Treatment Of Status Epilepticus Research Articles

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus

It is well accepted in the medical community that the initial medication of choice for status epilepticus is a benzodiazepine. If initial treatment with a benzodiazepine fails to terminate seizure activity, the next step in pharmaceutical treatment remains unclear. This study attempts to compare secondary treatments for status epilepticus.

Drug Trials in Status Epilepticus: Current Evidence and Future Concepts.

Status epilepticus (SE) is a neurologic emergency with high morbidity and mortality. After many advances in the field, several unanswered questions remain for optimal treatment after the early stage of SE. This narrative review describes some of the important drug trials for SE treatment that have shaped the understanding of the treatment of SE. The authors also propose possible clinical trial designs for the later stages of SE that may allow assessment of currently available and new treatment options. Status epilepticus can be divided into four stages for treatment purposes: early, established, refractory, and superrefractory. Ongoing convulsive seizures for more than 5 minutes or nonconvulsive seizure activity for more than 10 to 30 minutes is considered early SE. Failure to control the seizure with first-line treatment (usually benzodiazepines) is defined as established SE. If SE continues despite treatment with an antiseizure medicine, it is considered refractory SE, which is usually treated with additional antiseizure medicines or intravenous anesthetic agents. Continued seizures for more than 24 hours despite use of intravenous anesthetic agents is termed superrefractory SE. Evidence-based treatment recommendations from high-quality clinical trials are available for only the early stages of SE. Among the challenges for designing a treatment trial for the later stages SE is the heterogeneity of semiology, etiology, age groups, and EEG correlates. In many instances, SE is nonconvulsive in later stages and diagnosis is possible only with EEG. EEG patterns can be challenging to interpret and only recently have consensus criteria for EEG diagnosis of SE emerged. Despite having these EEG criteria, interrater agreement in EEG interpretation can be challenging. Defining successful treatment can also be difficult. Finally, the ethics of randomizing treatment and possibly using a placebo in critically ill patients must also be considered. Despite these challenges, clinical trials can be designed that navigate these issues and provide useful answers for how best to treat SE at various stages.

Phenytoin versus fosphenytoin for second-line treatment of status epilepticus: propensity score matching analysis using a nationwide inpatient database

PurposeFor status epilepticus, the choice of antiepileptic drugs for second-line treatment after benzodiazepine remains controversial: phenytoin or fosphenytoin are recommended, however, it has been unknown which is better. Using a nationwide database, we compared the efficacy and safety of them. MethodAn observational study conducted with the Japanese Diagnosis Procedure Combination inpatient database identified adult patients who had been admitted for status epilepticus and who had received intravenous diazepam on the day of admission from January 1, 2011 through December 31, 2015. Propensity score matching was applied to compare outcomes of the phenytoin and fosphenytoin groups. ResultsThe analysis examined data of 5265 patients: 2969 patients received phenytoin; 2296 received fosphenytoin, on the day of admission. One-to-one propensity score matching created 1871 matched pairs. No significant difference was found for vasopressor use on the day of admission (4.2 % vs. 4.4 %; odds ratio 1.07; 95 % confidence intervals 0.77–1.48; p = 0.69), or for mechanical ventilation on the day of admission, in-hospital mortality, length of hospital stay, or total hospitalization cost. Higher age, comorbidity of cardiac diseases and lower body mass index were associated significantly with increased vasopressor use, whereas the dose of phenytoin equivalents and the choice of fosphenytoin were not. ConclusionsThis nationwide observational study found no evidence that fosphenytoin provides higher efficacy or safety than phenytoin for treatment of status epilepticus in adults after diazepam. Age, cardiac disease and low body mass index were identified as independent risk factors for vasopressor use in both phenytoin and fosphenytoin.

Patient and Surrogate Postenrollment Perspectives on Research Using the Exception From Informed Consent: An Integrated Survey

It is important for researchers interested in trials using the exception from informed consent to understand the views and experiences of enrolled individuals. Previous studies have shown that patient and surrogate attitudes are generally positive. These studies were small and did not include pediatric patients, and interviews were often conducted long after trial enrollment. This study sought to explore attitudes toward exception from informed consent in a larger sample and more contemporaneous setting. A 10-item paper-and-pencil survey was integrated into the Established Status Epilepticus Treatment Trial, a randomized trial of 3 treatments for benzodiazepine-refractory status epilepticus in pediatric and adult patients. Primary domains included attitudes toward trial enrollment, exception from informed consent, and community consultation. Simple descriptive statistics, χ2, and Fisher's exact tests were conducted. Of 317 patients and surrogates, 90% agreed with or were neutral about the statement "I am glad that I/my family member was included in the Established Status Epilepticus Treatment Trial research study," whereas 10% disagreed. Twenty-seven percent disagreed with enrollment in the study without prospective consent. Black participants were more likely than white, other race, and unknown-race participants to disagree with enrollment without prospective consent (36% versus 23%, 14%, and 14%, respectively). Participants indicated that patients (81%), their families (65%), and those at risk for seizures (51%) were most important to include in community consultation. This study aimed to explore attitudes toward exception from informed consent enrollment among participants at all sites in a large, multicenter exception from informed consent trial. General acceptance of trial enrollment was high; acceptance of exception from informed consent specifically was somewhat lower, especially among black participants. Our findings provide further support for targeted community consultation focusing on individuals with connections to the disease under study. Future research should focus on communication in the postenrollment period, especially with individuals who may have concerns about exception from informed consent.

Efficacy, Safety, and Economics of Intravenous Levetiracetam for Status Epilepticus: A Systematic Review and Meta-Analysis

ObjectiveTo evaluate efficacy, safety, and economics profiles of intravenous levetiracetam (LEV) for status epilepticus (SE).MethodsWe searched PubMed, Embase, the Cochrane Library, Clinicaltrials.gov, and OpenGrey.eu for eligible studies published from inception to June 12th 2019. Meta-analyses were conducted using random-effect model to calculate odds ratio (OR) of included randomized controlled trials (RCTs) with RevMan 5.3 software.ResultsA total of 478 studies were obtained. Five systematic reviews (SRs)/meta-analyses, 9 RCTs, 1 non-randomized trial, and 27 case series/reports and 1 economic study met the inclusion criteria. Five SRs indicated no statistically significant difference in rates of seizure cessation when LEV was compared with lorazepam (LOR), phenytoin (PHT), or valproate (VPA). Pooled results of included RCTs indicated no statistically significant difference in seizure cessation when LEV was compared with LOR [OR = 1.04, 95% confidence interval (CI) 0.37 to 2.92], PHT (OR = 0.90, 95% CI 0.64 to 1.27), and VPA (OR = 1.47, 95% CI 0.81 to 2.67); and no statistically significant difference in seizure freedom within 24 h compared with LOR [OR = 1.83, 95% CI 0.57 to 5.90] and PHT (OR = 1.08, 95% CI 0.63 to 1.87). Meanwhile, LEV did not increase the risk of mortality during hospitalization compared with LOR (OR = 1.03, 95% CI 0.31 to 3.39), PHT (OR = 0.89, 95% CI 0.37 to 2.10), VPA (OR = 1.28, 95% CI 0.32 to 5.07), and placebo (plus clonazepam, OR = 0.73, 95% CI 0.16 to 3.38). LEV had lower need for artificial ventilation (OR = 0.23, 95% CI 0.06 to 0.92) and a lower risk of hypotension (OR = 0.15, 95% CI 0.03 to 0.84) compared to LOR. A trend of lower risk of hypotension and higher risk of agitation was found when LEV was compared with PHT. Case series and case report studies indicated psychiatric and behavioral adverse events of LEV. Cost-effectiveness evaluations indicated LEV as the most cost-effective non-benzodiazepines anti-epileptic drug (AED).ConclusionsLEV has a similar efficacy as LOR, PHT, and VPA for SE, but a lower need for ventilator assistance and risk of hypotension, thus can be used as a second-line treatment for SE. However, more well-conducted studies to confirm the role of intravenous LEV for SE are still needed.

Treatment of status epilepticus with zonisamide: A multicenter cohort study of 34 patients and review of literature

IntroductionWe present a summary of clinical cases of oral zonisamide (ZNS) used to treat refractory and super-refractory episodes of status epilepticus (SE). MethodsZonisamide administration in SE was identified in the clinical records of patients treated in Frankfurt and Marburg between 2011 and 2017. ResultsZonisamide was administered during a total of 37 SE episodes in 34 patients with a mean age of 58.7 ± 17.8 years, 21 of them were female (61.7%). The median latency from the onset of SE to administration of ZNS was 6.3 days. Patients had already undergone unsuccessful treatment with a median of three other antiseizure drugs (ASDs).The median initial dose of ZNS was 100 mg/d, titrated to a median maintenance dose of 400 mg/d. Patients underwent ZNS treatment for a median period of 7 days. Zonisamide was the final drug administered in 9 of 37 (24.3%) episodes, with a clinical effect attributed to ZNS observed in 6 of 37 (16.2%) episodes. An effect attributed to ZNS was observed in 5 out of 30 episodes of refractory SE (RSE) and in one out of 7 episodes of super-refractory SE (SRSE). Possible negative side effects of ZNS were observed in two patients (one patient each with ataxia and skin rash). The mortality rate in hospitalized patients was 10.4% (n = 4). ConclusionThe rate of SE resolution attributed to ZNS treatment (16.2%) can be considered relevant, particularly since ZNS treatment tends to be administered only after several other options have been tried, and has a treatment latency of over six days. Zonisamide may therefore be considered as an alternative oral treatment option in RSE and SRSE.

Implementation of a Standardized Seizure Action Plan to Improve Communication and Parental Education

BackgroundQuality measures have highlighted the need for efficient treatment of status epilepticus. One strategy is prevention of refractory status epilepticus through individualized seizure action plans. As a quality improvement project, we implemented a standardized seizure action plan to improve the delivery of key information to families of children with seizures. MethodsWe implemented our standardized seizure action plan using plan-do-study-act cycles. The plans were distributed to caregivers of children (zero to 18 years) seen for seizures in outpatient neurology clinics. Families were given questionnaires at the beginning of each visit to gauge their understanding of their child’s diagnosis, treatment, and comfort in emergency seizure management. Provider utilization rates and questionnaire responses were analyzed over time to assess the effectiveness of the action plan. ResultsProvider utilization rates of the standardized seizure action plan improved from 0% to 58.1%. At baseline, 31.5% caregivers indicated that they did not know their child’s epilepsy syndrome or seizure type, 29.6% did not know the emergency protocol at their child’s school, 9.2% did not know when to consider a seizure an emergency or what to do if their child’s seizure had become an emergency, and 17.5% were not comfortable administering rescue medication. Caregivers who received the action plan had improved responses at subsequent visits (P < 0.001), whereas those who did not receive the standardized form did not improve. ConclusionsStandardizing provision of seizure action plans in pediatric neurology clinic can improve key elements of caregiver education regarding epilepsy diagnoses and seizure emergencies.

Phenobarbital as alternate anticonvulsant for organophosphate-induced benzodiazepine-refractory status epilepticus and neuronal injury.

ObjectiveOrganophosphates (OPs) such as diisopropylfluorophosphate (DFP) and soman are lethal chemical agents that can produce seizures, refractory status epilepticus (SE), and brain damage. There are few optimal treatments for late or refractory SE. Phenobarbital is a second‐line drug for SE, usually after lorazepam, diazepam, or midazolam have failed to stop SE. Practically, 40 minutes or less is often necessary for first responders to arrive and assist in a chemical incident. However, it remains unclear whether administration of phenobarbital 40 minutes after OP intoxication is still effective. Here, we investigated the efficacy of phenobarbital treatment at 40 minutes postexposure to OP intoxication.MethodsAcute refractory SE was induced in rats by DFP injection as per a standard paradigm. After 40 minutes, subjects were given phenobarbital intramuscularly (30‐100 mg/kg) and progression of seizure activity was monitored by video‐EEG recording. The extent of brain damage was assessed 3 days after DFP injections by neuropathology analysis of neurodegeneration and neuronal injury by unbiased stereology.ResultsPhenobarbital produced a dose‐dependent seizure protection. A substantial decrease in SE was evident at 30 and 60 mg/kg, and a complete seizure termination was noted at 100 mg/kg within 40 minutes after treatment. Neuropathology findings showed significant neuroprotection in 100 mg/kg cohorts in brain regions associated with SE. Although higher doses resulted in greater protection against refractory SE and neuronal damage, they did not positively correlate with improved survival rate. Moreover, phenobarbital caused serious adverse effects including anesthetic or comatose state and even death.SignificancePhenobarbital appears as an alternate anticonvulsant for OP‐induced refractive SE in hospital settings. A careful risk‐benefit analysis is required because of negative outcomes on survival and cardio‐respiratory function. However, the need for sophisticated support and critical monitoring in hospital may preclude its use as medical countermeasure in mass casualty situations.

Effectiveness of ketamine in the treatment of refractory and super-refractory status epilepticus in children

Objective: To investigate the effectiveness of ketamine in the treatment of refractory status epilepticus (RSE) and super refractory status epilepticus (SRSE) in children. Methods: A retrospective study was conducted to collect and analyze the medical data of 18 children with RSE or SRSE who received ketamine in intensive care unit of Beijing Children's Hospital from January 2016 to December 2018. According to the different regimen of ketamine, all children were divided into the loading-maintenance group (7 cases) and the maintenance group (11 cases). According to the control of status epilepticus, the patients were divided into controlled group (11 cases) and non-responsive group (7 cases).Wilcoxon's rank sum test or Fisher's exact test were used to compare the effectiveness between groups. Results: There were 9 males and 9 females in the study group, aged 6.7 (4.5, 9.0) years. Seven cases had RSE and the remaining had SRSE. Four cases died during hospitalization. After the initiation of ketamine treatment, RSE and SRSE were controlled in 11 children. The duration of ketamine administration was 4 (2, 11) days. The dose was 2.2 (1.2, 5.3) mg/(kg·h) in all patients, and 2.4 (1.3, 6.0) mg/(kg·h), 2.0 (1.0, 4.0) mg/(kg · h) in the controlled and non-responsive group, respectively (Z=-0.272, P=0.791). The RSE or SRSE were terminated in all the 7 patients who received loading dose of ketamine, with the dose of 1.5 (0.3,1.6) mg/kg. In the 11 patients who only received maintenance treatment, 4 had the RSE and SRSE terminated, which showed a significantly lower effectiveness than in loading-maintenance group (7/7 vs. 4/11, P=0.01). Regarding the adverse reactions, saliva secretion increased in 8 children during the ketamine administration, otherwise unremarkable. Conclusion: Loading dose followed by maintenance of ketamine can control children's RSE and SRSE well, without significant adverse reactions.

Electroencephalographic analysis in soman-exposed 21-day-old rats and the effects of midazolam or LY293558 with caramiphen.

Acute nerve agent exposure induces status epilepticus (SE), which can cause brain damage or death. Research aiming at developing effective therapies for controlling nerve agent-induced SE is commonly performed in adult rats. The characteristics of nerve agent-induced SE in young rats are less clear; relevant knowledge is necessary for developing effective pediatric therapies. Here, we have used electroencephalographic (EEG) recordings and analysis to study seizures in postnatal day 21 rats exposed to 1.2 × LD50 of soman, and compared the antiseizure efficacy of midazolam (MDZ)-currently considered by the Food and Drug Administration to replace diazepam for treating SE in victims of nerve agent exposure-with that of LY293558, an AMPA/GluK1 receptor antagonist, administered in combination with caramiphen, an antimuscarinic with N-methyl-d-aspartate receptor antagonistic properties. Prolonged SE developed in 80% of the rats and was reflected in behavioral seizures/convulsions. Both MDZ and LY293558+ caramiphen stopped the SE induced by soman, but there was a significant recurrence of seizures within 24 h postexposure only in the MDZ-treated group, as revealed in the raw EEG data and their representation in the frequency domain using a fast Fourier transform and in spectral analysis over 24 hours. In contrast to the high efficacy of LY293558 + caramiphen, MDZ is not an effective treatment for SE induced by soman in young animals.

Propofol inhibited apoptosis of hippocampal neurons in status epilepticus through miR-15a-5p/NR2B/ERK1/2 pathway

ABSTRACTAlthough a previous study reported that propofol had a therapeutic effect in status epilepticus (SE), the mechanisms underlying the effect of propofol in SE remain unclear. The aim of this study was to explore the regulatory mechanisms underlying propofol-induced inhibition of SE.A rat SE model was established using the lithium–pilocarpine injection method. A qRT-PCR and Western blot were utilized to detect the expression of relative molecules. Cell apoptosis was evaluated by a flow cytometry assay. The interaction between miR-15a-5p and NR2B was assessed using a luciferase reporter assay.Propofol inhibited cell apoptosis and increased miR-15a-5p expression both in hippocampal tissues of SE rats and low Mg2+-induced hippocampal neurons. Propofol-induced attenuation of apoptosis of low Mg2+-induced hippocampal neurons was mediated by miR-15a-5p. miR-15a-5p targeted NR2B and negatively regulated its expression. Propofol downregulated NR2B expression, mediated by miR-15a-5p. In terms of the mechanism of action, propofol suppressed the apoptosis of Mg2+-induced hippocampal neurons through the miR-15a-5p/NR2B/ERK1/2 pathway. In vivo experiment suggested that propofol inhibited the apoptosis of hippocampal neurons in SE rats by upregulating miR-15a-5p.In terms of the molecular mechanism of propofol, it appears to inhibit apoptosis of hippocampal neurons in SE through the miR-15a-5p/NR2B/ERK1/2 pathway. The findings provide theoretical support for propofol treatment of SE.

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial

Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075. Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Status epilepticus severity score as a predictor for the length of stay at hospital for acute-phase treatment in convulsive status epilepticus

To date, hospital length of stay (LOS) determinants for convulsive status epilepticus’s (CSE) acute-phase treatment have not been sufficiently investigated, as opposed to those for status epilepticus’s (SE) outcome predictors, such as status epilepticus severity score (STESS). Here, we aimed at assessing the significance of STESS in the LOS in patients with CSE. We retrospectively reviewed consecutive adult patients with CSE who were transported to the emergency department of our urban tertiary care hospital in Tokyo, Japan. The study period was from August 2010 to September 2015. The primary endpoint was the LOS of patients with CSE who were directly discharged after acute-phase treatment, and survival analysis for LOS until discharge was conducted. As a result, among 132 eligible patients with CSE admitted to our hospital, 96 (72.7%) were directly discharged with a median LOS of 10 days (IQR: 4–19 days). CSE patients with severe seizures, represented by higher STESS (≥3), had a significantly longer LOS after adjustments with multiple covariates (p = 0.016, in restricted mean survival time analysis). Additionally, prediction for the binomial longer/shorter LOS achieved better performance when STESS was incorporated into the prediction model. Our findings indicate that STESS can also be used as a rough predictor of longer LOS at index admission of patients with CSE.

Abdominal Compartment Syndrome: A Rare Complication of Pentobarbital Treatment for New-Onset Refractory Status Epilepticus

Abdominal Compartment Syndrome: A Rare Complication of Pentobarbital Treatment for New-Onset Refractory Status Epilepticus

Clinical Effectiveness of Levetiracetam Compared to Fosphenytoin in the Treatment of Benzodiazepine Refractory Convulsive Status Epilepticus.

To determine whether levetiracetam is an alternative to fosphenytoin to control Benzodiazepine Refractory Status Epilepticus (BRSE) in pediatric population and also to compare the acute drug related side-effects and ventilation requirement among the both arms of anti-epileptic drug therapy. All consecutive children admitted with BRSE were randomized to group A, who received fosphenytoin at 20mg/kg phenytoin equivalents (PE) dose and group B who received levetiracetam at 40mg/kg over 10min. Time to terminate seizure (response latency) was measured. If seizure remained refractory after 20min of test drug administration, appropriate drug escalation was made according to pediatrician's discretion. All primary and secondary outcome measures were compared between the two therapeutic groups. Of 61 children enrolled over 18 mo period, 29 (47.5%) were randomized to group A and 32 (52.5%) were randomized to Group B. Baseline characteristics were comparable between the two groups. Among 61 children, 58(98%) required Pediatric Intensive Care Unit (PICU) admission and among those 5(8.2%) children required mechanical ventilation. Duration of PICU stay, hospital stay, the response latency and seizure recurrence were compared between both groups. Significant number of children received additional anti-epileptic drugs (AEDs) in fosphenytoin group [9/29(31%)] compared to levetiracetam group [2/32(7%)] to control seizure. Levetiracetam may be an effective alternative to fosphenytoin in management of BRSE in children but multicentric trials with large sample size are needed to substantiate this observation.

Analysis of the effect of valproic acid with different loading doses in treatment of children with status epilepticus

Objective To explore the effect of valproic acid with different loading doses in treatment of children with status epilepticus. Methods The data of children who were hospitalized in the intensive care unit of the Children′s Hospital Affiliated to Zhejiang University because of status epilepticus from January 1, 2013 to December 31, 2017 were collected.All the patients were divided into different groups according to loading dose of valproic acid.The effect were analyzed in different groups. Results (1)There were 66 children with status epilepticus were admitted, including 35 males and 31 females.Among all children with status epilepticus, the etiology included epilepsy(n=36, 54.5%), intracranial infection(n=16, 24.2%), hypoxic asphyxia (n=3, 4.5%), intracranial tumor(n=2, 3.0%), abnormal brain development(n=2, 3.0%), intracranial hemorrhage(n=2, 3.0%), and etiology was not clear(n=5, 7.6%). (2)All children with status epilepticus were divided into four groups according to different valproic acid loading dose(0 mg/kg, 10-15 mg/kg, 16-39 mg/kg, 40 mg/kg). There are no significant differences in gender and age among groups.There were no significant differences in duration of status epilepticus and epileptic treatment efficiency(P=0.402, 0.034). (3)All children were monitored for liver function after the treatment of sodium valproate, and no patient had been found increased alanine aminotransferase. Conclusion There are no significant differences in the effect of different valproic acid loading doses in children with status epilepticus, and no adverse side effects are observed in children with status epilepticus who received a dose of 40 mg/kg. Key words: Status epilepticus; Valproic acid; Loading dose

Is rat hippocampus section immunostaining an indicator for immunotherapy in cryptogenic adult new-onset refractory status epilepticus (NORSE)?

PurposeTo evaluate the meaning of immunostaining of rat hippocampus with respect to clinical manifestations, Status epilepticus(SE)severity, treatment, and prognosis of New-Onset Refractory Status Epilepticus(NORSE) patients. MethodsConsecutive patients with cryptogenic NORSE admitted to the neuro-intensive care unit (NICU) between January 2015 and October 2018 were screened, and those who had serum and cerebrospinal fluid (CSF) immunostaining were included. Subsequently, the patients were classified into positive and negative immunostain groups. Immunotherapy was initiated in patients who progressed to super-RSE (SRSE). The demographic, and clinical, and immunostaining data were collected. The prognosis was evaluated by modified Rankin scale (mRS) at discharge (short-term prognosis) and 6 months (long-term prognosis), with mRS score ≤2 defined as the favorable outcome. The clinical manifestations, treatment response, and prognosis were compared between the patients with positive and negative immunostains. Results4/18 patients had positive immunostaining on both CSF and serum, 8 (had positive immunostaining on serum only, while 6 had negative immunostaining on serum and CSF. Twelve (66.7 %) patients progressed to SRSE, with no difference between the positive and negative immunostaining groups (P = 1.000). 7/18 patients had a favorable outcome at discharge and 11/18 after 6 months. No significant difference on the prognosis was detected between patients with positive and negative serum/CSF immunostaining and between the patients with or without immunotherapy at discharge or 6-month follow-up (P = 0.657/P = 0.502, P = 0.445/P = 0.829, P = 0.622, P = 0.567, respectively). ConclusionsThe immunostaining on serum and/or CSF from NORSE patients did not indicate the progression to SRSE and clinical outcomes.

Seizures in patients with cancer.

Seizures are common in patients with cancer and either result from brain lesions, paraneoplastic syndromes, and complications of cancer treatment or are provoked by systemic illness (metabolic derangements, infections). Evaluation should include a tailored history, neurologic examination, laboratory studies, neuroimaging, and electroencephalogram. In unprovoked seizures, antiepileptic drug (AED) treatment is required, and a nonenzyme-inducing AED is preferred. Treatment of the underlying cancer with surgery, chemotherapy, and radiation therapy also can help reduce seizures. Benzodiazepines are useful in the treatment of both provoked seizures and breakthrough epileptic seizures and as first-line treatment for status epilepticus. Counseling for safety is an important component in the care of a patient with cancer who has seizures. Good seizure management can be challenging but significantly improves the quality of life during all phases of care, including end-of-life care.

In-vitro and in-vivo evaluation of chitosan-based thermosensitive gel containing lorazepam NLCs for the treatment of status epilepticus.

The objective of this study was to develop an in-situ gel containing lorazepam (LZM) loaded nanostructured lipid carriers (NLCs) for direct nose-to-brain delivery in order to increase drug therapeutic efficacy in the treatment of epilepsy. Accordingly, LZM loaded NLCs were formulated using emulsification solvent diffusion and evaporation method; then the effects of the formulation variables on different physicochemical characteristics of NLCs were investigated. Thermosensitive in-situ gels containing LZM-NLCs were prepared using a combination of chitosan and β-glycerol phosphate (β-GP). The anticonvulsant efficacy of LZM-NLCs-Gel was then examined using the pentylenetetrazole (PTZ) model. The optimised NLCs were spherical, showing the particle size of 71.70 ± 5.16 nm and the zeta potential of -20.06 ± 2.70 mV. The pH and gelation time for the chitosan solution with 15% (w/v) β-GP were determined to be 7.12 ± 0.03 and 5.33 ± 0.58 min, respectively. The in-vivo findings showed that compared with the control group and the group that received LZM-Gel, the occurrence of PTZ-induced seizures in the rats was significantly reduced by LZM-NLCs-Gel after intranasal administration. These results, therefore, suggested that the LZM-NLCs-Gel system could have potential applications for brain targeting through nasal route and might increase LZM therapeutic efficacy in the treatment of epilepsy.

Differential Expression of the Metabotropic P2Y Receptor Family in the Cortex Following Status Epilepticus and Neuroprotection via P2Y1 Antagonism in Mice.

Purinergic signaling via P2 receptors is now widely accepted to play a critical role during increased states of hyperexcitability and seizure-induced pathology. In the setting of seizures and epilepsy, most attention has been paid to investigating the fast-acting ATP-gated P2X receptor family. More recent evidence has now also provided compelling evidence of an involvement of the slower-acting P2Y receptor family during seizures. This includes data demonstrating expression changes of P2Y receptors in the hippocampus following acute seizures and during epilepsy and anticonvulsive properties of P2Y-targeting drugs; in particular drugs targeting the P2Y1 subtype. Seizures, however, also involve damage to extra-hippocampal brain regions such as the cortex, which is thought to contribute to the epileptic phenotype. To analyze expressional changes of the P2Y receptor family in the cortex following status epilepticus and to determine the impact of drugs interfering with P2Y1 signaling on cortical damage, we used a unilateral mouse model of intraamygdala kainic acid-induced status epilepticus. Analysis of cortical tissue showed that status epilepticus leads to a global up-regulation of the P2Y receptor family in the cortex including P2Y1, P2Y2, P2Y4, and P2Y6, with the P2Y1 and P2Y4 receptor subtypes showing the strongest increase. Supporting a detrimental role of P2Y1 activation during status epilepticus, treatment with the P2Y1 agonist MRS2365 exacerbated high frequency high amplitude spiking, synonymous with injury-causing electrographic activity, and treatment with the P2Y1 antagonists MRS2500 protected against seizure-induced cortical damage. Suggesting P2Y1-mediated effects are predominantly due to increased microglia activation, treatment with the broad-spectrum anti-inflammatory drug minocycline abolished the observed neuroprotective effects of P2Y1 antagonism. In conclusion, our results further support a role for P2Y1-mediated signaling during seizure generation and seizure-induced neurodegeneration, suggesting P2Y1-targeting therapies as novel treatment for drug-refractory status epilepticus.