Treatment Of Status Epilepticus Research Articles

Efficacy of Midazolam Vs Diazepam in The Treatment of Status Epilepticus

Efficacy of Midazolam Vs Diazepam in The Treatment of Status Epilepticus

Treatment of pediatric convulsive status epilepticus.

Status epilepticus is one of the most common life-threatening neurological emergencies in childhood with the highest incidence in the first 5 years of life and high mortality and morbidity rates. Although it is known that a delayed treatment and a prolonged seizure can cause permanent brain damage, there is evidence that current treatments may be delayed and the medication doses administered are insufficient. Here, we summarize current knowledge on treatment of convulsive status epilepticus in childhood and propose a treatment algorithm. We performed a structured literature search via PubMed and ClinicalTrails.org and identified 35 prospective and retrospective studies on children <18 years comparing two and more treatment options for status epilepticus. The studies were divided into the commonly used treatment phases. As a first-line treatment, benzodiazepines buccal/rectal/intramuscular/intravenous are recommended. For status epilepticus treated with benzodiazepine refractory, no superiority of fosphenytoin, levetirazetam, or phenobarbital was identified. There is limited data on third-line treatments for refractory status epilepticus lasting >30 min. Our proposed treatment algorithm, especially for children with SE, is for in and out-of-hospital onset aids to promote the establishment and distribution of guidelines to address the treatment delay aggressively and to reduce putative permanent neuronal damage. Further studies are needed to evaluate if these algorithms decrease long-term damage and how to treat refractory status epilepticus lasting >30 min.

Refractory and super-refractory status epilepticus and evidence for the use of ketamine: a scope review

Status epilepticus (SE) is a neurological emergency with serious consequences for neuronal tissues, therefore, it is considered the most serious manifestation of epilepsy. The response to treatment, its evolution time and duration, and the need to use one or more antiseizure drugs define SE as refractory or super-refractory. Ketamine has been used in SE management since the 90s when an article describing its use in treating SE was published. Since then, at least 24 publications have reported the use of ketamine for the treatment of SE in both adult and pediatric patients. This scoping review seeks to synthesize information on the use of drugs in super-refractory SE, specifically ketamine. Twenty articles were chosen for the final document construction. Few studies have investigated the use of ketamine in refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE). Most of the information comes from retrospective case series studies, mostly with small sample sizes, and although the information is heterogeneous, it points to the efficacy of ketamine as a third-line drug in RES and SRSE, in controlling seizures.

Evaluating salvage electroconvulsive therapy for the treatment of prolonged super refractory status epilepticus: A case series

Background and ObjectivesClinicians have treated super refractory status epilepticus (SRSE) with electroconvulsive therapy (ECT); however, data supporting the practice are scant and lack rigorous evaluation of continuous electroencephalogram (cEEG) changes related to therapy. This study aims to describe a series of patients with SRSE treated at our institution with ECT and characterize cEEG changes using a blinded review process. MethodsWe performed a single-center retrospective study of consecutive patients admitted for SRSE and treated with ECT from January 2014 to December 2022. Our primary outcome was the resolution of SRSE. Secondary outcomes included changes in ictal-interictal EEG patterns, anesthetic burden, treatment-associated adverse events, and changes in clinical examination. cEEG was reviewed pre- and post-ECT by blinded epileptologists. ResultsTen patients underwent treatment with ECT across 11 admissions (8 female, median age 57 years). At the time of ECT initiation, nine patients had ongoing SRSE while two had highly ictal patterns and persistent encephalopathy following anesthetic wean, consistent with late-stage SRSE. Super-refractory status epilepticus resolution occurred with a median time to cessation of 4 days (interquartile range [IQR]: 3–9 days) following ECT initiation. Background continuity improved in five patients and periodic discharge frequency decreased in six. There was a decrease in anesthetic use following the completion of ECT and an improvement in neurological exams. There were no associated adverse events. DiscussionIn our cohort, ECT was associated with improvement of ictal-interictal patterns on EEG, and resolution of SRSE, and was not associated with serious adverse events. Further controlled studies are needed.

Efficacy and safety of ketamine for neonatal refractory status epilepticus: case report and systematic review.

Evidence-based data on treatment of neonatal status epilepticus (SE) are scarce. We aimed to collect data on the efficacy and safety of ketamine for the treatment of neonatal SE and to assess its possible role in the treatment of neonatal SE. We described a novel case and conducted a systematic literature review on neonatal SE treated with ketamine. The search was carried out in Pubmed, Cochrane, Clinical Trial Gov, Scopus and Web of Science. Seven published cases of neonatal SE treated with ketamine were identified and analyzed together with our novel case. Seizures typically presented during the first 24 h of life (6/8). Seizures were resistant to a mean of five antiseizure medications. Ketamine, a NMDA receptor antagonist, appeared to be safe and effective in all neonates treated. Neurologic sequelae including hypotonia and spasticity were reported for 4/5 of the surviving children (5/8). 3/5 of them were seizure free at 1-17 months of life. Neonatal brain is more susceptible to seizures due to a shift towards increased excitation because of a paradoxical excitatory effect of GABA, a greater density of NMDA receptors and higher extracellular concentrations of glutamate. Status epilepticus and neonatal encephalopathy could further enhance these mechanisms, providing a rationale for the use of ketamine in this setting. Ketamine in the treatment of neonatal SE showed a promising efficacy and safety profile. However, further in-depth studies and clinical trials on larger populations are needed.

Utilization of the ketogenic diet for adults with status epilepticus

BackgroundThe ketogenic diet (KD) is a high-fat, low-carbohydrate diet with therapeutic potential in refractory seizures, both in outpatient and inpatient settings. Successful implementation of KD involves a multifaceted, interdisciplinary approach to address anticipated challenges. We sought to characterize the utilization of KD among healthcare providers caring for adults with status epilepticus (SE). MethodsWe distributed a web-based survey through professional societies, including the American Academy of Neurology (AAN), Neurocritical Care Society (NCS), American Epilepsy Society (AES), Neuro Anesthesia and Critical Care Society (NACCS), and the Academy of Nutrition and Dietetics (AND), and via research contacts. We asked respondents about practice experience and experience using KD as a treatment for SE. Descriptive statistics and Chi-square tests were used to analyze the results. ResultsOf 156 respondents, 80% of physicians and 18% of non-physicians reported experience with KD for SE. Anticipated difficulty in achieving ketosis (36.3%), lack of expertise (24.2%), and lack of resources (20.9%) were identified as the most important barriers limiting the utilization of KD. The absence of dietitians (37.1%) or pharmacists (25.7%) support was the most important missing resource. Reasons for stopping KD included perceived ineffectiveness (29.1%), difficulty achieving ketosis (24.6%), and side effects (17.3%). Academic centers had more experience with the use of KD and greater EEG monitoring availability and fewer barriers to its implementation. The need for randomized clinical trials supporting efficacy (36.5%) and better practice guidelines for implementation and maintenance of KD (29.6%) were cited most frequently as factors to increase utilization of KD. ConclusionThis study identifies important barriers to the utilization of KD as a treatment for SE despite evidence supporting its efficacy in the appropriate clinical context, namely lack of resources and interdisciplinary support, and lack of established practice guidelines. Our results highlight the need for future research to improve understanding of the efficacy and safety of KD along with better interdisciplinary collaborations to increase its utilization.

Comparison of Safety and Effectiveness between Levetiracetam and Phenytoin in the Treatment of Pediatric Status Epilepticus: A Meta- Analysis.

To evaluate the safety and effectiveness of levetiracetam and phenytoin by evaluating the events of seizure termination and recurrence in children. We used the internet databases PubMed, Embase, and Google Scholar to conduct a literature search for the appropriate studies. A meta-analysis was performed to calculate the odds ratio using fixed and random-effects models. We identified 15 studies that were eligible for the meta-analysis. The incidence of seizure termination within 24 h was 76.9% for levetiracetam and 70.5% for phenytoin. Levetiracetam had a higher number of seizure termination events than phenytoin (P = 0.005, I2 = 66%). The incidence of seizure recurrence within 24 h was 10% for levetiracetam and 15.6% for phenytoin. Phenytoin had a significantly higher number of seizure recurrence events than levetiracetam (P = 0.00007, I2 = 21%). The efficacy and safety of levetiracetam are superior to that of phenytoin in children with status epilepticus. Large Randomized Controlled Trial studies are needed to confirm the result in children.

Clonazepam Loading Dose in Status Epilepticus: Is More Always Better?

Benzodiazepines are the first treatment line in status epilepticus (SE). Despite their well-established benefit, benzodiazepines are frequently underdosed with potential detrimental consequences. In some European countries, clonazepam (CLZ) is commonly used as the first line treatment. The aim of this study was to explore the correlation between CLZ loading doses and SE outcome. This study included a retrospective analysis of a prospective registry in Lausanne, Switzerland (CHUV Lausanne University Hospital), including all SE episodes treated between February 2016 and February 2021. Only adults (>16 years old) were included with CLZ used as the first treatment line. Post-anoxic SE were excluded because of significant differences in physiopathology and prognosis. Patient characteristics, SE features, the validated SE severity score (STESS), and treatment characteristics were prospectively recorded. We considered loading doses of 0.015 mg/kg or higher (following commonly recommended loading doses)as high doses. We analyzed outcome in terms of number of treatment lines after the CLZ, proportion of refractory episodes, intubation for airways protection, intubation for SE treatment, and mortality. We performed univariable analyses to investigate the association between loading doses and clinical response. A multivariable stepwise backward binary logistic regression was applied for adjusting for potential confounders. Multivariable linear regression was similarly used to analyze CLZ dose as a continuous variable. We collected 251 SE episodes in 225 adult patients. Median CLZ loading dose was 0.010 mg/kg. CLZ high doses were used in 21.9% of SE episodes (in 43.8% for >80% of the high dose). Thirteen percent of patients with SE were intubated for airways control, while intubation was needed in12.7% for SE treatment. High CLZ loading doses were independently associated with younger age (median 62 versus 68 years old, p = 0.002), lesser weight (65kg versus 75kg, p = 0.001) and more frequent intubation for airways protection (23% vs 11%, p = 0.013), but differing CLZ dose was not associated with any outcome parameter. CLZ high doses were more frequently used for SE treatment in younger patients with healthy weight and were more often associated with intubation for airways protection, probably as an adverse event. Varying CLZ dose did not alter outcome in SE, raising the possibility that commonly recommended doses are above what is needed, at least in some patients. Our results suggest that CLZ doses in SE may be individualized depending on the clinical setting.

Efficacy of antiseizure medications in Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) is caused by deletion of the terminal region of chromosome 4 short arm and is frequently associated with intractable epilepsy. To evaluate the clinical features of epileptic seizures in WHS and the therapeutic efficacy of oral antiseizure medications (ASMs) Methods: Patients with WHS who were treated for epilepsy at the Saitama Children's Medical Center under 5 years of age were included. WHS was diagnosed based on genetic tests and clinical symptoms. Medical records regarding the age of onset of epilepsy, seizure type, treatment of status epilepticus (SE), and effectiveness of ASMs were retrospectively reviewed. Oral ASMs were considered effective when seizures were reduced by at least 50% compared to the pre-medication level. Eleven patients were included in the study. The median age at the onset of epilepsy was 9 months (range: 5-32 months). Unknown-onset bilateral tonic-clonic seizure was the most common type of seizure, occurring in ten patients. Focal clonic seizures occurred in four patients. Ten patients exhibited recurrent episodes of SE, and its frequency during infancy was monthly in eight patients and yearly in two. SE occurrence peaked at 1 year of age and decreased after 3 years of age. The most effective ASM was levetiracetam. Although WHS-associated epilepsy is intractable with frequent SE occurrence during infancy, improvement in seizure control is expected with age. Levetiracetam may be a novel ASM for WHS.

Cognition, emotional state, and quality of life of survivors after cardiac arrest with rhythmic and periodic EEG patterns

AimRhythmic and periodic patterns (RPPs) on the electroencephalogram (EEG) in comatose patients after cardiac arrest have been associated with high case fatality rates. A good neurological outcome according to the Cerebral Performance Categories (CPC) has been reported in up to 10% of cases. Data on cognitive, emotional, and quality of life outcomes are lacking. We aimed to provide insight into these outcomes at one-year follow-up. MethodsWe assessed outcome of surviving comatose patients after cardiac arrest with RPPs included in the ‘treatment of electroencephalographic status epilepticus after cardiopulmonary resuscitation’ (TELSTAR) trial at one-year follow-up, including the CPC for functional neurological outcome, a cognitive assessment, the hospital anxiety and depression scale (HADS) for emotional outcomes, and the 36-item short-form health survey (SF-36) for quality of life. Cognitive impairment was defined as a score of more than 1.5 SD below the mean on ≥ 2 (sub)tests within a cognitive domain. ResultsFourteen patients were included (median age 58 years, 21% female), of whom 13 had a cognitive impairment. Eleven of 14 were impaired in memory, 9/14 in executive functioning, and 7/14 in attention. The median scores on the HADS and SF-36 were all worse than expected. Based on the CPC alone, 8/14 had a good outcome (CPC 1–2). ConclusionNearly all cardiac arrest survivors with RPPs during the comatose state have cognitive impairments at one-year follow-up. The incidence of anxiety and depression symptoms seem relatively high and quality of life relatively poor, despite ‘good’ outcomes according to the CPC.

Tolerability and pharmacokinetics of intravenous allopregnanolone with and without midazolam pretreatment in two healthy dogs.

The neurosteroid allopregnanolone (ALLO) is under investigation as a treatment for benzodiazepine-refractory status epilepticus (SE). Here we assess the cardiopulmonary safety of intravenous ALLO by itself and after a clinically recommended dose of midazolam (MDZ) in two healthy adult beagles. Each dog received ALLO (1 mg/kg, IV), and after a washout period of 2 weeks, the dog was dosed with MDZ (0.2 mg/kg, IV) followed 10 min later by ALLO. Behavioral state, vital signs, arterial blood gasses, blood chemistries, and plasma ALLO concentrations were monitored for up to 6 h after dosing. The dogs appeared sleepy but were fully responsive after both treatments. No depression of mean arterial pressure or respiratory rate was noted. Blood gas measurements failed to show evidence of drug-induced acute respiratory acidosis. Estimated maximum plasma ALLO concentrations were in the range of 1500 to 3000 ng/mL. The results indicate that intravenous ALLO can be used safely to treat benzodiazepine-refractory SE, even when administered shortly after a benzodiazepine.

Comparison of three types of Epilepsy Surgery for the treatment of Refractory Status Epilepticus: A Single Center Experience (P9-1.005)

<h3>Objective:</h3> Comparing outcomes for three categories of epilepsy surgery in Refractory Status Epilepticus Patients (RSE). <h3>Background:</h3> Literature comparing morbidity and mortality outcomes between three types of epilepsy surgery for RSE patients is scarce. Previous case series have focused on one type of surgery or does not directly compare outcomes between the modalities. <h3>Design/Methods:</h3> A retrospective analysis for RSE between 2010 and 2021 was done. Sociodemographic data, semiology and etiology were collected. The patients were deidentified using our institute’s software, and comparison data was extracted from the secure system. Data collected included lag time between diagnosis and surgery, number of anti-seizure medications (ASMs) tried, EEG and imaging data, type of surgery performed, level of post-operative care, number of post-operative days admitted, complications and seizure freedom outcomes. <h3>Results:</h3> The mean age was 35.6 ± 23.5 years, with 4/12 patients being female. Seizure types were primarily generalized tonic-clonic or focal seizures with impaired awareness. A plethora of etiologies were included. The mean number of ASMs tried was 2.3 ± 1.4. Every patient had EEG and MRI Brain with ancillary testing such as grid placement. Out of 12, 6 had resection, 5 disconnections and 2 neuromodulations. 11/12 patients required an ICU admission and mean post-operative days admitted was 12 ± 11.2. Minor to no complications occurred in 33 % of all resection patients, and minor complications occurred in 40 % and 50 % patients of the disconnection and modulation patients. 3/4 and 3/5 of patients that had undergone resections and disconnections respectively had Class 1 outcomes in. Patients that received modulation had a Class 4 outcome and 1 patient death. <h3>Conclusions:</h3> Our study reveals that while there is no substantial difference between resection and disconnection, resections have slightly better outcomes and fewer complications. Modulation had poorer seizure freedom and may only be considered as a temporizing measure. <b>Disclosure:</b> Dr. Khan has received personal compensation for serving as an employee of University of Kentucky. Dr. Mirza has nothing to disclose. Dr. Mathias has received research support from My Epilepsy Society Non Profit Organization.

Resident-Driven Quality Improvement Project to Improve Treatment of Status Epilepticus (S4.007)

<h3>Objective:</h3> To establish interventions that address barriers to improve the treatment of status epilepticus (SE) at Geisinger Medical Center. <h3>Background:</h3> The American Epilepsy Society Guidelines recommend benzodiazepines (BZ) as first line treatment for seizures lasting greater than 5 minutes and loading antiseizure medications (ASM) in a 20–40-minute window. Delay and underdosing the initial treatment of SE is associated with longer duration of seizures, increased hospital stay, morbidity and mortality. The initial phase of our QI project found that at our institution the main barriers were lack of knowledge of treatment guidelines for SE, timely communication with pharmacy and nursing, and preparation of intravenous ASMs. <h3>Design/Methods:</h3> We implemented the following interventions: 1) educate prescribers in the neurology, emergency medicine, and critical care departments regarding the approved institutional protocol for SE and availability of an orderset with optimal dosing, 2) two-factor communication regarding SE medication orders to nursing and education of nursing and pharmacy staff regarding target administration times, 3) add ready-to-mix levetiracetam to nurse omnicells on high-volume floors, and 4) update the SE orderset to improve usability across multiple departments. We compared the use of appropriate doses of ASMs and time to administration of ASMs before and after the interventions. We analyzed data 9 months after the interventions. <h3>Results:</h3> We has 71 patient’s treated for SE during this time period. Use of high-dose BZ in SE increased from 32% to 47%. Use of second line ASMs at appropriate SE doses increased from 77% to 86%. The average BZ order-to-administration time was reduced from 10–14 minutes to 9 minutes and the average second line ASM order-to-administration time was reduced from 86 minutes to 45 minutes. <h3>Conclusions:</h3> Our resident-driven QI project led to improvement in dosing and timing of administration of BZ and second line ASMs. BZ dosing continues to be a major area for improvement. <b>Disclosure:</b> Dr. Houck has nothing to disclose. Dr. Alario has nothing to disclose. Dr. Owens has nothing to disclose. Dr. Seemiller has nothing to disclose.

Dual antiglutamatergic treatment in patients with status epilepticus: a case series (P9-1.008)

<h3>Objective:</h3> To assess clinical and electrographic outcomes in patients receiving dual anti-glutamatergic therapy in status epilepticus. <h3>Background:</h3> Status epilepticus continues to be a challenging neurological emergency with high morbidity and mortality. To our knowledge, this is the first case series describing EEG patterns and clinical outcomes in patients treated with Ketamine and Perampanel concomitantly. <h3>Design/Methods:</h3> Retrospectively analyzed records of 25 patients treated with IV Ketamine for Status Epilepticus (SE), Refractory SE (RSE), and Super RSE (SRSE) between January 2019 and January 2022. RSE and SRSE are defined per the new classification/nomenclature. The following parameters were analyzed: Modified Rankin Scale (mRS) at admission and discharge, days on IV ketamine, time to resolution of status epilepticus, presence, or absence of burst suppression after initiating treatment and presence of beta pattern and its sustainability on EEG after treatment. We compared these parameters in patients who received Perampanel concomitantly with Ketamine to those who didn’t. <h3>Results:</h3> 21 out of 25 patients were treated with ketamine and other agents, and 4 patients with Ketamine and Perampanel. The incidence of beta pattern appearance on EEG after starting patients on Ketamine and Perampanel was achieved in all 4 patients (100%) in comparison to (61.9%) in Ketamine-only group. Burst suppression pattern was recorded in 75% of patients treated with Ketamine and Perampanel compared to 28.5% in the other. The time to resolution of status epilepticus was significantly shorter in Ketamine-only group. The average number of days on IV anesthetic was slightly lower in patient treated with concomitant Perampanel. The average increase in mRS was also lower in the group of interest. <h3>Conclusions:</h3> Dual anti-glutamatergic therapy could provide a favorable approach to treating status epilepticus, which yet needs to be further investigated through larger randomized control studies. <b>Disclosure:</b> Dr. Souidan has nothing to disclose. Prof. ANDRADE MACHADO has nothing to disclose. Dr. Lagnf has nothing to disclose. Dr. Pokharel has nothing to disclose. Dr. Elsayed has nothing to disclose.

Treatment of status epilepticus: Physiology, pharmacology, and future directions.

The review presents retrospective, present views and future perspectives on the treatment of status epilepticus (SE). First, presynaptic, postsynaptic, and extrasynaptic mechanisms underlying sustaining ongoing seizure activity are highlighted. Next, mechanism-based choices of antiseizure medications capable of promptly arresting SE are introduced. Finally, challenges associated with translating the advances in laboratory research in clinical practice are discussed.

Perspective: Vagal nerve stimulation in the treatment of new-onset refractory status epilepticus.

Resistance to drug therapy is a major hurdle in new-onset refractory status epilepticus (NORSE) treatment and there is urgent need to develop new treatment approaches. Non-drug approaches such as neuromodulation offer significant benefits and should be investigated as new adjunct treatment modalities. An important unanswered question is whether desynchronizing networks by vagal nerve stimulation (VNS) may improve seizure control in NORSE patients. We present a summary of published NORSE cases treated with VNS and our own data, discuss possible mechanisms of action, review VNS implantation timing, stimulation setting titration protocols and outcomes. Further, we propose avenues for future research. We advocate for consideration of VNS for NORSE both in early and late stages of the presentation and hypothesize a possible additional benefit from implantation in the acute phase of the disease. This should be pursued in the context of a clinical trial, harmonizing inclusion criteria, accuracy of documentation and treatment protocols. A study planned within our UK-wide NORSE-UK network will answer the question if VNS may confer benefits in aborting unremitting status epilepticus, modulate ictogenesis and reduce long-term chronic seizure burden.

Status epilepticus prognosis following levetiracetam administration: Analysis of loading doses.

Recommended loading doses of levetiracetam (LEV) for status epilepticus (SE) treatment have increased over time. However, this was not evidence-based, and the benefit of the increase remains unclear. The effect of different LEV loading doses on SE prognosis was explored. This is a retrospective analysis of an SE adult registry (January 2016-December 2021), including patients receiving LEV as a second-line SE treatment. Patients were stratified according to LEV loading doses (threshold 35 mg/kg). Main outcomes were global mortality, LEV use as last SE treatment, and return to baseline conditions at discharge, exploring LEV as a dichotomized or continuous dose. Among 202 patients, 44 received LEV at ≥35 mg/kg and 158 below it. Global mortality, adjusted for SE severity and potentially fatal aetiology, was more frequent in the high LEV dose group (27.2% vs. 17.1%, odds ratio 3.14, 95% confidence interval 1.23-8.06; p = 0.017), whilst LEV prescription as last treatment and return to baseline conditions were comparable. Considering continuous LEV dosages or mortality in ongoing SE, however, no outcome reached statistical significance. Lower LEV loading doses do not seem to correlate with worse clinical outcome, challenging current guidelines. Further studies, ideally prospective, are needed on this topic.

Eslicarbazepine acetate for the treatment of status epilepticus.

Due to the high mortality of patients with refractory status epilepticus (SE), new antiseizure medications (ASMs) are needed to improve long-term outcomes. In this study, we evaluated the efficacy and safety of eslicarbazepine acetate (ESL), a new sodium channel blocker, based on the data from a large epilepsy register. Data on the efficacy and safety of ESL for the treatment of refractory SE were gathered from the Mainz Epilepsy Registry (MAINZ-EPIREG). Logistic regression was applied to identify predictors of status interruption. In total, 64 patients with remote symptomatic refractory SE were treated with ESL. No cases of idiopathic generalized epilepsy were included. The average age was 61.4 ± 11.0 years. The median number of administered ASMs before the start of ESL was three. On average, 2 days had elapsed since the onset of SE before the administration of ESL. The initial dose of 800 mg/day was increased up to a maximum daily dose of 1600 mg in case of nonresponse. In 29 of 64 patients (45.3%), the SE could be interrupted within 48 h of ESL therapy. In patients with poststroke epilepsy, the control of SE was achieved in 62% of patients (15/23). The earlier initiation of ESL therapy was an independent predictor of control of SE. Hyponatraemia occurred in five patients (7.8%). Other side effects were not observed. Based on these data, ESL may be used as an adjunct therapy for the treatment of refractory SE. The best response was found in patients with poststroke epilepsy. In addition, early initiation of ESL therapy appears to result in better control of SE. Besides a few cases of hyponatraemia, no other adverse events were detected.

Delayed tezampanel and caramiphen treatment but not midazolam protects against long-term neuropathology after soman exposure.

Prolonged status epilepticus (SE) can cause brain damage; therefore, treatment must be administered promptly after seizure onset to limit SE duration and prevent neuropathology. Timely treatment of SE is not always feasible; this would be particularly true in a mass exposure to an SE-inducing agent such as a nerve agent. Therefore, the availability of anticonvulsant treatments that have neuroprotective efficacy even if administered with a delay after SE onset is an imperative. Here, we compared the long-term neuropathology resulting from acutely exposing 21-day-old male and female rats to the nerve agent soman, and treating them with midazolam (3 mg/kg) or co-administration of tezampanel (10 mg/kg) and caramiphen (50 mg/kg), at 1 h postexposure (~50 min after SE onset). Midazolam-treated rats had significant neuronal degeneration in limbic structures, mainly at one month postexposure, followed by neuronal loss in the basolateral amygdala and the CA1 hippocampal area. Neuronal loss resulted in significant amygdala and hippocampal atrophy, deteriorating from one to six months postexposure. Rats treated with tezampanel-caramiphen had no evidence of neuropathology, except for neuronal loss in the basolateral amygdala at the six-month timepoint. Anxiety was increased only in the midazolam-treated rats, at one, three, and six months postexposure. Spontaneous recurrent seizures appeared only in midazolam-treated rats, at three and six months postexposure in males and only at six months in females. These findings suggest that delayed treatment of nerve agent-induced SE with midazolam may result in long-lasting or permanent brain damage, while antiglutamatergic anticonvulsant treatment consisting of tezampanel and caramiphen may provide full neuroprotection.

Status epilepticus and benzodiazepine treatment: Use, underdosing and outcome - insights from a retrospective, multicentre registry

ObjectiveTo explore the reasons for and outcomes of non- or undertreatment with benzodiazepines (BZDs) in status epilepticus (SE). MethodsWe retrospectively analysed all SE patients from the urban area of Cologne over two years. Results328 SE patients were eligible, and only 72% were initially treated with BZDs. Of these, only 21.6% were treated sufficiently with BZDs according to current guidelines. SE patients not initially treated with BZDs were significantly older, had less often known epilepsy, had a prolonged arrival time to the emergency room, and presented more often with a non-generalised convulsive semiology. Regarding adequate dosages, patients with a generalised convulsive SE seemed to benefit from a sufficient BZD dosing with significantly shortened mean ventilation duration (37.1 to 208 h), decreased mean intensive care unit (1.7 to 5 days) and in-hospital stay (4.1 to 8.8 days). In contrary, aggressive BZD treatment in non-generalised convulsive SE resulted in a longer inpatient stay (9.2 to 5.8 days) and lower favourable outcome rates at discharge (16% to 63%). ConclusionsThe current SE treatment guidelines for first-line BZD therapy in SE were violated in most patients. Sufficient BZD dosing was beneficial in generalised convulsive SE, but not in other forms of SE. SE semiology might be crucial for treatment decisions with BZDs. Further treatment evidence especially in non-generalised convulsive SE is urgently needed.