Termination Of Status Epilepticus Research Articles

The efficacy and safety of ketamine in the treatment of super-refractory status epilepticus: a systematic review.

Ketamine, as an anesthetic, has been considered for terminating status epilepticus (SE); however, due to the urgency and severity of the condition, there are currently no randomized controlled trials internationally assessing the efficacy of ketamine for treating super-refractory status epilepticus. Similarly, there appears to be a lack of systematic reviews addressing this topic in the literature. Therefore, this systematic review aims to explore the effectiveness and safety of ketamine for terminating super-refractory status epilepticus. We conducted a systematic search on PubMed, EMBASE, and Web of Science databases. Manuscripts unrelated to the research on super-refractory status epilepticus were excluded, as were manuscripts published in non-English languages. The quality assessment and risk of bias were evaluated using the MINORS criteria. Data extraction was limited to qualitative synthesis due to the unsuitability of the data for meta-analysis. Out of 782 studies retrieved from electronic databases, 11 met the inclusion criteria. Among them, 10 studies were retrospective, and 1 study was prospective. Patient data for inclusion were sourced from the case registries of the researchers' respective hospitals. Across all included studies, the administration of ketamine significantly reduced the duration of status epilepticus and demonstrated higher safety compared to patients not receiving ketamine treatment for super-refractory status epilepticus. Additionally, early administration of ketamine correlated with improved treatment outcomes. The risk of bias across all studies was deemed low. This systematic review suggests that ketamine may be a feasible treatment option for super-refractory status epilepticus. However, given the critical nature of super-refractory status epilepticus, clinicians should prioritize its termination over evaluating the efficacy of specific medications, ensuring patient safety remains paramount. If feasible in real-world medical settings, future research should focus on designing randomized controlled trials to observe the specific efficacy and mechanisms of ketamine. Careful validation is necessary before considering ketamine as a first-line treatment for super-refractory status epilepticus.

Desirability of Outcome Ranking for Status Epilepticus: A Benefit-Risk Approach to Design and Analyses of Clinical SE Trials.

Most clinical trials of treatment efficacy evaluate benefits and harms separately. Investigators generally rate the primary outcome of a trial with a binary outcome measure and consider harms separately as adverse events. This approach fails to recognize finer gradations of patient response, correlations between benefits and harms, and the overall effects on individual patients. For example, in status epilepticus trials, efficacy is often defined as the absence of clinically apparent seizures with recovery of consciousness. Such an efficacy outcome fails to recognize that some causes of status epilepticus, such as subarachnoid hemorrhage or stroke, may not be accompanied by return of consciousness, and the need to intubate a patient may be classified as treatment failure even if status was successfully terminated. The Desirability of Outcome Ranking (DOOR) method uses a different approach. The DOOR method involves comparing the experiences of trial participants in different treatment arms by the desirability of the overall patient outcome. Using status epilepticus treatment as an example, a patient who experiences successful termination of status epilepticus but with major side effects would have a less desirable outcome than a patient with treatment success and minor side effects, who in turn would have a less desirable outcome than a patient with treatment success but no side effects. This is a patient-centered approach because it considers treatment efficacy in the context of the costs borne by the patient, for example, toxicity in achieving efficacy. Thus, DOOR considers both the benefits and harms to individual patients in assessing the outcome of a clinical trial. In this article, we present the rationale for the use of DOOR, the issues involved in the development of and statistical analyses of an ordinal outcome, and an example of the potential application of the DOOR method to a clinical trial of convulsive status epilepticus.

Status Epilepticus in Children: Experience in a Portuguese Tertiary Hospital

Purpose: Status epilepticus (SE) is a life-threatening neurological emergency, frequently diagnosed in pediatric patients. We aimed to characterize our pediatric cases of SE in an 11-year period according to the 2015 International League Against Epilepsy report. Methods: Clinical electronic records were retrospectively reviewed. All pediatric SE cases admitted from January 2010 to December 2020 were included, excluding neonates. SE was considered refractory if it persisted despite the administration of two appropriate antiseizure medications at acceptable doses.Results: We included 102 episodes, 55 (53.9%) in boys. The median age was 2.5 years (interquartile range, 1.3 to 5.0). Most episodes were classified as SE with prominent motor features (92.2%), and the most frequent etiological classification was acute symptomatic cause (84.3%). A benzodiazepine was used as the first-line antiseizure medication in 99 (97%) cases, of which diazepam was preferred (93%). The preferred second-line medication was phenytoin (65.7%). Midazolam was the most frequently responsible for termination of SE when given in a continuous infusion (47%). Episodes of SE were classified as refractory in 81 (79.4%) cases. Episodes of >60 minutes were more frequent in patients diagnosed with epilepsy (<i>P</i>=0.036), focal motor SE (<i>P</i><0.001), and non-convulsive SE (<i>P</i>=0.037). The in-hospital mortality rate was 2.9%. Conclusion: Most of our findings are in accord with the current literature. Epilepsy, non-convulsive SE, and focal motor SE were associated with prolonged duration (>60 minutes), which reinforces the significance of the underlying neurological disease and semiological standardization in pediatric SE.

Inflammation as Treatment Target for Status Epilepticus.

Status epilepticus (SE) is a serious neurological disease that manifests as prolonged seizures that last more than 5 minutes and between such episodes, patients do not regain consciousness. It can result in cognitive defects, brain damage, or even death. It is commonly known that one of the causes can be an inflammatory process, but here we will focus on inflammation as a result of new onset refractory status epilepticus and, related to this, new promising forms of SE treatment. Particular emphasis has been focused on new-onset refractory status epilepticus (NORSE). Based on public research databases, drugs with anti-inflammatory activity - commonly used in different spheres of medicine - have been reviewed as potentially treating status epilepticus. There is seizable clinical research suggesting that drugs that decrease inflammatory processes might be effective in terminating status epilepticus. There is growing evidence showing that adding anti-inflammatory drugs to basic antiepileptic treatment enhances the efficiency of the therapeutic process, with special potential in NORSE cases.

Complications of Influenza A or B Virus Infection in Individuals With SCN1A-Positive Dravet Syndrome.

To determine the frequency and spectrum of complications of influenza infection in individuals with SCN1A-positive Dravet syndrome (SCN1A-DS). Individuals with SCN1A-DS were identified in neurologists' care at 2 hospitals in Melbourne, Australia, with additional searches of EEG databases, the Victorian PAEDS FluCan influenza database, and the University of Melbourne Epilepsy Genetics Research Program database. Medical records were searched and families questioned to identify individuals who had an influenza infection; reported infections were confirmed by pathology report. For these individuals, we obtained baseline clinical characteristics and clinical details of the influenza infection. Twenty-one of 82 individuals (26%) had 24 documented influenza infections (17 influenza A and 7 influenza B) at age 0.5-25 years (median 4 years). All presented to hospital, 18/24 (75%) for status epilepticus or seizure exacerbations. Recovery was prompt in 18/24 (75%) infections, delayed but complete in 1/24 (4%) and incomplete in 5/24 (21%). One child died from influenza pneumonia, and long-term neurologic sequelae were seen with 4 infections. These individuals were poorly responsive after termination of status epilepticus. Brain imaging in 2 showed cerebral edema and 1 also having imaging features of laminar necrosis. All have ongoing neurologic deficits compared with their baseline, 1 having profound global impairment. Our data show that patients with SCN1A-DS are highly susceptible to neurologic complications during and severe sequelae after influenza infection, including moderate to severe persistent neurologic impairments and death. Safe administration of the seasonal influenza vaccine should be prioritized for this population.

Effect of morphine administration after status epilepticus on epileptogenesis in rats

IntroductionMorphine is widely used in patients and has been reported to alter seizure threshold, but its role in the development of epilepsy is unknown. In this study, role of morphine administration in the development of epilepsy using the status epilepticus (SE) model was determined in rats. MethodsRats experiencing SE with lithium-pilocarpine (LiP) were randomized into four groups– saline, morphine low dose (5 mg/kg, s.c.), morphine high dose (5–20 mg/kg, s.c.), and naloxone (1 mg/kg, s.c.). Treatments were started 90 min after termination of SE and repeated twice daily for next three days. Rats were video monitored daily for 21 days to determine onset and frequency of spontaneous convulsive seizures (SS). ResultsMorphine in low doses increased frequency of SS (1.51 ± 0.15 vs LiP 0.60 ± 0.12 seizures/rat/day, p-value = 0.0026) and seizures occurred during handling (SDH) (0.08 ± 0.02 vs LiP control 0.01 ± 0.01) (p-value = 0.0018). In high doses, no significant change in SS and SDH was found as compared to LiP. No effect of morphine on the onset of SS and percentage of rats experienced SS was found. No effect of naloxone per se was found on SS. ConclusionMorphine administration after SE does not affect epileptogenesis as no change in the onset of SS and percentage of rats experiencing SS was found. However, it might alter the susceptibility and frequency of SS. As no other study is available with a similar finding, it needs further evaluation.

Real-World Midazolam Use and Outcomes With Out-of-Hospital Treatment of Status Epilepticus in the United States

Guidelines recommend 10-mg intramuscular midazolam as the first-line treatment option for status epilepticus. However, in real-world practice, it is frequently administered intranasally or intravenously and is dosed lower. Therefore, we used conventional and instrumental variable approaches to examine the effectiveness of midazolam in a national out-of-hospital cohort. This retrospective cohort study of adults with status epilepticus used the ESO Data Collaborative research dataset (January 1, 2019, to December 31, 2019). The exposures were the route and dose of midazolam. We performed hierarchical logistic regression and 2-stage least squares regression using agency treatment patterns as an instrument to examine our outcomes, rescue therapy, and ventilatory support. There were 7,634 out-of-hospital encounters from 657 EMS agencies. Midazolam was administered intranasally in 20%, intravenously in 46%, and intramuscularly in 35% of the encounters. Compared with intramuscular administration, intranasal midazolam increased (risk difference [RD], 6.5%; 95% confidence interval [CI], 2.4% to 10.5%) and intravenous midazolam decreased (RD,-11.1%; 95% CI,-14.7% to-7.5%) the risk of rescue therapy. The differences in ventilatory support were not statistically significant (intranasal RD,-1.5%; 95% CI,-3.2% to 0.3%; intravenous RD,-0.3%; 95% CI,-1.9% to 1.2%). Higher doses were associated with a lower risk of rescue therapy (RD,-2.6%; 95% CI,-3.3% to-1.9%) and increased ventilatory support (RD, 0.4%; 95% CI, 0.1% to 0.7%). The instrumental variable analysis yielded similar results, except that dose was not associated with ventilatory support. The route and dose of midazolam affect clinical outcomes. Compared with intramuscular administration, intranasal administration may be less effective and intravenous administration more effective in terminating status epilepticus, although the differences between these and previous results may reflect the nature of real-world data as opposed to randomized data.

Reponse of second-line treatment in focal status epilepticus: A tertiary hospital experience

ObjectiveTo investigate the response to various antiseizure medications (ASMs) in the treatment of focal status epilepticus (SE) in the established phase, and the effect of administering several ASMs prior to sedation. MethodsAll SE cases in patients aged > 16 years treated with non-BZDs ASMs were prospectively collected in our centre from February 2011 to April 2019. In total, 281 episodes were analysed. ResultsMedian age at SE onset was 65.1 years; 47 % were focal motor and 53 % focal non-motor episodes. SE cessation was achieved in 79 % episodes with second-line drugs, whereas a third line (anesthetics) was required in 47 episodes. SE cessation was achieved in only 27 % with the first ASM, 48 % with the second, and 51 % with the third. Prompt resolution of the SE episode with a first or second ASM was associated with a better outcome than episodes requiring a larger number of drugs (p = 0.024). The first option in our sample was levetiracetam in 70 % of cases. Among the total of non-responding SE cases treated with levetiracetam as the first ASM option, 107 were subsequently given lacosamide (seizure cessation in 53.3 %) and 34 valproic acid (seizure cessation in 29.4 %) (p = 0.015). ConclusionOur findings further support the notion that early termination of SE with a first or second ASM confers a better functional outcome. The large difference in response between the first ASM and consecutive ones suggests that the sum of different ASMs might be the key to resolving focal SE.

Low Serum Pyridoxine Levels Worsen Seizure Control in Adult Epilepsy Patients.

Background: Vitamin B6 (pyridoxine) is an important cofactor in the process by which glutamic acid decarboxylase (GAD) converts the excitatory, pro-epileptogenic neurotransmitter, glutamate, into the inhibitory, anti-epileptogenic neurotransmitter, gamma-aminobutyric acid (GABA). This concept has been established in infants with pyridoxine-dependent epilepsy as well as adult patients with other epilepsy subtypes who presented with medication-resistant status epilepticus, with both patient groups experiencing cessation of seizure activity following pyridoxine administration. Given our knowledge of the role of vitamin B6 in the conversion of glutamate to GABA, its effect on seizure control in infants with specific epilepsy subtypes, reports of adult-onset seizures associated with vitamin B6 deficiency, and vitamin B6’s role in terminating status epilepticus in adult patients with other types of epilepsy, we suspect that low vitamin B6 levels in adult epilepsy patients may correlate with poor seizure control across all epilepsy subtypes. This study seeks to determine whether there is a relationship between pyridoxine levels and the level of seizure control in adults with epilepsy, regardless of their seizure type.Methods: After obtaining institutional review board approval, we prospectively enrolled 32 patients (age range: 25-57 years) with epilepsy who presented to our clinic. Patients who did not meet the study criteria or who were diagnosed with psychogenic non-epileptic seizures (PNES) were excluded from the study (n = 2). Patients were classified as well-controlled (WC) or poorly controlled (PC) based on the absence or presence of a seizure within the last three months, respectively. After classification as WC or PC, pyridoxine serum levels and anti-seizure medication (ASM) levels were drawn in that clinic visit, following patient consent. All patients were contacted regarding pyridoxine and serum ASM levels, and patients that were found to be deficient in pyridoxine were treated with appropriate supplementation. At the end of the recruitment period, we performed analyses to determine if there was a statistically significant relationship between PC status and serum pyridoxine levels.Results: Of 32 patients, two patients were diagnosed with psychogenic non-epileptic events and were subsequently excluded. Of 30 patients, 10 had PC epilepsy. Median (interquartile range) serum B6 levels were 35.8 (26.8-54.2) in patients with WC epilepsy and 17.5 (10.1-41.3) in patients with PC epilepsy (P = 0.11). In the PC group, 6/10 (60%) of the patients demonstrated low serum pyridoxine compared to 3/20 (15%) in the WC group (P = 0.03).Conclusion: There was a statistically significant relationship between serum pyridoxine levels and seizure control. If appropriate, pyridoxine supplementation should be considered, especially in critically ill adult patients with refractory or PC seizures despite good adherence to ASMs.

Time-dependent neuropathology in rats following organophosphate-induced status epilepticus

Exposure to high levels of a cholinesterase inhibiting organophosphorus (OP) agent often results in seizures that progress to status epilepticus (SE). Survivors of OP-induced SE often display neuropathological consequences the days following SE. In the current study, the temporal profile of neuropathology after SE was investigated in a rat model of diisopropylfluorophosphate (DFP)-induced SE. Adult Sprague-Dawley rats were injected with DFP to induce SE for one hour. Following termination of electrographic SE with urethane (0.8 g/kg, sc), cohorts of rats were euthanized 3, 24 and 48 h later and brain tissue was processed to determine immediate early gene and inflammatory mediator expression as well as blood-brain barrier changes and neurodegeneration. After SE rats displayed a time-dependent upregulation of immediate early genes such as cFos and ΔFosB as well as pro-inflammatory mediators COX-2, IL-1β and IL-6. The profile of positive cFos staining, but not ΔFosB, coincided temporally with heightened brain activity measured by cortical electroencephalography (EEG). Neurodegeneration in limbic brain regions was absent 3 h after SE, but prominent 24 h later and continued to increase 48 h after SE. Serum albumin was detected in the cortex 3 h after SE suggesting early loss of blood brain barrier integrity. However, the blood-brain barrier appeared repaired 48 h after SE. This study demonstrates that following OP-poisoning in rats, immediate early gene expression in the brain precedes neuroinflammation followed by erosion of the blood-brain barrier and neurodegeneration. The study also demonstrates that seizure activity in brain nuclei coincides with cFos expression. Together, these studies give insight into the temporal molecular changes in the brain following organophosphate-induced status epilepticus.

Протиепілептичні препарати з ноотропним ефектом — оптимальний вибір за необхідності комплексної терапії коморбідних розладів

У статті наведено результати огляду, присвяченого пошуку оптимальних методів лікування пацієнтів з епілепсією, які мають супутні когнітивні порушення. Встановлено, що протиепілептичні препарати з ноотропним ефектом є найбільш оптимальним вибором у плані комплаєнсу терапії, а також зменшення частоти побічних ефектів у разі монотерапії порівняно з комбінованим застосуванням ноотропів і протиепілептичних препаратів. Одним з препаратів вибору, позитивний вплив якого на когнітивні функції в пацієнтів з епілепсією доведено, є леветирацетам. Завдяки високому профілю безпеки він може бути рекомендований до застосування в літніх пацієнтів з епілепсією, у тому числі для усунення в них епілептичного статусу, а також може використовуватися при поєднанні хвороби Альцгеймера з епілепсією. Перспективним напрямом подальших досліджень є вивчення можливостей застосування леветирацетаму при травматичних ушкодженнях нервової системи.

Prediction of Postictal Delirium Following Status Epilepticus in the ICU: First Insights of an Observational Cohort Study.

To identify early predictors of postictal delirium in adult patients after termination of status epilepticus. Retrospective study. ICUs at a Swiss tertiary academic medical center. Status epilepticus patients treated on the ICUs for longer than 24 hours from 2012 to 2018. None. Primary outcome was postictal delirium during post-status epilepticus treatment defined as an Intensive Care Delirium Screening Checklist greater than or equal to 4. Associations with postictal delirium were secondary outcomes. A time-dependent multivariable Cox proportional hazards model was used to identify risks of postictal delirium. It included variables that differed between patients with and without delirium and established risk factors for delirium (age, sex, number of inserted catheters, illness severity [quantified by the Sequential Organ Failure Assessment and Status Epilepticus Severity Score], neurodegenerative disease, dementia, alcohol/drug consumption, infections, coma during status epilepticus, dose of benzodiazepines, anesthetics, and mechanical ventilation). Among 224 patients, post-status epilepticus Intensive Care Delirium Screening Checklist was increased in 83% with delirium emerging in 55% with a median duration of 2 days (interquartile range 1-3 d). Among all variables, only the history of alcohol and/or drug consumption was associated with increased hazards for delirium in multivariable analyses (hazard ratio = 3.35; 95% CI, 1.53-7.33). Our study provides first exploratory insights into the risks of postictal delirium in adult status epilepticus patients treated in the ICU. Delirium following status epilepticus is frequent, lasting mostly 2-3 days. Our findings that with the exception of a history of alcohol and/or drug consumption, other risk factors of delirium were not found to be associated with a risk of postictal delirium may be related to the limited sample size and the exploratory nature of our study. Further investigations are needed to investigate the role of established risk factors in other status epilepticus cohorts. In the meantime, our results indicate that the risk of delirium should be especially considered in patients with a history of alcohol and/or drug consumption.

Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine.

Organophosphate (OP) exposure induces status epilepticus (SE), a medical emergency with high morbidity and mortality. Current standard medical countermeasures lose efficacy with time so that treatment delays, in the range of tens of minutes, result in increasingly poor outcomes. As part of the Countermeasures Against Chemical Threats Neurotherapeutics Screening Program, we previously developed a realistic model of delayed treatment of OP-induced SE using the OP diisopropyl fluorophosphate (DFP) to screen compounds for efficacy in the termination of SE and elimination of neuronal death. Male rats were implanted for electroencephalogram (EEG) recordings 7 days prior to experimentation. Rats were then exposed to DFP, and SE was induced for 60 minutes and then treated with midazolam (MDZ) plus one of three antiseizure drugs (ASDs)-phenobarbital (PHB), memantine (MEM), or dexmedetomidine (DMT)-in conjunction with antidotes. EEG was recorded for 24 hours, and brains were stained with Fluoro-Jade B for quantification of degenerating neurons. We found that PHB + MDZ induced a prolonged suppression of SE and reduced neuronal death. MEM + MDZ treatment exacerbated SE and increased mortality; however, surviving rats had fewer degenerating neurons. DMT + MDZ significantly suppressed SE with only a minimal reduction in neuronal death. These data demonstrate that delayed treatment of OP-induced SE with other ASDs, when added to MDZ, can achieve greater seizure suppression with additional reduction in degenerating neurons throughout the brain compared with MDZ alone. The effect of a drug on the severity of seizure activity did not necessarily determine the drug's effect on neuronal death under these conditions. SIGNIFICANCE STATEMENT: This study assesses the relative effectiveness of three different delayed-treatment regimens for the control of organophosphate-induced status epilepticus and reduction of subsequent neuronal death. The data demonstrate the potential for highly effective therapies despite significant treatment delay and a potential disconnect between seizure severity and neuronal death.

Dynamic oxygen changes during status epilepticus and subsequent endogenous kindling.

ObjectiveBrain tissue oxygen (partial oxygen pressure [pO2]) levels are tightly regulated to stay within the normoxic zone, with deviations on either side resulting in impaired brain function. Whereas pathological events such as ischemic attacks and brief seizures have previously been shown to result in pO2 levels well below the normoxic zone, oxygen levels during prolonged status epilepticus (SE) and the subsequent endogenous kindling period are unknown.MethodsWe utilized two models of acquired temporal lobe epilepsy in rats: intrahippocampal kainic acid infusion and prolonged perforant pathway stimulation. Local tissue oxygen was measured in the dorsal hippocampus using an optode during and for several weeks following SE.ResultsWe observed hyperoxia in the hippocampus during induced SE in both models. Following termination of SE, 88% of rats initiated focal self‐generated spiking activity in the hippocampus within the first 7 days, which was associated with dynamic oxygen changes. Self‐generated and recurring epileptiform activity subsequently organized into higher‐frequency bursts that became progressively longer and were ultimately associated with behavioral seizures that became more severe with time and led to postictal hypoxia.SignificanceInduced SE and self‐generated recurrent epileptiform activity can have profound and opposing effects on brain tissue oxygenation that may serve as a biomarker for ongoing pathological activity in the brain.

Midazolam and isoflurane combination reduces late brain damage in the paraoxon-induced status epilepticus rat model

Organophosphates (OPs) are widely used as pesticides and have been employed as warfare agents. OPs inhibit acetylcholinesterase, leading to over-stimulation of cholinergic synapses and can cause status epilepticus (SE). OPs poisoning can result in irreversible brain damage and death. Despite termination of SE, recurrent seizures and abnormal brain activity remain common sequelae often associated with long-term neural damage and cognitive dysfunction. Therefore, early treatment for prevention of seizures is of high interest. Using a rat model of paraoxon poisoning, we tested the efficacy of different neuroprotective and anti-epileptic drugs (AEDs) in suppressing early seizures and preventing brain damage. Electrocorticographic recordings were performed prior, during and after injection of 4.5 LD50 paraoxon, followed by injections of atropine and toxogonin (obidoxime) to prevent death. Thirty minutes later, rats were injected with midazolam alone or in combination with different AEDs (lorazepam, valproic acid, phenytoin) or neuroprotective drugs (losartan, isoflurane). Outcome measures included SE duration, early seizures frequency and epileptiform activity duration in the first 24 -hs after poisoning. To assess delayed brain damage, we performed T2-weighted magnetic resonance imaging one month after poisoning. SE duration and the number of recurrent seizures were not affected by the addition of any of the drugs tested. Delayed brain injury was most prominent in the septum, striatum, amygdala and piriform network. Only isoflurane anesthesia significantly reduced brain damage. We show that acute treatment with isoflurane, but not AEDs, reduces brain damage following SE. This may offer a new therapeutic approach for exposed individuals.

α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor Plasticity Sustains Severe, Fatal Status Epilepticus.

Generalized convulsive status epilepticus is associated with high mortality. We tested whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor plasticity plays a role in sustaining seizures, seizure generalization, and mortality observed during focal onset status epilepticus. We also determined whether modified AMPA receptors generated during status epilepticus could be targeted with a drug. Electrically induced status epilepticus was characterized by electroencephalogram and behavior in GluA1 knockout mice and in transgenic mice with selective knockdown of the GluA1 subunit in hippocampal principal neurons. Excitatory and inhibitory synaptic transmission in CA1 neurons was studied using patch clamp electrophysiology. The dose response of N,N,H,-trimethyl-5-([tricyclo(3.3.1.13,7)dec-1-ylmethyl]amino)-1-pentanaminiumbromide hydrobromide (IEM-1460), a calcium-permeable AMPA receptor antagonist, was determined. Global removal of the GluA1 subunit did not affect seizure susceptibility; however, it reduced susceptibility to status epilepticus. GluA1 subunit knockout also reduced mortality, severity, and duration of status epilepticus. Absence of the GluA1 subunit prevented enhancement of glutamatergic synaptic transmission associated with status epilepticus; however, γ-aminobutyric acidergic synaptic inhibition was compromised. Selective removal of the GluA1 subunit from hippocampal principal neurons also reduced mortality, severity, and duration of status epilepticus. IEM-1460 rapidly terminated status epilepticus in a dose-dependent manner. AMPA receptor plasticity mediated by the GluA1 subunit plays a critical role in sustaining and amplifying seizure activity and contributes to mortality. Calcium-permeable AMPA receptors modified during status epilepticus can be inhibited to terminate status epilepticus. ANN NEUROL 2020;87:84-96.

Suppressive effects of levetiracetam on neuroinflammation and phagocytic microglia: A comparative study of levetiracetam, valproate and carbamazepine

We previously reported that treatment with levetiracetam (LEV) after status epilepticus (SE) termination by diazepam (DZP) prevents the development of spontaneous recurrent seizures. LEV suppresses increased expression levels of proinflammatory mediators during epileptogenesis after SE, but how LEV acts in neuroinflammatory processes is not yet known. In this study, we examined the effects of LEV on neuroinflammation and phagocytic microglia in vivo and in vitro and compared the effects of LEV with those of representative antiepileptic drugs valproate (VPA) and carbamazepine (CBZ). Repeated treatment with LEV for 30 days after the termination of pilocarpine-induced SE by DZP almost completely prevented the incidence of spontaneous recurrent seizures, while administration of VPA or CBZ showed no effect on the seizures. LEV clearly suppressed phagocytosis of mononuclear phagocytes, and cytokine expression was observed 2 days after SE. VPA attenuated neuroinflammation only, and CBZ showed no effect on changes after SE. Treatment with LEV significantly suppressed BV-2 microglial activation, which was defined by morphological changes, phagocytic activity and cytokine expression. By contrast, VPA and CBZ did not affect BV-2 microglial activity. In summary, LEV directly suppresses excess microglial phagocytosis during epileptogenesis, which might prevent the occurrence of spontaneous recurrent seizures after SE.

Role of NMDA receptors in the pathophysiology and treatment of status epilepticus.

SummaryThis review considers the role of N‐methyl‐d‐aspartate receptors in the pathophysiology and treatment of status epilepticus (SE). NMDA receptors play a critical role in sustaining SE by mediating the plasticity of γ‐aminobutyric acid (GABA)‐A and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors, neuronal loss, and epileptogenesis. In parallel, there is growing interest in using the NMDA receptor antagonist ketamine in the treatment of refractory SE. Ketamine has proved to be safe for use in refractory and super‐refractory SE in patients. The pilot studies also suggest that ketamine may be efficacious for termination of refractory SE.

Early withdrawal of non-anesthetic antiepileptic drugs after successful termination of nonconvulsive seizures and nonconvulsive status epilepticus

PurposeMultiple antiepileptic drugs (AEDs) are often necessary to treat nonconvulsive seizures (NCS) and nonconvulsive status epilepticus (NCSE). AED polypharmacy places patients at risk for adverse side effects and drug–drug interactions. Identifying the likelihood of seizure relapse when weaning non-anesthetic AEDs may provide guidance in the critical care unit. MethodNinety-nine adult patients with successful treatment of electrographic-proven NCS or NCSE on continuous critical care EEG (CCEEG) monitoring were identified retrospectively. Patients were determined to undergo an AED wean if the number of non-anesthetic AEDs was reduced at the time of discharge compared to the number of non-anesthetic AEDs at primary seizure cessation. Primary outcome was recurrent seizures either clinically or by CCEEG during hospitalization. Secondary outcome measures included hospital length of stay and discharge disposition. ResultsThe rate of recurrent seizures in the wean group was not statistically different when compared to the group that did not undergo an AED wean (17% vs. 13%, respectively; p = 0.77). The wean group had a median value of 4 (IQR: 3–4) non-anesthetic AEDs at the time of primary seizure cessation compared with 3 (IQR: 2–3) in the non-wean group (p < 0.0001). However, both groups had similar values of AEDs at discharge (median of 2 (IQR: 2–3) vs. 3 (IQR: 2–3) for wean and non-wean groups respectively; p = 0.40). Discharge disposition (favorable, acceptable, or unfavorable) was similar between groups (p = 0.32). ConclusionsEarly weaning of non-anesthetic AEDs does not increase the risk of recurrent seizures in patients treated for NCS or NCSE during their hospitalization.

Anticonvulsive Effects of Licofelone on Status Epilepticus Induced by Lithium-pilocarpine in Wistar Rats: a Role for Inducible Nitric Oxide Synthase.

Background and PurposeStatus epilepticus (SE) is a neurological disorder with high prevalence and mortality rates, requiring immediate intervention. Licofelone is a cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitor, which its effectiveness to treat osteoarthritis has been approved. Increasing evidence suggests an involvement of COX and LOX enzymes in epileptic disorders. Thus, in the present study we investigate possible effects of licofelone on prevention and termination of SE. We also evaluated whether the nitrergic system could participate in this effect of licofelone.MethodsWe have utilized lithium-pilocarpine model of SE in adult Wistar rats to assess the potential effect of licofelone on seizure susceptibility. Licofelone was administered 1 h before pilocarpine. To evaluate probable role of nitric oxide (NO) system, L-arginine (60 mg/kg, i.p.), as a NO precursor; L-NAME (15 mg/kg, i.p.), as a non-selective nitric oxide synthase (NOS) inhibitor; aminoguanidine (100 mg/kg, i.p.), as an inducible NOS (iNOS) inhibitor and 7-nitroindazole (60 mg/kg, i.p.), as a neuronal NOS inhibitor were injected 15 min before licofelone. Also, licofelone and diazepam 10 mg/kg were administered 30 minutes after onset of SE.ResultsPre-treatment with licofelone at the dosage of 10 mg/kg, significantly prevented the onset of SE in all subjects (p < 0.001). L-arginine significantly inverted this anticonvulsant effect (p < 0.05). However, L-NAME and aminoguanidine, potentiated the anticonvulsant effect of licofelone (p < 0.05, p < 0.01). Licofelone could not terminate seizures after onset which was terminated by diazepam.ConclusionsOur findings showed that anticonvulsive effects of licofelone on SE could be mediated by iNOS. Also, we suggest that COX/5-LOX activation is possibly required in the initial stage of onset but SE recruits extra excitatory pathways with prolongation.