal pattern of stimulation and the mechanism of the antiseizure effects are uncertain. Establishing the efficacy of VNS in an animal model of epilepsy would provide an experimental preparation with which to address these questions. We sought to determine whether VNS exerted antiseizure effects in the kindling model of epilepsy. Methods: We implanted adult rats with bipolar stimulating electrodes in the right amygdala and VNS devices around the left vagus nerve. Following induction of kindling, electrographic seizure threshold (EST) was determined by quantifying the amygdala electrode current required to evoke a seizure. Once stable ESTs were established, VNS devices were programmed to deliver U.S. Food and Drug Administration (FDA)–approved, clinically used (standard) or an experimental (microburst) pattern of stimulation of variable intensity. VNS devices were programmed identically in control animals except that no current was delivered. EST was examined at 60 min and 1 week in the control and vagus nerve stimulated groups. Key Findings: Significant reductions of EST values were detected in control animals when tested both 60 min and 1 week following device programming. Both clinically used and experimental patterns of VNS prevented the reduction of EST evident in control animals when tested either 60 min or 1 week after device programming. Significance: These findings establish an experimental preparation with which to elucidate the antiseizure mechanisms of VNS and to determine patterns of VNS most effective at elevating seizure threshold.     

首次自发性癎性发作后复发危险性的前瞻性研究

目的 研究首次自发性痫性发作后复发的危险性,并探讨影响其复发的潜在危险因素。方法 选择1998年10月～2000年6月间我院就诊的新近出现痫性发作患者150例(其中首次痫性发作66例),随访2年,记录有无再次复发,应用Kaplan—Meier乘积限法估算复发率,针对66例首次痫性发作患者,应用Cox比例风险模型的单因素和多因素分析来研究影响首次痫性发作后复发的潜在危险因素。结果 150例首诊患者2年中复发109例,累积复发率为72．67％;而其中的66例首次痫性发作患者2年中复发36例,累积复发率为54．55％。Cox单因素和多因素分析表明,首次痫性发作后,症状性发作复发的危险性较大;另外EEG异常、首次发作出现在睡眠状态中、首次发作持续时间较长等亦是复发的危险因素,而3—12岁间出现的首次痫性发作复发率较低。结论 有两次或多次发作史者,其复发率高于单次发作者;首次痫性发作的某些临床特点可以帮助判断其复发危险性。     

Different presurgical characteristics and seizure outcomes in children with focal cortical dysplasia type I or II

Purpose:   Cortical dysplasia (FCD) is a frequent cause of epilepsy in childhood. Two major pathological variants are distinguished, FCD type I and II. The aim of the study was to characterize differences between FCD type I and II with respect to imaging and EEG findings, clinical and neuropsychological presentations, and surgical outcome.
Methods:   Forty children with refractory epilepsy and histopathologically confirmed FCD were retrospectively analyzed. FCD type I was identified in 24 and FCD type II in 16 patients.
Results:   Characteristic MRI abnormalities in FCD type I included subtle white matter signal changes and regional reduction of the white matter volume. Typical MRI findings in FCD type II were increased cortical thickness, transmantle sign, gray-white matter junction blurring, fluid-attenuated inversion recovery (FLAIR) and proton density (PD) gray matter signal changes as well as T1w, and PD white matter signal changes. Continuous EEG slowing was significantly more common in patients with FCD type I. Children with FCD type I presented with lower levels of intelligence and were suffering more often from maladaptive behavior and behavioral disorders. Surgical outcome was significantly worse in the FCD type I group (seizure freedom was achieved in 21% FCD type I patients and in 75% FCD type II subjects, p < 0.001).
Conclusions:   Clinically important differences were found in children with distinct histopathological subtypes of FCD. Due to prominent neuropsychological deficits and worse seizure outcome, treatment strategies in FCD type I are more challenging than previously reported and these children should be recognized and specifically addressed within the incoherent group of patients with malformative brain disorders.     

Two types of neuroplasticities in the kindling phenomenon: effects of chronic MK-801 and methamphetamine

Using the low-frequency kindling technique, we studied the effects of chronic MK-801 and chronic methamphetamine (MAP) administration on hippocampal kindling seizure development. In experiment 1, MK-801 (0.05, 0.1 mg/kg i.p.) was administered 2 h before each electrical stimulation until kindling developed into stage-3 seizure. In experiment 2, we started daily electrical stimulations two weeks after the last injection of chronic MAP administration (6 mg/kg/day, 14 days). The number of stimulating pulses required for the triggering of epileptic afterdischarge (pulse-number threshold, PNT) was used as an indicator of the seizure threshold. PNT, afterdischarge duration (ADD) and behavioral seizure stage (BSS) of each induced seizure in the initial stage of kindling; the kindling rates for stage 3 and stage 5 seizures; seizure parameters at the completion of kindling of the drug-treated groups were recorded and compared to the values of each saline-treated control group. Our result showed that MK-801 administration prior to each electrical stimulation selectively and significantly increased PNT in the initial stage of kindling without affecting other seizure parameters. Chronic pretreatment of MAP caused a selective and significant decrease of PNT of the first two stimulations in the kindling process. Taken together with the previous studies, these results suggest that long-term potentiation plays an important role in the development of the excitability of seizure focus but not of the induced seizure's propagation in the hippocampal kindling phenomenon. Clinically MK-801 seems to be a more efficacious drug in preventing the induction of seizures than in suppressing the acquired seizures.     

MK801 prevents quinolinic acid-induced behavioral deficits and neurotoxicity in the striatum

Bilateral intrastriatal injections of quinolinic acid (QA) (180 nmoles) induced weight loss and neurologic and behavioral deficits including convulsions, decreased catalepsy response to haloperidol, increased nocturnal locomotor activity, and abnormal feeding behavior in adult male Sprague-Dawley rats. Pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK801 (4 mg/kg IP) 30 min prior to stereotaxic surgery prevented the appearance of all QA-induced behavioral abnormalities and prevented weight loss. Twelve weeks after surgery the QA-lesioned animals recovered to sham levels on feeding behavior and nocturnal locomotor activity, but showed persistent reductions in haloperidol-induced catalepsy. Histological examination of the QA-lesioned brains showed extensive lesions of the dorsolateral striatum and frontoparietal cortex. MK801 pretreatment protected against these lesions. These results confirm that MK801 treatment prevents the appearance of neuropathological damage after QA neurotoxicity, and further show that neuronal protection with MK801 is correlated with the absence of QA-induced behavioral deficits.     

EEG and video-EEG seizure monitoring has limited utility in patients with hypothalamic hamartoma and epilepsy

Purpose: Hypothalamic hamartomas (HHs) are a malformation of the ventral hypothalamus and tuber cinereum, associated with gelastic seizures and epilepsy. We sought to determine the spectrum of electroencephalography (EEG) abnormalities in a large cohort of HH patients. Methods: Data was collected for HH patients undergoing evaluation between 2003 and 2007. Data included seizure history, prior treatment, and results of diagnostic studies. After informed consent, data were entered into a database. Key Findings: We reviewed 133 HH patients. Mean age at time of data analysis was 15.7 years (59.4% male). Most patients had gelastic (77%) and/or complex partial seizures (58%). Records for 102 EEG studies on 73 patients were reviewed. Interictal epileptiform abnormalities were seen in 77%, localizing predominately to the temporal and frontal regions. Records for 104 video‐EEG (VEEG) studies on 65 patients were reviewed. Of 584 gelastic seizures (GS) captured, no ictal EEG change was noted in 438 (75%). Of GS with localizing features, 89% suggested onset from the temporal and/or frontal regions. There were 160 complex partial seizures (CPS). For those with localizing features, 100% localized to the temporal and/or frontal head regions. EEG and VEEG findings correlated with the side of HH attachment. VEEG did not influence outcome. Significance: EEG features in HH patients are diverse. The majority of gelastic seizures fail to demonstrate change in the EEG. The lack of EEG changes with many clinical seizures, and the false localization seen in those events with an ictal change suggest the utility of EEG is limited in the evaluation of these patients.