Neonatal status epilepticus due to lamination disorder without significant cell death

Background: Malformations of the cerebral cortex may be associated with severe epilepsy and status epilepticus. It has been shown that status epilepticus models induce excitotoxic cell death. In humans, very few data are available. Case and results: We report a case of a multifocal disorder of the lamination diagnosed in a neonate, borne at 30 weeks’ gestation, who died from a refractory status epilepticus at two months and half. This abnormality was not detected by repeated MRI studies. Only microscopic investigations permitted to identify this disorder of the lamination. We found also little cell death or cell loss. Discussion: Our report highlights the possible false negative results of MRI in a newborn. We can also discuss that immature human brain maybe less sensitive to neuronal injury than mature as described in animal models.     

Seizure Suppression by High Frequency Optogenetic Stimulation Using In Vitro and In Vivo Animal Models of Epilepsy

BackgroundElectrical high frequency stimulation (HFS) has been shown to suppress seizures. However, the mechanisms of seizure suppression remain unclear and techniques for blocking specific neuronal populations are required.ObjectiveThe goal is to study the optical HFS protocol on seizures as well as the underlying mechanisms relevant to the HFS-mediated seizure suppression by using optogenetic methodology.MethodsThy1-ChR2 transgenic mice were used in both vivo and in vitro experiments. Optical stimulation with pulse trains at 20 and 50 Hz was applied on the focus to determine its effects on in vivo seizure activity induced by 4-AP and recorded in the bilateral and ipsilateral-temporal hippocampal CA3 regions. In vitro methodology was then used to study the mechanisms of the in vivo suppression.ResultsOptical HFS was able to generate 82.4% seizure suppression at 50 Hz with light power of 6.1 mW and 80.2% seizure suppression at 20 Hz with light power of 2.0 mW. The suppression percentage increased by increasing the light power and saturated when the power reached above-mentioned values. In vitro experimental results indicate that seizure suppression was mediated by activation of GABA receptors. Seizure suppression effect decreased with continued application but the suppression effect could be restored by intermittent stimulation.ConclusionsThis study shows that optical stimulation at high frequency targeting an excitatory opsin has potential therapeutic application for fast control of an epileptic focus. Furthermore, electrophysiological observations of extracellular and intracellular signals reveled that GABAergic neurotransmission activated by optical stimulation was responsible for the suppression.     

Conversion from immediate-release to extended-release lamotrigine improves seizure control

BackgroundImmediate release lamotrigine (LTG-IR) dosing can be limited by peak toxicity. It is thought that peak levels are responsible for some adverse effects such as dizziness, blurred vision, double vision and unsteadiness. At the same time, trough levels may be associated with reduced seizure threshold. The use of extended release lamotrigine (LTG-XR) to replace LTG-IR will be associated with less fluctuation in drug levels-lower peak levels may reduce adverse effects and higher trough levels may improve seizure control. This hypothesis was tested by analyzing seizure control and adverse effects before and after conversion from LTG-IR to LTG-XR in patients who underwent such conversion in 2009–2011.MethodsWe searched our patient database to identify patients converted from LTG-IR to LTG-XR for persistent seizures or adverse effects from August 2009 until December 31, 2011. We included only patients who took LTG-IR and LTG-XR for at least 6 months each. We excluded patients with nonepileptic seizures, progressive cause of epilepsy, or not keeping a seizure record. We collected the following parameters: age at conversion, LTG-IR dose and dosing schedule, duration on that dose, LTG-XR dose and dosing schedule, LTG serum level before and after conversion, duration of LTG-XR treatment, seizure frequency before and after conversion, and change in adverse experience profile. We also recorded baseline AEDs and any AED change during the course of the analysis.ResultsFifty five patients (26 female) satisfied the inclusion/exclusion criteria. Their mean age was 45 years (range 23 to 86). Ten were on LTG-IR monotherapy, 24 took LTG-IR plus one other AED, most commonly levetiracetam, and the remaining 21 took LTG-IR plus at least 2 other AEDs. The mean LTG-IR dose was 544 mg/day (range 150–1100 mg/day). The mean LTG-IR serum level was 11.6 (available in 53 patients-range 4.6–21 mcg/ml). Twenty six patients were converted to the same dose and one patient took a mixture of LTG-XR and LTG-IR at the same total daily dose, while 21 had their dose slightly increased and 7 had their dose slightly decreased due to adverse effects. The mean serum level after conversion was 11.8 (available in 49 patients-range 2.6–21.2 mcg/ml). As a result of the conversion, 26 patients (47%) experienced >50% reduction in seizure frequency. There was a 46% median reduction in seizure frequency overall. Seven patients reported improvement in adverse effects.ConclusionA conversion from LTG-IR to LTG-XR can help improve seizure control in some individuals with drug-resistant epilepsy, in addition to improving tolerability. While it is indicated in individuals experiencing peak adverse effects, it should also be considered in patients who have received incomplete seizure control from LTG-IR.     

Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is a condition characterized by an imbalance between excitation and inhibition in the temporal lobe. Hallmarks of this change are axon sprouting and accompanying synaptic reorganization in the temporal lobe. Synthetic and endogenous cannabinoids have variable therapeutic potential in treating intractable temporal lobe epilepsy, in part because cannabinoid ligands can bind multiple receptor types. This study utilized in vitro electrophysiological methods to examine the effect of transient receptor potential vanilloid type 1 (TRPV1) activation in dentate gyrus granule cells in a murine model of TLE. Capsaicin, a selective TRPV1 agonist had no measurable effect on overall synaptic input to granule cells in control animals, but significantly enhanced spontaneous and miniature EPSC frequency in mice with TLE. Exogenous application of anandamide, an endogenous cannabinoid that acts at both TRPV1 and cannabinoid type 1 receptors (CB1R), also enhanced glutamate release in the presence of a CB1R antagonist. Anandamide reduced the EPSC frequency when TRPV1 were blocked with capsazepine. Western blot analysis of TRPV1 receptor indicated protein expression was significantly greater in the dentate gyrus of mice with TLE compared with control mice. This study indicates that a prominent cannabinoid agonist can increase excitatory circuit activity in the synaptically reorganized dentate gyrus of mice with TLE by activating TRPV1 receptors, and suggests caution in designing anticonvulsant therapy based on modulating the endocannabinoid system.     

Anticonvulsant efficacy of antihistamine cyproheptadine in rats exposed to the chemical warfare nerve agent soman

Organophosphate compounds, such as soman and sarin, are highly toxic chemical warfare nerve agents that cause a build-up of acetylcholine in synapses and neuromuscular junctions. Current therapies aim to prevent seizures and protect against brain injury following exposure. The present study was designed to evaluate the effectiveness of the antihistamine cyproheptadine in improving survival and controlling seizures in rats exposed to soman. Rats were pretreated with the oxime reactivator HI-6 (125 mg/kg, ip) 30 min prior to soman exposure (225 μg/kg, sc) and then treated with atropine methylnitrate (AMN, 2.0 mg/kg, im) 1 min after soman. Cyproheptadine (10, 13, 16 or 20 mg/kg, ip) was given at one of three time points: 1 min after soman intoxication, at the onset of soman-induced seizures or 5 min after seizure onset. Control animals were exposed to soman and given an equivalent volume of sterile water instead of cyproheptadine. The incidence of seizures, mortality, neuron counts, neuropathology and apoptosis in specific regions of the brain were evaluated. In animals given HI-6 and AMN the incidence of soman-induced seizure and mortality rate within the first 24 h were 100%. When cyproheptadine was given at a dose of 13 or 20 mg/kg 1 min after soman exposure, the incidence of seizures was reduced from 100% to 13% and 30%, respectively. In addition, cyproheptadine given at 1 min after soman exposure increased the survival rate to 100% regardless of dose. When cyproheptadine was administered at seizure onset, seizures were terminated in 100% of the animals at doses above 10 mg/kg. The survival rate with cyproheptadine treatment at the onset of seizure was ≥83%. Seizures terminated in ≥75% of the animals that received cyproheptadine 5 min after soman-induced seizure onset. When given at 5 min after seizure onset the survival rate was 100% at all tested doses of cyproheptadine. The neuropathology scores and the number of TUNEL positive cells in the brain regions examined decreased at all time points and cyproheptadine doses tested. These observations indicate that cyproheptadine treatment can effectively control seizures, improve survival, reduce seizure duration and reduce the number of dying cells in the brain following soman exposure.     

Epilepsy: A Clinical Overview

The diagnosis and treatment of seizures and epilepsy is a common task of the physician. Approximately 1 in 10 people will have a seizure during their lifetime. Epilepsy is the tendency to have unprovoked seizures. Epilepsy is the fourth most common neurological disorder and affects 1 in 26 people in the United States and 65 million people worldwide. Evaluation of a patient presenting with a seizure involves excluding an underlying neurologic or medical condition, classifying the seizure type and determining if the patient has epilepsy. Proper treatment requires accurate diagnosis of the epilepsy type and syndrome and use of a medication that is effective and without adverse effects. Most patients can achieve complete seizure control with medication, but if medication is unsuccessful, surgical treatment can be an option. Special situations in the care of people with epilepsy include status epilepticus, women with epilepsy, the older adult, and safety issues.     

发热感染相关性癫痫综合征研究进展北大核心CSCD

发热感染相关性癫痫综合征是最严重、罕见的癫痫性脑病之一,常影响既往健康且发育正常的学龄期儿童,前驱非特异性感染数天后出现逐渐加重的惊厥发作,并迅速进展为惊厥持续状态,其病因及发病机制不明,缺乏特定生物学标志物,治疗效果较差,但早期识别、合理治疗有助于改善预后。     

Modulation in time of the interictal spiking pattern related to epileptic seizures

ObjectiveTo test the hypothesis that significant changes in the occurrence of interictal epileptiform electroencephalography (EEG) discharges (EDs) are associated with seizures: while some EDs are pro-convulsive, increasing at seizure-occurrence, others are protective, showing decrease related to seizures.MethodsWe analyzed 102 consecutive, long-term video-EEG monitoring sessions, from 98 patients. Using a semi-automated spike-detection method, we quantified the occurrence of EDs, grouped according to their location and morphology (clusters) and we constructed graphical representation of data, showing changes in time of the spiking patterns (spike-histograms). We compared the spike-histograms with the time-points of the seizures (pre-, peri- and postictal changes).ResultsTotally 179 ED-clusters were identified. Modulation of the spiking pattern, associated with seizures, was observed in 66 clusters (37%), from 47 patients (48%). Most of these changes (40 clusters; 61%) were related to increase in the spiking-pattern.ConclusionsChanges in spiking-pattern were associated with more than one third of the EDs. Both increasing and decreasing patterns were observed.SignificanceEDs are more often pro-convulsive, with increasing spiking patterns associated with seizures. However, in more than one third of the ED clusters modulated by seizures, the spiking pattern decreased, raising the possibility of an anticonvulsive function of these discharges.     

Delta oscillation underlies the interictal spike changes after repeated transcranial direct current stimulation in a rat model of chronic seizures

BackgroundTranscranial direct current stimulation (tDCS) provides a noninvasive polarity-specific constant current to treat epilepsy, through a mechanism possibly involving excitability modulation and neural oscillation.ObjectiveTo determine whether EEG oscillations underlie the interictal spike changes after tDCS in rats with chronic spontaneous seizures.MethodsRats with kainic acid-induced spontaneous seizures were subjected to cathodal tDCS or sham stimulation for 5 consecutive days. Video-EEG recordings were collected immediately pre- and post-stimulation and for the subsequent 2 weeks following stimulation. The acute pre-post stimulation and subacute follow-up changes of interictal spikes and EEG oscillations in tDCS-treated rats were compared with sham. Ictal EEG with seizure behaviors, hippocampal brain-derived neurotrophic factor (BDNF) protein expression, and mossy fiber sprouting were compared between tDCS and sham rats.ResultsInterictal spike counts were reduced immediately following tDCS with augmented delta and diminished beta and gamma oscillations compared with sham. Cathodal tDCS also enhanced delta oscillations in normal rats. However, increased numbers of interictal spikes with a decrease of delta and theta oscillations were observed in tDCS-treated rats compared with sham during the following 2 weeks after stimulation. Resuming tDCS suppressed the increase of interictal spike activity. In tDCS rats, hippocampal BDNF protein expression was decreased while mossy fiber sprouting did not change compared with sham.ConclusionsThe inverse relationship between the changes of delta oscillation and interictal spikes during tDCS on and off stimulation periods indicates that an enhanced endogenous delta oscillation underlies the tDCS inhibitory effect on epileptic excitability.