Ongoing Seizure Activity Research Articles

Case Series: Continuous electroencephalographic monitoring of status epilepticus in dogs and cats: 10 patients (2004–2005)

AbstractObjective – To describe the use of continuous electroencephalographic (EEG) monitoring for management of status epilepticus (SE) in dogs and cats.Design – Retrospective study.Setting – University teaching hospital.Animals – Ten patients (7 dogs, 3 cats) with SE of differing etiology (idiopathic epilepsy, n=3; toxicity, n=4; meningoencephalitis, n=2; undefined, n=1).Interventions – The EEG was recorded continuously from 5 stainless‐steel needle electrodes inserted SC. Animals were treated with diazepam and phenobarbital followed by either propofol (n=3) or pentobarbital (n=7) as a continuous rate of infusion.Measurements and Main Results – Clinical seizures stopped after induction of anesthesia in each animal. The EEG, however, still showed distinct epileptiform patterns (spikes, polyspikes) in all animals. Paroxysms were suppressed by increasing the infusion rate of either pentobarbital or propofol. A burst‐suppression pattern was achieved in 5 animals. EEG epileptiform activity reappeared in 4 animals when attempting to taper the dose after >6 hours of anesthesia. This was interpreted as ongoing EEG seizure activity and an increased risk for clinical seizures, and the anesthetic dosage was adjusted accordingly.Conclusion – Continuous EEG monitoring appears to be a useful tool for therapeutic monitoring of SE in dogs and cats. It allows the detection of EEG seizures without the appearance of clinical seizures. Further investigations with blinded investigators and homogeneous animal groups to define therapeutic endpoints are warranted.

Efferent and afferent vagal actions on cortical blood flow and kainic acid-induced seizure activity in urethane anesthetized rats

Autonomic dysfunction during seizures can induce bradyarrhythmia via efferent vagal overactivity. We studied cardiovascular, brain blood flow, and electroencephalographic consequences of vagal stimulation during seizures in rats. Efferent vagal stimulation reduced seizure activity, completely suppressing it at high frequencies, by reducing heart rate, arterial pressure, and cortical blood flow. Afferent vagal activation was more variable, and the highest stimulation frequencies also appeared to reduce cortical blood flow. We conclude that efferent vagal activity can arrest ongoing seizure activity by ultimately decreasing hippocampal blood flow. Afferent vagal activity (which does not occur during seizures) may have a similar action.

How useful is EEG and EEG monitoring in the acutely ill and how to interpret it?

How useful is EEG and EEG monitoring in the acutely ill and how to interpret it?

Seizure elements and seizure element transitions during tonic–clonic seizure activity in the synapsin I/II double knockout mouse: A neuroethological description

Inactivation of genes for the synaptic terminal proteins synapsin I and synapsin II leads to development of epileptic seizures in mice (Syn-DKO mice) in which no other behavioral abnormalities or any gross anatomical brain deformities have been reported. In humans, mutated synapsin I is associated with epilepsy. Thus, the Syn-DKO mouse might model human seizure development. Here we describe a neuroethological analysis of behavioral elements and relationships between these elements during seizures in Syn-DKO mice. The seizure elements belong to one of three clusters each characterized by specific patterns of activity: truncus-dominated elements, myoclonic elements, and running-fit activity. The first two clusters, constituting the majority of seizural activity, evolve quite differently during ongoing seizure activity. Whereas truncus-dominated elements unfold in a strict sequence, the myoclonic elements wax and wane more independently, once myoclonic activity has started. These differences may point to neurobiological mechanisms relevant to both rodent and human epilepsies.

Dynamics of Evoked Local Field Potentials in the Hippocampus of Epileptic Rats With Spontaneous Seizures

A change in neuronal network excitability within the hippocampus is one of the hallmarks of temporal lobe epilepsy (TLE). In the dentate gyrus (DG), however, neuronal loss and mossy fiber sprouting are associated with enhanced inhibition rather than progressive hyperexcitability. The aim of this study was to investigate how alterations in excitability take place in association with spontaneous seizures expressed in the DG before, during, and after a seizure. For this purpose, we used freely moving rats that had developed spontaneous seizures after a kainate-induced status epilepticus (SE). Continuous EEG was recorded in the DG during several days along with local field potentials (LFPs) that were evoked every 15-30 s by applying paired-pulse stimuli to the angular bundle. Input-output relations showed increased paired pulse depression in epileptic compared with control rats, suggesting a rather strong inhibition in the DG during the interictal state. A characteristic pattern of changes in intrinsic excitability was observed during the ictal period: an increase in the population spike (PS) amplitude, mostly during the early phase of a seizure and often followed by a decrease of the main evoked potential amplitude. The paired-pulse extracellular postsynaptic potential (fEPSP) ratio increased during the seizure and did slowly recover to preictal levels after the seizure ended. Although clear changes in excitability occurred during and after seizure activity, changes of LFP parameters were more subtle before seizure onset; a significant reduction of LFP and PS amplitudes was observed that started 1-2 min in advance in approximately 33% of the cases; in approximately 18%, an increase of LFP/PS amplitude was observed; in the other cases, no significant change was observed. Taken together, these results provide evidence that, in this experimental model, DG physiology is more likely to follow the already ongoing seizure activity rather than to contribute to its generation.

Ketamine successfully terminates malignant status epilepticus

A 22-year-old woman with mitochondriopathy and pre-existing epilepsy developed status epilepticus (SE) not responding to benzodiazepines, phenytoin, thiopental, and propofol. SE was terminated within days after supplemental administration of continuous ketamine infusion to midazolam. The case suggests strong anticonvulsant properties of ketamine even after failure of GABAergic anesthetics, likely due to increased NMDA receptor expression with ongoing seizure activity. Thus, ketamine should be incorporated into therapeutic regimens for difficult-to-treat SE.

Purpura fulminans due to imported falciparum malaria

Sir, Purpura fulminans (PF) is usually associated with meningococcemia or invasive pneumococcal infection. Here, we report a case of PF due to imported Plasmodium falciparum malaria in an asplenic patient. A 51-year-old Caucasian man was admitted to the Emergency Department because of fever and confusion. He had just returned 13 days earlier after a long stay in Madagascar. He had a history of posttraumatic splenectomy in his childhood. He had no antimalarial chemoprophylaxis. He had fever and asthenia 4 days before the admission, and took one dose of dirithromycin orally. Once in the Emergency Department, he was confused, his blood pressure was 100/ 60 mmHg, and his temperature 38.7 C. A peripheral blood smear revealed erythrocytes infected by P. falciparum. A treatment with intravenous quinine was initiated without loading dose. The patient was transferred to the ICU where he presented generalized tonic–clonic seizure and coma, leading to intubation for mechanical ventilation and sedation with midazolam and fentanyl. At this point, he was severely shocked (blood pressure 60/40 mmHg) and anuric. A physical examination showed cold extremities and extensive necrotic and purpuric skin lesions on his hands and legs. There was no focal neurological deficit or neck stiffness. All peripheral pulses were palpable. The rest of the examination showed no abnormalities. Parasitemia was 12%. Arterial blood gas measurements showed: pH 7.21; pCO2 31 mmHg; bicarbonate level 12 mmol/L and PaO2/FiO2 ratio 315. Laboratory studies revealed the following values: blood urea nitrogen 24 mmol/L; serum creatinine 437 lmol/L; lactates 6.5 mmol/L; serum bilirubin166 lmol/L; normal glycemia. Other laboratory test results are displayed in Table 1. He received intravenous fluid, norepinephrin, low dose hydrocortisone, intravenous quinine, ceftriaxone after blood cultures, and renal replacement by continuous venovenous hemofiltration (ultrafiltration rate at 33 mL/kg per h). CT scan of the brain showed a subarachnoid hemorrhage. An electroencephalogram revealed no ongoing seizure activity. Vitamin K and platelets transfusion were given for 3 days, and fibrinogen and antithrombin concentrates on day 5. All blood cultures remained negative. The purpura progressed to skin necrosis of the two forefeet. The patient’s condition improved progressively, but his two forefeet were amputated 2 months later and the patient was discharged to a rehabilitation unit. Secondary hematological explorations revealed no deficiency of protein C, protein S, and antithrombin. The most likely diagnosis was falciparum malaria complicated by disseminated intravascular

Standard antiepileptic drugs fail to block epileptiform activity in rat organotypic hippocampal slice cultures

Earlier studies had demonstrated that tonic-clonic seizure-like events (SLEs) resembling electrographic correlates of limbic seizures in animals and humans can be induced in organotypic hippocampal slice cultures (OHSCs). We have explored OHSCs for their suitability to serve as in vitro models of limbic seizures for studying seizure mechanisms and screening new antiepileptic compounds. OHSCs were cultivated according to the interface method. Neuronal activity and extracellular potassium concentration were recorded under submerged conditions. SLEs were induced by lowering magnesium concentration or by applying the potassium channel blocker 4-aminopyridine. The effects of standard antiepileptic drugs (AEDs), carbamazepine, phenytoin, valproic acid, clonazepam, diazepam and phenobarbital sodium on SLEs were analysed. In more than 93% of OHSCs, AEDs did not prevent the induction of SLEs or stop ongoing seizure activity even when toxic concentrations were applied. This pharmacoresistance was independent of the method of seizure provocation, postnatal age at explantation (P2-P10) and cultivation time in vitro (2 months). SLEs were reversibly blocked by glutamate antagonists or the GABA(A)-agonist muscimol. We present a simple to establish in vitro model of tonic-clonic SLEs that is a priori pharmacoresistant and thus has an advantage over animal models of pharmacoresistant seizures in which responders and non-responders can be sorted out only after an experiment. OHSCs could be suitable for exploring mechanisms of pharmacoresistant seizures and be used for the identification of new anticonvulsive compounds eventually effective in drug refractory epilepsy.

Increasing synchronization may promote seizure termination: Evidence from status epilepticus

Objective To test whether increasing synchronization of neuronal activity might be causally related to seizure termination. Methods Neuronal synchronization was assessed by the relative changes of the eigenvalue spectrum of the equal-time correlation matrix computed from a short window sliding along multi-channel EEGs, recorded with either intracranial or surface electrodes. Results Synchronization dynamics of six status epilepticus EEG recordings from six patients were assessed. In all six recordings EEG synchronization fluctuated around relatively low levels during ongoing epileptiform activity. Synchronization only persistently increased before, or in one case, at the end of status epilepticus. Ongoing seizure activity stopped without pharmacological intervention in one patient. In four of the five other cases, the persistent increase of synchronization followed administration of anticonvulsant drugs. Conclusions Our findings support the hypothesis that increasing synchronization of neuronal activity may be considered as an emergent self-regulatory mechanism for seizure termination. Significance The traditional concept is challenged that increasing neuronal synchronization during epileptic seizures is always pathological and should be suppressed. On the contrary, our findings imply that therapeutic interventions to increase synchronization during seizures might be beneficial.

Studies of stimulus parameters for seizure disruption using neural network simulations

A large scale neural network simulation with realistic cortical architecture has been undertaken to investigate the effects of external electrical stimulation on the propagation and evolution of ongoing seizure activity. This is an effort to explore the parameter space of stimulation variables to uncover promising avenues of research for this therapeutic modality. The model consists of an approximately 800 mum x 800 mum region of simulated cortex, and includes seven neuron classes organized by cortical layer, inhibitory or excitatory properties, and electrophysiological characteristics. The cell dynamics are governed by a modified version of the Hodgkin-Huxley equations in single compartment format. Axonal connections are patterned after histological data and published models of local cortical wiring. Stimulation induced action potentials take place at the axon initial segments, according to threshold requirements on the applied electric field distribution. Stimulation induced action potentials in horizontal axonal branches are also separately simulated. The calculations are performed on a 16 node distributed 32-bit processor system. Clear differences in seizure evolution are presented for stimulated versus the undisturbed rhythmic activity. Data is provided for frequency dependent stimulation effects demonstrating a plateau effect of stimulation efficacy as the applied frequency is increased from 60 to 200 Hz. Timing of the stimulation with respect to the underlying rhythmic activity demonstrates a phase dependent sensitivity. Electrode height and position effects are also presented. Using a dipole stimulation electrode arrangement, clear orientation effects of the dipole with respect to the model connectivity is also demonstrated. A sensitivity analysis of these results as a function of the stimulation threshold is also provided.

Prehospital Intranasal Midazolam for the Treatment of Pediatric Seizures

The local emergency medical services (EMS) council implemented a new pediatric treatment protocol using a Mucosal Atomization Device (MAD) to deliver intranasal (IN) midazolam for seizure activity. We sought to compare outcomes in seizing pediatric patients treated with IN midazolam using a MAD (IN-MAD midazolam) to those treated with rectal (PR) diazepam, 18 months before and after the implementation of the protocol. Of 857 seizure patients brought by EMS to our emergency department (ED), 124 patients (14%) had seizure activity in the presence of EMS and were eligible for inclusion in this study. Of the 124 patients eligible for this study, 67 patients (54%) received no medications in the prehospital setting, 39 patients (32%) were treated with IN-MAD midazolam, and 18 patients (15%) were treated with PR diazepam. Median seizure time noted by EMS was 19 minutes longer for PR diazepam (30 minutes) when compared with IN-MAD midazolam (11 minutes, P = 0.003). Patients treated with PR diazepam in the prehospital setting were significantly more likely to have a seizure in the ED (odds ratio [OR], 8.4; confidence interval [CI], 1.6-43.7), ED intubation (OR, 12.2; CI, 2.0-75.4), seizure medications in the ED to treat ongoing seizure activity (OR, 12.1; CI, 2.2-67.8), admission to the hospital (OR, 29.3; CI, 3.0-288.6), and admission to the pediatric intensive care unit (OR, 53.5; CI, 2.7-1046.8). The IN-MAD midazolam controlled seizures better than PR diazepam in the prehospital setting and resulted in fewer respiratory complications and fewer admissions.

When benzodiazepines fail: How effective is second line therapy for status epilepticus in children?

To define the characteristics and management of children presenting to the ED of a major tertiary paediatric hospital with convulsive status epilepticus (CSE). To determine the timing and efficacy of therapeutic interventions in this group and to identify factors that influence the effectiveness of treatment. A retrospective audit of all children who presented to an ED of a tertiary paediatric hospital in CSE over a 3 year period. Thirty-seven cases were identified. Prehospital treatment had been administered in 51%. Uncomplicated seizure control was achieved in 30% with the combination of first and second line therapy. Rapid sequence induction (RSI) of anaesthesia was required in 70% for the control of ongoing seizure activity (21 cases) or to support severe respiratory depression (five cases). This requirement for RSI was increased to 85% in those with seizure duration in excess of 30 min and 89% of those who received prehospital treatment. Of those who required RSI, 35% were treated for periods in excess of 60 min before this intervention was performed. Standard second line anticonvulsant treatment was relatively ineffective in terminating seizures in children who presented in CSE not responsive to benzodiazepines. Failure to respond to prehospital treatment and prolonged seizure duration at presentation both predict poor therapeutic response. Third line treatment with RSI of anaesthesia is often delayed while waiting for second line treatment to work.

The Clinical Features, Diagnosis, and Prognosis of Nonconvulsive Status Epilepticus

Nonconvulsive status epilepticus (NCSE) is a state of ongoing seizure activity for at least 30 minutes, with cognitive or behavioral changes, but without convulsive clinical manifestations. It requires EEG for confirmation. It has been categorized into groups having focal or generalized EEG epileptic activity; and by etiology and level of consciousness (which predict outcome). Points of contention include the evolving definition of what constitutes NCSE, various reasons for a delayed, missed, or misidentified diagnosis, and the optimal management of these conditions.

Pharmacologic management of convulsive status epilepticus in childhood

The incidence of convulsive status epilepticus in children is approximately 20–50/100,000/year, and is an emergency requiring prompt medical intervention. Prolonged seizures lasting over 5 min are unlikely to stop spontaneously, and time-to-treatment influences treatment response. Prolonged seizures should thus be treated as early status epilepticus. Mortality and morbidity increase significantly with the length of ongoing seizure activity, especially after 60 min. Benzodiazepines remain the first-line drug therapy due to their rapid onset of action. Recent studies imply that buccal midazolam is more effective and easier to administer than rectal diazepam. Phenytoin/fosphenytoin and phenobarbital administered intravenously remain the second-line treatments of choice, whilst barbiturates and midazolam as intravenous anesthetics are used for third-line treatment. Electroencephalogram monitoring is essential to evaluate the electrophysiologic treatment response and depth of anesthesia, especially in refractory status epilepticus. In the future, more individualized protocols and pathways are needed in order to optimize treatment responses. Randomized clinical trials are needed to evaluate new treatment protocols, which should not only stop the seizures more effectively but also be safer and include some neuroprotective elements to halt the cascade of neuronal injury and minimize the risk for neurologic morbidity caused by the convulsive status epilepticus.

Time Course and Mapping of Cerebral Perfusion during Amygdala Secondarily Generalized Seizures

Measurement of local cerebral blood flow (LCBF) is routinely used to locate the areas involved in generation and spread of seizures in epilepsy patients. Because the spatial distribution and extent of ictal CBF depends on the epileptogenic network, but also on the timing of injection of tracer, we used a rat model of amygdala-kindled seizures to follow the time-dependent changes in the distribution of LCBF changes. Rats were implanted in the left amygdala and were fully kindled. LCBF was measured by the quantitative [(14)C]iodoantipyrine autoradiographic technique bilaterally in 35 regions. The tracer was injected at 30 s before seizure induction (early ictal), simultaneous with the application of stimulation (ictal), at 60 s after stimulation (late ictal), at the end of the electrical afterdischarge (early postictal), and at 6 min after the stimulation (late postictal). Rates of LCBF increased over control levels during the early ictal phase ipsilaterally in medial amygdala, frontal cortex, and ventromedian thalamus and bilaterally in the whole hippocampus, thalamic nuclei, and basal ganglia. During the ictal phase, all regions underwent hyperperfusion (81-416% increases). By 60 s after stimulation, rates of LCBF returned to control levels in most brain areas, despite ongoing seizure activity. At later times, localized foci of hypoperfusion were observed in hippocampus bilaterally, with a slight predominance in CA1 on the side of origin of the seizures. This study shows a rapid spread of activation from the stimulated amygdala bilaterally to numerous limbic, cortical, and subcortical structures. The largest hyperperfusion was recorded during the ictal period with tracer injections simultaneous with the stimulation. The unilateral site of origin of seizures led to minor asymmetrical and lateralized findings, merely at early ictal and late postictal times, whereas intermediate tracer injections induced bilateral changes. Only late postictal measurements allowed the identification of significant changes in focal structures: the hippocampus is known to play a critical role in the spread of limbic seizures.

Behavioral aspects of pediatric epilepsy syndromes

Apart from control of the seizures, two of the most important factors in determining how well a child with epilepsy progresses toward independence are cognition and behavior. The diagnosis of the correct epilepsy syndrome often provides information with regard to probability of good seizure control and intellectual outcome. However, relatively little has been published on the behavioral aspects of the various epilepsy syndromes. In West syndrome there is emerging evidence that early effective treatment might improve outcome in terms of both cognition and behavior. The work on this syndrome in children with tuberous sclerosis has demonstrated an association between temporal lobe tubers and autism. In Dravet syndrome, a variety of psychiatric disorders have been reported, including hyperactivity and autistic features. This is another epilepsy syndrome that tends to be resistant to treatment, implying that the prognosis has to be guarded. The behavioral problems reported with Lennox–Gastaut syndrome also include autistic features, as well as generally sluggish behavior. It is very likely that these characteristics largely reflect the effect of ongoing seizure activity. Autistic features, aggression, and hyperkinesis have been described with Landau–Kleffner syndrome. The behavior may improve dramatically with appropriate medical treatment or after multiple subpial transection. Although the syndrome of benign partial seizures with centrotemporal or rolandic spikes is said to have a very good prognosis, it is becoming increasingly evident that behavioral problems such as concentration difficulties, tempers, hyperactivity, and impulsivity might occur. Juvenile myoclonic epilepsy has been associated with very variable behavioral traits, sometimes with immature personality features and poor social adjustment suggesting frontal lobe dysfunction. Because many of the reports of behavioral disturbance associated with epilepsy syndromes are anecdotal and do not include validated measures of behavior it would be unwise to draw firm conclusions from them at this stage. Carefully conducted prospective studies, paying particular attention to any behavioral improvements that occur with successful treatment of the epilepsy, are required.

Abnormalities in hippocampi remote from the seizure focus: a T2 relaxometry study.

The aim of this study was to determine whether partial epilepsy is associated with abnormalities in hippocampi that are not the primary seizure focus. As hippocampal T2 relaxometry is useful for identifying abnormalities that are not obvious on visual assessment of MRI, this was the method employed. Of 457 consecutive children and young adults from whom T2 relaxometry data were obtained, 96 had well characterized partial epilepsy and were enrolled, along with 27 control subjects. The patients were divided on the basis of clinical, video-EEG and visual MRI assessment into three groups: (i) those with temporal lobe epilepsy (TLE) and mesial temporal sclerosis (MTS) (MTS-TLE); (ii) lesional TLE (l-TLE); or (iii) extratemporal epilepsy (ETE). There was a significant and similar prolongation of T2 relaxation time identified in hippocampi remote from the seizure focus in all patient groups when compared with control subjects. In the non-sclerotic hippocampus of patients with MTS, T2 relaxation time was prolonged by a mean of 3.3 ms [95% confidence interval (CI), 0.8-5.9 ms; P = 0.01], patients with l-TLE had prolongation of T2 relaxation time by a mean of 4.3 ms (95% CI, 1.8-7.1 ms; P = 0.001) and those with ETE had prolongation of T2 relaxation time by a mean of 3.7 ms (95% CI, 1.6-6.6 ms; P = 0.006) compared with control subjects after adjustment for age. Unsurprisingly, in patients with MTS-TLE, T2 relaxation time in the sclerotic hippocampus was prolonged by a mean of 19 ms (95% CI = 14.6-22.4 ms; P < 0.001). The similarity in the extent of prolongation of T2 relaxation time in hippocampi that are not the primary epileptogenic focus, the wide variety of structural associations and the varied sites of epileptogenic foci, considered together, suggest that the abnormalities are likely to be caused by ongoing seizure activity rather than by underlying aetiology or site of epileptogenic focus.

Intramuscular diazepam pharmacokinetics in soman-exposed guinea pigs.

Intramuscular (i.m.) diazepam is included by the US military as an anticonvulsant in the standard therapeutic regimen for organophosphorus nerve agent intoxication. In this study we investigated the pharmacokinetics of diazepam after i.m. administration while monitoring pharmacodynamic (electroencephalogram, EEG) data in soman-exposed guinea pigs. Prior to experiments the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered pyridostigmine (0.026 mg x kg(-1) i.m.) 30 min prior to soman (56 microg x kg(-1), 2 x LD50; subcutaneously, s.c.), which was followed in 1 min by atropine sulfate (2 mg x kg(-1) i.m.) and pralidoxime chloride (25 mg x kg(-1) i.m.). All animals receiving this regimen developed seizure activity. Diazepam (10 mg x kg(-1) i.m.) was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure terminated or not terminated at 30 min after diazepam. Serial blood samples were obtained from each animal. Diazepam (10 mg x kg(-1) i.m.) terminated seizure activity in 52% of the animals within 30 min. The pharmacokinetics were characterized by a one-compartment model with first-order absorption and elimination. The maximum plasma concentrations (Cmax) were 991 and 839 ng x ml(-1) for seizure terminated and not terminated, respectively. Mean plasma concentrations of diazepam were significantly different (P < 0.05) for seizure terminated vs not terminated groups at 30 min. The plasma Cmax in seizure-terminated animals in this study is similar to the minimum range of plasma diazepam (200-800 ng x ml(-1)) reported to suppress seizure activity in humans. It has been reported in an earlier study that the minimum effective i.m. dose (0.1 mg x kg(-1)) required to prevent soman-induced convulsions in Rhesus monkeys produces a mean Cmax of 50 ng x ml(-1) for diazepam. The data from our current study suggest that a higher dose (and corresponding Cmax) is necessary to terminate ongoing seizure activity.

RNA Editing at the Q/R Site for the Glutamate Receptor Subunits GLUR2, GLUR5, and GLUR6 in Hippocampus and Temporal Cortex from Epileptic Patients

Posttranscriptional editing of mRNA is a phenomenon that generates molecular heterogeneity and functional variety. With the intention to test if RNA editing plays a role in pathological processes, which contribute to seizure maintenance, we examined the ratio of the unedited (Q) to edited (R) form of the AMPA receptor subunit GluR2 and kainate receptor subunits GluR5 and GluR6 in the hippocampus and temporal cerebral cortex, both excised from patients with pharmacoresistant temporal lobe epilepsies. We compared the data with samples from nonepileptic human control tissue (autopsy tissue). The ratio of Q/R editing was analyzed by means of reverse transcription-polymerase chain reaction followed by a restriction enzyme assay. We found that the editing efficiency for the kainate receptor subunits GluR5 and GluR6 was significantly higher in temporal cortex than in normal controls. The alteration in GluR5 and GluR6 mRNA editing in the neocortical tissue may reflect an adaptive reaction of ongoing seizure activity to prevent excessive Ca2+ influx.

Reduction of Pentylenetetrazole-Induced Seizure Activity in Awake Rats by Seizure-Triggered Trigeminal Nerve Stimulation

Stimulation of the vagus nerve has become an effective method for desynchronizing the highly coherent neural activity typically associated with epileptic seizures. This technique has been used in several animal models of seizures as well as in humans suffering from epilepsy. However, application of this technique has been limited to unilateral stimulation of the vagus nerve, typically delivered according to a fixed duty cycle, independently of whether ongoing seizure activity is present. Here, we report that stimulation of another cranial nerve, the trigeminal nerve, can also cause cortical and thalamic desynchronization, resulting in a reduction of seizure activity in awake rats. Furthermore, we demonstrate that providing this stimulation only when seizure activity begins results in more effective and safer seizure reduction per second of stimulation than with previous methods. Seizure activity induced by intraperitoneal injection of pentylenetetrazole was recorded from microwire electrodes in the thalamus and cortex of awake rats while the infraorbital branch of the trigeminal nerve was stimulated via a chronically implanted nerve cuff electrode. Continuous unilateral stimulation of the trigeminal nerve reduced electrographic seizure activity by up to 78%, and bilateral trigeminal stimulation was even more effective. Using a device that automatically detects seizure activity in real time on the basis of multichannel field potential signals, we demonstrated that seizure-triggered stimulation was more effective than the stimulation protocol involving a fixed duty cycle, in terms of the percent seizure reduction per second of stimulation. In contrast to vagus nerve stimulation studies, no substantial cardiovascular side effects were observed by unilateral or bilateral stimulation of the trigeminal nerve. These findings suggest that trigeminal nerve stimulation is safe in awake rats and should be evaluated as a therapy for human seizures. Furthermore, the results demonstrate that seizure-triggered trigeminal nerve stimulation is technically feasible and could be further developed, in conjunction with real-time seizure-predicting paradigms, to prevent seizures and reduce exposure to nerve stimulation.