The association between seizure clustering and convulsive status epilepticus in patients with intractable complex partial seizures

PURPOSE: We examined the association between seizure clustering and convulsive status epilepticus (SE) in patients with intractable complex partial seizures, to identify whether patients whose seizures typically cluster are at high risk for convulsive SE (CSE). METHODS: Seventy-six patients with intractable complex partial epilepsy who underwent presurgical evaluation in the Montefiore Epilepsy Management Unit from 1993 to 1997 were contacted and interviewed about typical seizure frequency and distribution and history of CSE. Seizure clustering was defined as three or more complex partial seizures within a 24-h period, with return to baseline between seizures. RESULTS: Of the 76 patients contacted, 21 (28%) had experienced at least one episode of CSE, and 36 (47%) typically experienced clustered seizures. SE occurred in 16 (44%) of 36 patients with clustered seizures, and in five (12.5%) of 40 patients with nonclustered seizures (p < 0.002). Of 53 patients with temporal lobe epilepsy, CSE occurred in 13 (50%) of 26 patients with clustered seizures, and four (14.8%) of 27 patients with nonclustered seizures (p < 0.006). CONCLUSIONS: Patients with intractable complex partial or localization-related epilepsy who typically experience seizure clustering are at a significantly higher risk for CSE than are patients with nonclustered seizures.     

Antioxidants and free radical scavengers do not consistently delay seizure onset in animal models of acute seizures

A number of herbal compounds with direct antioxidant activity slow the onset, or completely block, the occurrence of seizures. This increase in latency has been proposed to be due to the antioxidant activity. This hypothesis was directly tested by determining the effects of Trolox, a vitamin E analog, vitamin C, melatonin, and alpha-lipoic acid on the latency to acute seizures induced with pilocarpine, kainic acid, or subcutaneous pentylenetetrazol (PTZ) in adult rats. Trolox, vitamin C, and alpha-lipoic acid had significant anticonvulsant activity against pilocarpine, but there were no acute changes in reduced glutathione levels at 15 or 120 minutes. Other than reduced mortality with vitamin C in the PTZ model, none of the antioxidants had a significant effect against PTZ- or kainic acid-induced seizures. The lack of consistent anticonvulsant effect suggests that the antioxidant activity of the herbal preparations cannot account for the delay in seizure onset.     

Interictal respiratory variability predicts severity of hypoxemia after generalized convulsive seizures

Objective

Severe respiratory dysfunction induced by generalized convulsive seizures (GCS) is now thought to be a common mechanism for sudden unexpected death in epilepsy (SUDEP). In a mouse model of seizure-induced death, increased interictal respiratory variability was reported in mice that later died of respiratory arrest after GCS. We studied respiratory variability in epilepsy patients as a predictive tool for severity of postictal hypoxemia, a potential biomarker for SUDEP risk. We then explored the relationship between respiratory variability and central CO₂ drive, measured by the hypercapnic ventilatory response (HCVR).

Methods

We reviewed clinical, video-electroencephalography, and respiratory (belts, airflow, pulse oximeter, and HCVR) data of epilepsy patients. Mean, SD, and coefficient of variation (CV) of interbreath interval (IBI) were calculated. Primary outcomes were: (1) nadir of capillary oxygen saturation (SpO₂) and (2) duration of oxygen desaturation. Poincaré plots of IBI were created. Covariates were evaluated in univariate models, then, based on Akaike information criteria (AIC), multivariate regression models were created.

Results

Of 66 GCS recorded in 131 subjects, 30 had interpretable respiratory data. In the multivariate model with the lowest AIC value, duration of epilepsy was a significant predictor of duration of oxygen desaturation. Duration of tonic phase and CV of IBI during the third postictal minute correlated with SpO₂ nadir, whereas CV of IBI during non-rapid eye movement sleep had a negative correlation. Poincaré plots showed that long-term variability was significantly greater in subjects with ≥200 s of postictal oxygen desaturation after GCS compared to those with <200 s desaturation. Finally, HCVR slope showed a negative correlation with measures of respiratory variability.

Significance

These results indicate that interictal respiratory variability predicts severity of postictal oxygen desaturation, suggesting its utility as a potential biomarker. They also suggest that interictal respiratory control may be abnormal in some patients with epilepsy.     

Automated differentiation between epileptic and nonepileptic convulsive seizures

Our objective was the clinical validation of an automated algorithm based on surface electromyography (EMG) for differentiation between convulsive epileptic and psychogenic nonepileptic seizures (PNESs). Forty‐four consecutive episodes with convulsive events were automatically analyzed with the algorithm: 25 generalized tonic–clonic seizures (GTCSs) from 11 patients, and 19 episodes of convulsive PNES from 13 patients. The gold standard was the interpretation of the video‐electroencephalographic recordings by experts blinded to the EMG results. The algorithm correctly classified 24 GTCSs (96%) and 18 PNESs (95%). The overall diagnostic accuracy was 95%. This algorithm is useful for distinguishing between epileptic and psychogenic convulsive seizures. Ann Neurol 2015;77:348–351.     

Chemoconvulsant seizures: Advantages of focally-evoked seizure models

Studies of short and long-term changes in regional metabolism, blood flow, gene expression (including immediate early genes and genes for neurotrophic factors), sprouting and cell death following seizures are pivotal to an under-standing of the neural networks responsible for the generation of seizures. At the same time, this information forms a basis for understanding the pathophysiology associated with chronic, recurrent seizures. Systemic chemoconvulsant seizure models, produced by systemically administered chemoconvulsant agents, although convenient, are plagued with difficulties which confound the interpretation of their effects on the nervous system. These difficulties include widespread direct cellular and physiological effects of the chemoconvulsant drugs, most of which are independent of seizures. In addition, numerous physiological changes occur as a secondary consequence of, or ancillary to, seizures, and it can be especially difficult to separate these effects from the direct effects of the propagated seizure discharge itself. Some of these difficulties can be overcome by the use of focally-evoked seizure models. Such models avoid the diffuse presence of drug throughout the CNS and thereby eliminate most of the direct cellular and physiologic actions of the drug apart from seizure-induction. Large regions of the brain distant from the focal site of drug application then can be examined for molecular, structural and physiologic changes uncomplicated by the presence of drug. Moreover, different focal sites of drug application can be compared to evaluate the specificity of the molecular changes to the neural network engaged in the seizure discharge. For example, limbic seizures, evoked by chemoconvulsant application into area tempestas, can be compared with brainstem convulsions evoked by chemoconvulsant application into inferior colliculus. Studies using focal drug application have also been successful in producing distant damage following status epilepticus and in demonstrating distant neuroprotection. The importance of identifying seizure-specific pathophysiological alterations is discussed in the context of focal vs. systemic chemoconvulsant seizure models.

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Sommario Studi su modificazioni a breve e lungo termine del metabolismo regionale, del flusso, della espressione genica, dei fenomeni degenerativi e rigenerativi conseguenti alle crisi forniscono informazioni cruciali per la comprensione dei meccanismi neuronali responsabili della generazione delle crisi. Modelli sperimentali prodotti dalla somministrazione sistemica di agenti chimici convulsivanti, benché utili danno risultati di difficile interpretazione. Le difficoltà interpretative derivano dai molti effetti cellulari e fisiologici dei farmaci convulsivanti che sono indipendenti dalle crisi. Inoltre numerosi effetti fisiologici secondari o collaterali alle crisi sono difficilmente discriminabili da quelli direttamente dipendenti dalla scarica critica. Alcune di queste difficoltà possono essere superate dall'uso di modelli di crisi focali, nei quali l'effetto epilettogeno diretto delle sostanze impiegate non è contaminato dagli effetti generali. In questo modo le modificazioni molecolari, strutturali e fisiologiche che si verificano in regioni lontane dalla zona di applicazione del farmaco possono essere studiate senza l'interferenza dei suoi effetti diretti. Per di più in questi modelli lo studio comparativo delle diverse zone di applicazione dell'agente epilettogeno permette di valutare la specificità delle modificazioni molecolari in rapporto all'aggregato neuronale generatore della scarica critica. Ad esempio crisi limbiche evocate da applicazione di chemoconvulsivanti nell'area tempestas possono essere studiate comparativamente con convulsioni troncoencefaliche da somministrazione di chemoconvulsivanti nel collicolo inferiore. L'applicazione locale di farmaci si è dimostrata in grado di indurre danni a distanza conseguenti a stato epilettico e ha rivelato l'esistenza di neuroprotezione a distanza. L'importanza dell'identificazione di alterazioni epilettogene specifiche per tipo di crisi viene discussa nel contesto di modelli di crisi epilettiche indotte da somministrazione focale o generalizzata di chemoconvulsivanti.

     

Influence of dietary zinc on convulsive seizures and hippocampal NADPH diaphorase-positive neurons in seizure susceptible EL mouse

Adequate, high and deficient dietary levels of zinc (Zn) were compared in seizure-susceptible EL mice with respect to convulsions and to nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase-positive hippocampal neurons. Diaphorase positivity is associated with nitric oxide (NO) production. Convulsive seizures in the EL mice given the various diets did not differ over 1–4 weeks, but convulsions in EL mice given the Zn-deficient diet for 4 weeks were more effectively suppressed by injection of zonisamide (ZNS) (75 mg/kg intraperitoneally) than in mice receiving high- or adequate-Zn diet for the same period. Numbers of NADPH diaphorase-positive neurons in the CA1/CA2 region of the hippocampal formation were significantly higher in mice given the Zn-deficient diet for 4 weeks than in mice fed adequate Zn. Mice receiving the high-Zn diet for the same period had significantly fewer NADPH diaphorase-positive neurons in the subiculum than mice with adequate Zn. These results suggest that Zn deficiency inhibits convulsive seizures of EL mice, and that dietary Zn influences numbers of NO producing neurons in the hippocampal formation.     

Interactions between angiotensin II, GABA and diazepam in convulsive seizures

In experiments on male mice, we studied the effects of gamma-aminobutyric acid (GABA), angiotensin II (AT II), administered intracerebroventricularly, diazepam, injected intraperitoneally, and combinations of GABA + AT II and diazepam + AT II on convulsive seizures induced by pentylenetetrazol (PTZ) (80 mg/kg subcutaneously) and 3-mercaptopropionic acid (3-MPA) (40 mg/kg intraperitoneally). The anticonvulsant effects of GABA and diazepam on PTZ-induced seizures were increased by AT II in doses which did not significantly influence seizures. AT II applied together with GABA or diazepam in ineffective doses provoked a strong anticonvulsant effect on both PTZ- and 3-MPA-induced seizures. These results indicate that the anticonvulsant effects of GABA and diazepam on PTZ- and 3-MPA-induced seizures might effectively be potentiated by the octapeptide AT II. It is suggested that AT II operates as an endocoid acting on GABA, respectively benzodiazepine recognition sites in the CNS.     

Anxiogenic-like consequences in animal models of complex partial seizures

Several kinds of psychiatric symptoms (anxiety, depression, schizophrenia) have been associated with epilepsies, and clinical data suggest that patients with seizures involving limbic structures are the most prone to develop behavioural disorders between the seizures (i.e. interictally). Studying the neurobiological mechanisms that underlie these symptoms is difficult in humans because of different interfering factors (e.g. psychosocial difficulties, pharmacological side-effects, lesions), which can be avoided in animal models. Using repetitive electrical stimulations (kindling) or local applications of a neuroexcitotoxin in limbic structures (mainly the amygdala and hippocampus), several authors have reported lasting changes of emotional reactivity in cats and rats. These changes appear as anxiety-related reactions expressed as a hyperdefensiveness in the cat, or a reduction of spontaneous exploration in tests predictive of anxiogenic effects in the rat. Some neuroplasticity processes known to develop during epileptogenesis (neuronal hyperexcitability, modulation of GABA/benzodiazepine transmission) may participate in these lasting changes of behaviour, especially in structures involved in the control of fear-promoted reactions (amygdala, periaqueductal grey matter). In addition, endogenous control systems may also play a critical role in the occurrence of interictal behavioural disorders.     

Benzyl alcohol suppresses seizures in two different animal models

ABSTRACT

Introduction: We have been exploring the effects of dihydroprogesterone in female amygdala-kindled rats. For intraperitoneal (i.p.) time–response studies, we used a vehicle containing the common solvent, benzyl alcohol (BnOH). The vehicle containing BnOH was also tested alone as a control.

Method and Results: Unexpectedly, it was found that the vehicle containing BnOH had clear-cut anti-seizure effects in the kindling model, with an ED50 of 100 mg/kg. In a follow-up study, dose- and time–response studies of i.p. BnOH were done in male mice in the maximal pentylenetetrazol (PTZ) model. BnOH suppressed PTZ seizures in a dose-dependent manner, with an ED50 of 300 mg/kg against hindlimb tonic extension. Effects were fully established at 5-min post injection and lasted for an hour.

Conclusion: BnOH is not an inert solvent. It has clear-cut anti-seizure effects against both focal and generalized seizures.     

Temporal relationship between awakening and seizure onset in nocturnal partial seizures

Clinical awakening can be seen just before or after seizure onsets. In this study we determined the time between onset of seizures and awakening in patients with frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). Sixty-eight patients who underwent video-EEG monitoring with simultaneous PSG were retrospectively examined. TLE or FLE patients having seizures during sleep were included. Seizure onset and awakening onset were marked according to clinical and electrophysiological features. The duration between awakening and seizure onset was compared in patients with TLE and FLE. Twenty-five patients who had been diagnosed with TLE (17) or FLE (8) had a total of 75 seizures during sleep. All seizures except one, occurred during NREM sleep in both TLE and FLE patients. The seizure onsets were before awakening in 49 seizures (FLE: 20, TLE: 29) and the awakening preceded the seizure onsets in 12 seizures (FLE: 3, TLE: 9). The duration between seizure onset and the awakening was shorter in FLE, either in seizures with preceding awakening or not (p=0.014, p=0.015). Awakening was mostly seen after onset of seizures rather than before, especially in TLE. But in patients with FLE the duration between seizure onset and awakening was shorter. The localization of epileptic activity may play a role for the timing of awakening mechanisms during nocturnal partial seizures.     

MicroRNA与癫痫突触重塑

癫痫是常见的神经系统疾病之一,其病因和发病机制十分复杂,迄今仍不是十分清楚.突触重塑是癫痫患者脑组织中的重要病理改变,亦是癫痫反复发作的原因,其发生机制是目前研究的热点.microRNA(简称miRNA)是一类在进化过程中高度保守的内源性非编码的单链RNA,其功能是负调控靶基因的表达,与树突棘生长、突触重塑和突触蛋白合成关系密切.     

Modulation of seizure threshold by vagus nerve stimulation in an animal model for motor seizures

De Herdt V, De Waele J, Raedt R, Wyckhuys T, El Tahry R, Vonck K, Wadman W, Boon P. Modulation of seizure threshold by vagus nerve stimulation in an animal model for motor seizures.
Acta Neurol Scand: 2010: 121: 271–276.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – The precise mechanism of action of vagus nerve stimulation (VNS) in suppressing epileptic seizures remains to be elucidated. This study investigates whether VNS modulates cortical excitability by determining the threshold for provoking focal motor seizures by cortical electrical stimulation before and after VNS. Material and methods – Male Wistar rats (n = 8) were implanted with a cuff‐electrode around the left vagus nerve and with stimulation electrodes placed bilaterally on the rat motor cortex. Motor seizure threshold (MST) was assessed for each rat before and immediately after 1 h of VNS with standard stimulation parameters, during two to three sessions on different days. Results – An overall significant increase of the MST was observed following 1 h of VNS compared to the baseline value (1420 μA and 1072 μA, respectively; P < 0.01). The effect was reproducible over time with an increase in MST in each experimental session. Conclusions – VNS significantly increases the MST in a cortical stimulation model for motor seizures. These data indicate that VNS is capable of modulating cortical excitability.     

Repetition of audiogenic seizures in genetically epilepsy-prone rats induces cortical epileptiform activity and additional seizure behaviors.

Repetition of seizures appears to increase severity in a number of seizure models, but the nature of these severity increases has not been elucidated in naturally occurring genetic epilepsy models. The genetically epilepsy-prone rat (GEPR) is highly susceptible to many seizure provoking stimuli, and high intensity acoustic stimuli induce audiogenic seizures (AGS). The role of forebrain structures in AGS in the GEPR has not been clear, and the presence of cortical epileptiform EEG activity in the GEPR is controversial. The present study examined the effects of 21 daily AGS repetitions on behavior and EEG activity recorded from the cortex of two GEPR substrains that exhibit moderate (GEPR-3) or severe AGS (GEPR-9). The results indicated that AGS repetition induced seizure severity increases in both GEPR substrains and resulted in prominent cortical epileptiform EEG activity. The AGS behavioral patterns remained distinctly different in the two substrains throughout seizure repetition. In each substrain a different additional behavioral phase was expressed; the GEPR-9 exhibited post-tonic clonus, and the GEPR-3 exhibited facial and forelimb clonus. These findings indicate that seizure repetition results in expansion of the neuronal network subserving AGS to involve forebrain structures. The medial geniculate body and amygdala appear to be part of this expanded network, and long-term potentiation, which was reported in the pathway between the latter brain structures, may be involved. These data suggest that recruitment of forebrain structures into the AGS neuronal network appears to be essential for production of the additional ictal behaviors evoked by AGS repetition.     

Subcortical structures and pathways involved in convulsive seizure generation.

Convulsive seizures in animal models usually involve one or more of the following components: (1) limbic motor seizures, (2) explosive running-bouncing clonic seizures, and (3) tonic extensor seizures. Each of these components depends on specific and experimentally separable anatomic substrates. Limbic motor seizures depend on forebrain structures for their initiation and propagation, with the prepiriform, piriform, and entorhinal cortices playing a prominent role in conjunction with hippocampus, amygdala, substantia innominata, and mediodorsal thalamus. In contrast, seizures involving running-bouncing clonus or tonic extension depend on neural substrates in the brainstem and do not appear to require the integrity of the forebrain for their development or expression. The inferior colliculus is a region from which running-bouncing seizures can be elicited by chemical or electrical stimulation. Tonic extensor seizures depend on the integrity of the nucleus reticularis pontis oralis, but a specific locus responsible for triggering these seizures has yet to be identified. Under conditions of chronic or repeated seizure activity over prolonged time periods, seizures evoked from the hindbrain can recruit forebrain circuits; conversely, repeated stimulation of forebrain limbic circuits (e.g., kindling) can modify susceptibility to brainstem convulsions. These long-term alterations may result from changes in the activity of seizure "gating" pathways, which are circuits that influence seizure susceptibility by modulating the threshold for the initiation and/or propagation of the seizures. In general, these pathways are not part of any core seizure propagation pathway per se. In many cases, the gating substrates are relatively nonselective as to the type of seizure they can influence. In this category, the substantia nigra and its related circuits within the basal ganglia serve a prominent role. In addition, ascending noradrenergic projections have been implicated in the regulation of seizure threshold. Other gating mechanisms involve thalamic circuitry and pathways originating in cerebellum.     

The effect of the 'classic' ketogenic diet on animal seizure models

Bough et al. have recently demonstrated anticonvulsant effects of the 'classic' ketogenic diet (KD) in the pentylenetetrazol infusion model in rats. Proconvulsant effects were seen, however, when the 'classic' diet was tested against maximal electroshock (MES) seizures. These differing results may reflect the fact that the two models involve different kinds of epileptogenic stimulus, or, as Bough et al. note that the two tests involve different stimulation paradigms. The pentylenetetrazol infusion paradigm is a threshold test, whereas the MES test employs a stimulus which is well above threshold. The present experiments were designed to test the effects of the 'classic' KD against seizures triggered in rats by both threshold and suprathreshold levels of electricity and pentylenetetrazol. The threshold tests employed were the pentylenetetrazol infusion test, and the threshold electroconvulsive shock (ECS) test. The subcutaneous pentylenetetrazol (scMET) test was also included, since it is sometimes considered to be a 'threshold' test. The suprathreshold tests employed were the maximal pentylenetetrazol test (MMT) and the maximal electroshock test (MES). The KD failed to suppress seizures in either of the tests involving suprathreshold stimulation (MMT and MES), although there was a significant increase in latency in the MMT test. Small but significant threshold elevations (15-20%) were seen, however, in both the pentylenetetrazol infusion test and the ECS threshold test. No seizure suppression was seen in the scMET test, which actually employs a suprasthreshold stimulus. These data indicate that the KD has significant anticonvulsant effects against both chemically and electrically triggered seizures, but that they consist of small elevations in threshold which will be seen only when threshold measures are used.     

Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures

Cannabis sativa has been associated with contradictory effects upon seizure states despite its medicinal use by numerous people with epilepsy. We have recently shown that the phytocannabinoid cannabidiol (CBD) reduces seizure severity and lethality in the well-established in vivo model of pentylenetetrazole-induced generalised seizures, suggesting that earlier, small-scale clinical trials examining CBD effects in people with epilepsy warrant renewed attention. Here, we report the effects of pure CBD (1, 10 and 100mg/kg) in two other established rodent seizure models, the acute pilocarpine model of temporal lobe seizure and the penicillin model of partial seizure. Seizure activity was video recorded and scored offline using model-specific seizure severity scales. In the pilocarpine model CBD (all doses) significantly reduced the percentage of animals experiencing the most severe seizures. In the penicillin model, CBD (≥ 10 mg/kg) significantly decreased the percentage mortality as a result of seizures; CBD (all doses) also decreased the percentage of animals experiencing the most severe tonic-clonic seizures. These results extend the anti-convulsant profile of CBD; when combined with a reported absence of psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a diverse range of human epilepsies.