Regional determinants for outcome and cost of status epilepticus.

OBJECTIVE: Status epilepticus (SE) requires informed management. Since regional differences exist in practice and outcome, we aimed to characterize the epidemiology of SE and identify the factors associated with cost-effective management at the sole level IV epilepsy center of Central New York (CNY). METHODS: We searched for patients aged 18 years or older admitted at our center's hospitals from February 2018 to November 2019 with the discharge diagnosis of SE. Seventy-seven individuals with definite SE were included. We constructed models to determine the main factors that impact the refractoriness of SE, the clinical outcome, and the estimated cost of hospitalization. RESULTS: The rate of SE-related disability was 20.8% and the all-cause mortality 36.4%. Our analysis showed that initial anti-seizure medication (ASM) choice did not have a significant influence on the clinical outcome; nor did it affect the refractoriness of SE. Likewise, our anesthetic regimen did not alter the disease course or outcome. In line with prior studies, we demonstrated that age carried a negative predictive value to the SE-related disability and mortality (CI95% [-0.02, 0], p < 0.001). Interestingly, we found that use of midazolam (CI95% [-20.8, -0.08], p = 0.05) and anoxic brain injury as the underlying etiology (CI95% [-33.5, -1.59], p = 0.03) were marginally associated with shorter hospitalizations and reduced cost. The latter might reflect the rapidly-deteriorating course of anoxic brain injury, complicated by its higher likelihood of refractoriness (CI95% [0.14, 0.79], p = 0.006), and consequently, the decision to withdraw care. CONCLUSION: Taken together, we described the demographics, management, and prognosis of SE locally and further defined the potential determinants for the cost-effective care. We found that similar to other studies, age was the main determinant factor in prognosis. We also noticed that midazolam usage was associated with shorter hospital stay, suggesting that strategic use of midazolam may reduce the direct cost of management of SE. These findings can be adopted to optimize SE management in CNY.

A Simulation-Based Assessment of Levetiracetam Concentrations Following Fixed and Weight-Based Loading Doses: A Meta-Regression and Pharmacokinetic Modeling Analysis.

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight-based loading doses of LEV with respect to established therapeutic target concentrations. Meta-regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight-based dosing) to achieve maximum (Cpeak) and 12-h (C12h) plasma concentrations that exceed 12 mg/L. The meta-regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight-based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight-based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing.

Economic review of point-of-care EEG.

Aims: Point-of-care electroencephalogram (POC-EEG) is an acute care bedside screening tool for the identification of nonconvulsive seizures (NCS) and nonconvulsive status epilepticus (NCSE). The objective of this narrative review is to describe the economic themes related to POC-EEG in the United States (US).Materials and methods: We examined peer-reviewed, published manuscripts on the economic findings of POC-EEG for bedside use in US hospitals, which included those found through targeted searches on PubMed and Google Scholar. Conference abstracts, gray literature offerings, frank advertisements, white papers, and studies conducted outside the US were excluded.Results: Twelve manuscripts were identified and reviewed; results were then grouped into four categories of economic evidence. First, POC-EEG usage was associated with clinical management amendments and antiseizure medication reductions. Second, POC-EEG was correlated with fewer unnecessary transfers to other facilities for monitoring and reduced hospital length of stay (LOS). Third, when identifying NCS or NCSE onsite, POC-EEG was associated with greater reimbursement in Medical Severity-Diagnosis Related Group coding. Fourth, POC-EEG may lower labor costs via decreasing after-hours requests to EEG technologists for conventional EEG (convEEG).Limitations: We conducted a narrative review, not a systematic review. The studies were observational and utilized one rapid circumferential headband system, which limited generalizability of the findings and indicated publication bias. Some sample sizes were small and hospital characteristics may not represent all US hospitals. POC-EEG studies in pediatric populations were also lacking. Ultimately, further research is justified.Conclusions: POC-EEG is a rapid screening tool for NCS and NCSE in critical care and emergency medicine with potential financial benefits through refining clinical management, reducing unnecessary patient transfers and hospital LOS, improving reimbursement, and mitigating burdens on healthcare staff and hospitals. Since POC-EEG has limitations (i.e. no video component and reduced montage), the studies asserted that it did not replace convEEG.

Acute Valproate-Induced Encephalopathy in Status Epilepticus: A Registry-Based Assessment.

BACKGROUND: Valproate-induced encephalopathy (VIE) affects between 0.1% and 2.5% of patients under long-term epilepsy treatment. Its frequency and characteristics in adults with status epilepticus (SE) is, however, unknown. OBJECTIVE: The aim of this study was to characterize the frequency and the clinico-biological characteristics of VIE in adult SE patients. METHODS: We reviewed all patients included in our institutional SE registry who were treated for an SE episode between November 2021 and February 2023 and identified 39 patients who received valproate for their SE treatment. Acute VIE was defined by worsening of consciousness having led to the discontinuation of valproate, and improvement of consciousness within 96 hours after discontinuation of valproate during acute hospital treatment. RESULTS: Patients had a mean valproate intravenous loading dose of 34.5 mg/kg and a mean maintenance dose of 15.3 mg/kg/d (1078 mg/d). Four out of 29 patients with measured ammonium had hyperammonemia. We identified four (10%) patients fulfilling acute VIE criteria. Median time from administration of valproate to the occurrence of VIE, and to resolution of VIE after cessation of valproate treatment, was 2 days for each. Three of the four VIE patients had no associated hyperammonemia. Patients who developed VIE more frequently had a history of liver disease (p = 0.023), and tended to be younger, but other clinical variables did not differ significantly from patients without VIE, including valproate loading or maintenance doses, SE cause, duration or severity, other concomitant antiseizure medications (none received topiramate, phenobarbital, or primidone). CONCLUSION: Pending larger studies, VIE in SE seems relatively frequent and difficult to foresee; clinical alertness to symptoms is mandatory, even without hyperammonemia, and valproate withdrawal should be considered in suspected cases.

Quantitative assessment of burst suppression as a predictor of seizure recurrence in refractory status epilepticus.

OBJECTIVE: To determine whether quantitative EEG analysis of burst suppression can predict seizure recurrence in patients with refractory status epilepticus (RSE) being treated with anesthetic doses of continuous IV antiseizure medications (cIVASM). METHODS: Quantitative assessment of burst suppression (including epileptiform discharges [EDs] and evolution) in 31 occasions (from 27 patients), and correlation with seizure recurrence up to 48 hours post sedative wean. RESULTS: Occasions resulting in seizure recurrence (vs. no seizure recurrence) had lower burst (8.4 vs. 10.6 µV) and interburst interval (IBI) (4.2 vs. 4.8 µV) average amplitude, duration (bursts 2.8 vs. 3.6 s: IBIs 3.6 vs. 4.4 s); and burst total power (0.4 vs. 0.7 µV2). Bursts (0.86 vs. 0.60) and IBIs (0.28 vs. 0.07) with EDs, higher number of EDs within bursts (mean 2.1 vs. 1.4) and IBIs (0.6 vs. 0.2), and positive evolution measures all predicted seizure recurrence, although EDs had the greatest adjusted odds ratio on multivariate analysis. CONCLUSIONS: For patients in burst suppression, successful wean of cIVASM was not determined by classical burst suppression measures, but instead how "epileptiform" bursts and IBIs were, as determined by EDs in both bursts and IBIs and surrogates for evolution within bursts. SIGNIFICANCE: If confirmed, these objective measures could be used during clinical care to help determine when to wean cIVASM in patients with RSE.

Costs and cost-driving factors of acute treatment of status epilepticus in children and adolescents: A cohort study from Germany.

OBJECTIVE: To provide data on inpatient costs and cost-driving factors in children and adolescents due to non-refractory (NSE), refractory (RSE), and super-refractory status epilepticus (SRSE). METHODS: All children and adolescents treated for status epilepticus (SE) between 2011 and 2018 at the Frankfurt University Hospital were analyzed for health care utilization. RESULTS: We evaluated 223 admissions in 174 patients (6.8 ± 5.1 years, median 5.5 years, range 0.1-17.5 years, 109 males [62.6%]) treated for SE. Mean costs of hospital treatment were €5,711 (median €2,330, range = €654-€102,414) per patient per admission, with a mean length of stay (LOS) of 9.2 days (median 5.0, range = 1-101), resulting in mean costs of €621 per SE treatment day. Course of SE had a significant impact on the mean costs, which were €3,386 in NSE (median €2,139, range €654-€38,236, €529 per treatment day; 37% of total inpatient costs due to SE), €7,409 in RSE (median €2,772, range €700-€38,236; €612 per treatment day, 38% of total inpatient costs due to SE) and €17,436 in SRSE (median €6,911, range €2,138-102,414; €842 per treatment day, 25% of total inpatient costs due to SE). Independent cost-driving factors were three or more treatment steps, acute-symptomatic etiology, and unfavorable modified Rankin Scale score at admission. Increased LOS was predicted by three or more treatment steps and unfavorable modified Rankin Scale score at admission. Overall mortality at discharge was 1.3% (three patients). CONCLUSIONS: Acute treatment of SE, and particularly RSE and SRSE, is associated with high hospital costs and prolonged LOS. Patients with disabilities are at risk for an unfavorable course of SE, resulting in prolonged LOS. In general, mortality associated with SE is low in children and adolescents, however three or more treatment steps are associated with high treatment costs.

Pre-hospital and emergency department treatment of convulsive status epilepticus in adults: an evidence synthesis.

BACKGROUND: Convulsive status epilepticus is defined as ≥ 5 minutes of either continuous seizure activity or repetitive seizures without regaining consciousness. It is regarded as an emergency condition that requires prompt treatment to avoid hospitalisation and to reduce morbidity and mortality. Rapid pre-hospital first-line treatment of convulsive status epilepticus is currently benzodiazepines, administered either by trained caregivers in the community (e.g. buccal midazolam, rectal diazepam) or by trained health professionals via intramuscular or intravenous routes (e.g. midazolam, lorazepam). There is a lack of clarity about the optimal treatment for convulsive status epilepticus in the pre-hospital setting. OBJECTIVES: To assess the current evidence on the clinical effectiveness and cost-effectiveness of treatments for adults with convulsive status epilepticus in the pre-hospital setting. DATA SOURCES: We searched major electronic databases, including MEDLINE, EMBASE, PsycInfo®, CINAHL, CENTRAL, NHS Economic Evaluation Database, Health Technology Assessment Database, Research Papers in Economics, and the ISPOR Scientific Presentations Database, with no restrictions on publication date or language of publication. Final searches were carried out on 21 July 2020. REVIEW METHODS: Systematic review of randomised controlled trials assessing adults with convulsive status epilepticus who received treatment before or on arrival at the emergency department. Eligible treatments were any antiepileptic drugs offered as first-line treatments, regardless of their route of administration. Primary outcomes were seizure cessation, seizure recurrence and adverse events. Two reviewers independently screened all citations identified by the search strategy, retrieved full-text articles, extracted data and assessed the risk of bias of the included trials. Results were described narratively. RESULTS: Four trials (1345 randomised participants, of whom 1234 were adults) assessed the intravenous or intramuscular use of benzodiazepines or other antiepileptic drugs for the pre-hospital treatment of convulsive status epilepticus in adults. Three trials at a low risk of bias showed that benzodiazepines were effective in stopping seizures. In particular, intramuscular midazolam was non-inferior to intravenous lorazepam. The addition of levetiracetam to clonazepam did not show clear advantages over clonazepam alone. One trial at a high risk of bias showed that phenobarbital plus optional phenytoin was more effective in terminating seizures than diazepam plus phenytoin. The median time to seizure cessation from drug administration varied from 1.6 minutes to 15 minutes. The proportion of people with recurrence of seizures ranged from 10.4% to 19.1% in two trials reporting this outcome. Across trials, the rates of respiratory depression among participants receiving active treatments were generally low (from 6.4% to 10.6%). The mortality rate ranged from 2% to 7.6% in active treatment groups and from 6.2% to 15.5% in control groups. Only one study based on retrospective observational data met the criteria for economic evaluation; therefore, it was not possible to draw any robust conclusions on cost-effectiveness. LIMITATIONS: The limited number of identified trials and their differences in terms of treatment comparisons and outcomes hindered any meaningful pooling of data. None of the included trials was conducted in the UK and none assessed the use of buccal midazolam or rectal diazepam. The review of economic evaluations was hampered by lack of suitable data. CONCLUSIONS: Both intravenous lorazepam and intravenous diazepam administered by paramedics are more effective than a placebo in the treatments of adults with convulsive status epilepticus, and intramuscular midazolam is non-inferior to intravenous lorazepam. Large well-designed clinical trials are needed to establish which benzodiazepines are more effective and preferable in the pre-hospital setting. STUDY REGISTRATION: This study is registered as PROSPERO CRD42020201953. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 26, No. 20. See the NIHR Journals Library website for further project information.

Epilepsy is a common condition that results from abnormal electrical activity in the brain and causes seizures (stiffening and uncontrolled jerking ­ known as a 'fit'). The most severe form of epilepsy is called 'convulsive status epilepticus', which involves continuous seizure activity for 5 minutes or more, or repetitive seizures without recovery of consciousness. Convulsive status epilepticus can be very dangerous and requires prompt treatment to avoid hospitalisation and prevent complications. Although several drugs are available for the treatment of convulsive status epilepticus in the community or in the emergency department, it is unclear which one is most effective in stopping seizures. We brought together results from all available clinical studies that looked at the use of drugs to treat adults with convulsive status epilepticus either before arriving at hospital or on arrival at the emergency department. In the literature, we found four studies (1234 adults) assessing drugs delivered by paramedics through an injection into a vein or into muscle. In general, the drugs used by paramedics (benzodiazepines) were effective in stopping seizures, but we were unable to identify any particular drug or way of administering it as being more successful than others. Future research is needed to establish which drugs are most effective and preferable. It is also important to improve adherence to clinical guidelines with regard to the use of these drugs. For the pre-hospital treatment of convulsive status epilepticus, little evidence was available to decide which drug treatment is the best in terms of value for money. Future studies could assess the (1) impact of treatments on costs and outcomes over the whole course of a seizure episode (2) long-term impact of different treatments on patients' quality of life and (3) health and social care needs.

Automated Pupillometry for Assessment of Treatment Success in Nonconvulsive Status Epilepticus.

BACKGROUND: Altered pupillary function may reflect nonconvulsive status epilepticus (NCSE). Neurological pupil index (NPi) assessed by automated pupillometry is a surrogate marker of global pupillary function. We aimed to assess NPi changes in relation to NCSE treatment response. METHODS: In this prospective observational study, serial automated pupillometry was performed in 68 NCSE episodes. In accordance with local standards, patients were treated with clonazepam (1-2 mg), levetiracetam (40 mg/kg), and lacosamide (5 mg/kg) in a stepwise approach under continuous electroencephalography monitoring until NCSE was terminated. Patients with refractory NCSE received individualized regimens. NPi was assessed bilaterally before and after each treatment step. For statistical analysis, the lower NPi of both sides (minNPi) was used. Nonparametric testing for matched samples and Cohen's d to estimate effect size were performed. Principal component analysis was applied to assess the contribution of baseline minNPi, age, sex, and NCSE duration to treatment outcome. RESULTS: In 97.1% of 68 episodes, NCSE could be terminated; in 16.2%, NCSE was refractory. In 85.3% of episodes, an abnormal baseline minNPi ≤ 4.0 was obtained. After NCSE termination, minNPi increased significantly (p < 0.001). Cohen's d showed a strong effect size of 1.24 (95% confidence interval 0.88-1.61). Baseline minNPi was higher in clonazepam nonresponders vs. responders (p = 0.008), minNPi increased in responders (p < 0.001) but not in nonresponders. NCSE refractivity was associated with normal baseline minNPi (principal component analysis, component 1, 32.6% of variance, r = 0.78), male sex, and longer NCSE duration (component 2, 27.1% of variance, r = 0.62 and r = 0.78, respectively). CONCLUSIONS: Automated pupillometry may be a helpful noninvasive neuromonitoring tool for the assessment of patients with NCSE and response to treatment.

Association Between Treatment Progression, Disease Refractoriness, and Burden of Illness Among Hospitalized Patients With Status Epilepticus.

Importance: Status epilepticus (SE) is associated with poor clinical outcomes and high cost. Increased levels of refractory SE require treatment with additional medications and carry increased morbidity and mortality, but the associations between SE refractoriness, clinical outcomes, and cost remain poorly characterized. Objective: To examine differences in clinical outcomes and costs associated with hospitalization for SE of varying refractoriness. Design, Setting, and Participants: A cross-sectional study of 43 988 US hospitalizations from January 1, 2016 to December 31, 2018, was conducted, including patients with primary or secondary International Statistical Classification of Diseases, Tenth Revision, diagnosis specifying "with status epilepticus." Exposure: Patients were categorized by administration of antiseizure drugs given during hospitalization. Low refractoriness denoted treatment with none or 1 intravenous antiseizure drug. Moderate refractoriness denoted treatment with more than 1 intravenous antiseizure drug. High refractoriness denoted treatment with 1 or more intravenous antiseizure drug, more than 1 intravenous anesthetic, and intensive care unit admission. Main Outcomes and Measures: Outcomes included discharge disposition, hospital length of stay, intensive care unit length of stay, hospital-acquired conditions, and cost (total and per diem). Results: Among 43 988 hospitalizations for SE, 22 851 patients (51.9%) were male; mean age was 49.9 years (95% CI, 49.7-50.1 years). There were 14 694 admissions (33.4%) for low refractory, 10 140 (23.1%) for moderate refractory, and 19 154 (43.5%) for highly refractory SE. In-hospital mortality was 11.2% overall, with the highest rates among patients with highly (18.9%) compared with moderate (6.3%) and low (4.6%) refractory SE (P < .001 for all comparisons). Median hospital length of stay was 5 days (interquartile range [IQR], 2-10 days) with greater length of stay in highly (8 days; IQR, 4-15 days) compared with moderate (4 days; IQR, 2-8 days) and low (3 days; IQR, 2-5 days) refractory SE (P < .001 for all comparisons). Patients with highly refractory SE also had greater hospital costs, with median costs of $25 105 (mean [SD], $41 858 [$59 063]) in the high, $10 592 (mean [SD], $18 328 [$30 776]) in the moderate, and $6812 (mean [SD], $11 532 [$17 228]) in the low refractory cohorts (P < .001 for all comparisons). Conclusions and Relevance: Status epilepticus apparently continues to be associated with a large burden on patients and the US health system, with high mortality and costs that increase with disease refractoriness. Interventions that prevent SE from progressing to a more refractory state may have the potential to improve outcomes and lower costs associated with this neurologic condition.

Preclinical Assessment of a New Hybrid Compound C11 Efficacy on Neurogenesis and Cognitive Functions after Pilocarpine Induced Status Epilepticus in Mice.

Status epilepticus (SE) is a frequent medical emergency that can lead to a variety of neurological disorders, including cognitive impairment and abnormal neurogenesis. The aim of the presented study was the in vitro evaluation of potential neuroprotective properties of a new pyrrolidine-2,5-dione derivatives compound C11, as well as the in vivo assessment of the impact on the neurogenesis and cognitive functions of C11 and levetiracetam (LEV) after pilocarpine (PILO)-induced SE in mice. The in vitro results indicated a protective effect of C11 (500, 1000, and 2500 ng/mL) on astrocytes under trophic stress conditions in the MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) test. The results obtained from the in vivo studies, where mice 72 h after PILO SE were treated with C11 (20 mg/kg) and LEV (10 mg/kg), indicated markedly beneficial effects of C11 on the improvement of the neurogenesis compared to the PILO control and PILO LEV mice. Moreover, this beneficial effect was reflected in the Morris Water Maze test evaluating the cognitive functions in mice. The in vitro confirmed protective effect of C11 on astrocytes, as well as the in vivo demonstrated beneficial impact on neurogenesis and cognitive functions, strongly indicate the need for further advanced molecular research on this compound to determine the exact neuroprotective mechanism of action of C11.

Assessment of benzodiazepine dosing strategies for the management of status epilepticus in the emergency department.

PURPOSE: Although guidelines recommend specific benzodiazepine doses for the treatment of generalized convulsive status epilepticus (GCSE), underdosing appears to be common. The purpose of this investigation was to assess benzodiazepine dosing strategies for the initial management of GCSE in patients presenting to the Emergency Department (ED). METHODS: This was a retrospective review of adult patients who received benzodiazepines in the ED for treatment of GCSE. Characteristics of those achieving seizure cessation following initial benzodiazepine therapy were assessed. RESULTS: 222 patients presented to the ED and received 403 doses of benzodiazepines, of which 1.5% conformed with recommendations. First-line therapy was successful in 86.8% of patients with an average dose of 1.6 mg (0.02 mg/kg). No difference in dosing was noted between those experiencing early cessation and those that did not (p = 0.132). Patients experiencing early cessation were significantly less likely to receive further doses, be intubated, or be admitted to the intensive care unit (ICU) or hospital (p < 0.05 for all comparisons). Those that received early antiepileptic drug therapy were significantly less likely to receive additional benzodiazepine doses, be intubated, or be admitted to the ICU or hospital (p < 0.05 for all comparisons). CONCLUSIONS: According to guideline recommendations, there was consistent underdosing of benzodiazepines noted in both prehospital and ED settings. Early seizure cessation and the early receipt of an antiepileptic drug were found to be associated with multiple significant clinical outcomes. Future investigations should explore optimal dosing strategies for benzodiazepines as well as the impact of early antiepileptic drug administration.

Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT.

BACKGROUND: Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death. The current first-choice second-line drug is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA), for which there is no robust scientific evidence. OBJECTIVE: To determine whether phenytoin or levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is the more clinically effective intravenous second-line treatment of paediatric convulsive status epilepticus and to help better inform its management. DESIGN: A multicentre parallel-group randomised open-label superiority trial with a nested mixed-method study to assess recruitment and research without prior consent. SETTING: Participants were recruited from 30 paediatric emergency departments in the UK. PARTICIPANTS: Participants aged 6 months to 17 years 11 months, who were presenting with convulsive status epilepticus and were failing to respond to first-line treatment. INTERVENTIONS: Intravenous levetiracetam (40 mg/kg) or intravenous phenytoin (20 mg/kg). MAIN OUTCOME MEASURES: Primary outcome - time from randomisation to cessation of all visible signs of convulsive status epilepticus. Secondary outcomes - further anticonvulsants to manage the convulsive status epilepticus after the initial agent, the need for rapid sequence induction owing to ongoing convulsive status epilepticus, admission to critical care and serious adverse reactions. RESULTS: Between 17 July 2015 and 7 April 2018, 286 participants were randomised, treated and consented. A total of 152 participants were allocated to receive levetiracetam and 134 participants to receive phenytoin. Convulsive status epilepticus was terminated in 106 (70%) participants who were allocated to levetiracetam and 86 (64%) participants who were allocated to phenytoin. Median time from randomisation to convulsive status epilepticus cessation was 35 (interquartile range 20-not assessable) minutes in the levetiracetam group and 45 (interquartile range 24-not assessable) minutes in the phenytoin group (hazard ratio 1.20, 95% confidence interval 0.91 to 1.60; p = 0.2). Results were robust to prespecified sensitivity analyses, including time from treatment commencement to convulsive status epilepticus termination and competing risks. One phenytoin-treated participant experienced serious adverse reactions. LIMITATIONS: First, this was an open-label trial. A blinded design was considered too complex, in part because of the markedly different infusion rates of the two drugs. Second, there was subjectivity in the assessment of 'cessation of all signs of continuous, rhythmic clonic activity' as the primary outcome, rather than fixed time points to assess convulsive status epilepticus termination. However, site training included simulated demonstration of seizure cessation. Third, the time point of randomisation resulted in convulsive status epilepticus termination prior to administration of trial treatment in some cases. This affected both treatment arms equally and had been prespecified at the design stage. Last, safety measures were a secondary outcome, but the trial was not powered to demonstrate difference in serious adverse reactions between treatment groups. CONCLUSIONS: Levetiracetam was not statistically superior to phenytoin in convulsive status epilepticus termination rate, time taken to terminate convulsive status epilepticus or frequency of serious adverse reactions. The results suggest that it may be an alternative to phenytoin in the second-line management of paediatric convulsive status epilepticus. Simple trial design, bespoke site training and effective leadership were found to facilitate practitioner commitment to the trial and its success. We provide a framework to optimise recruitment discussions in paediatric emergency medicine trials. FUTURE WORK: Future work should include a meta-analysis of published studies and the possible sequential use of levetiracetam and phenytoin or sodium valproate in the second-line treatment of paediatric convulsive status epilepticus. TRIAL REGISTRATION: Current Controlled Trials ISRCTN22567894 and European Clinical Trials Database EudraCT number 2014-002188-13. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 58. See the NIHR Journals Library website for further project information.

Most epileptic tonic­clonic seizures, also called convulsions, last for < 4 minutes and stop spontaneously. A convulsion that lasts for > 5 minutes is called convulsive status epilepticus. This may cause neurological abnormalities or, rarely, death. There is good scientific evidence for the best first-line medicine, called a benzodiazepine, to stop convulsive status epilepticus. When a benzodiazepine has not stopped status, a second-line medicine is given. The usual second-line medicine, which has been used for > 50 years, is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA). However, it stops status in only half of children. It must be given slowly because it can cause unpleasant and potentially serious side effects. A new medicine called levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) may be more effective. It seems to have less serious side effects than phenytoin. However, there is no good scientific evidence as to whether phenytoin or levetiracetam is better. A randomised controlled trial is the best scientific way to decide which of these two medicines is better. The Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children (EcLiPSE) trial was a randomised controlled trial that compared levetiracetam with phenytoin. A total of 152 children were randomised to receive levetiracetam and a total of 134 children were randomised to receive phenytoin. Research without prior consent was shown to be acceptable to parents, doctors and nurses. Parents' consent to use their child's data and continue in the trial was provided after the emergency situation was resolved. Convulsive status epilepticus stopped in 70.4% of the levetiracetam-treated children and in 64% of the phenytoin-treated children. The median time to status stopping was 35 minutes in the levetiracetam-treated children and 45 minutes in the phenytoin-treated children. Only one participant on phenytoin (vs. none on levetiracetam) experienced serious side effects that were thought to be caused by their treatment. None of the results showed any statistically significant or meaningful difference between levetiracetam and phenytoin. However, the results suggest that levetiracetam might be an alternative choice to phenytoin.

Assessment of midazolam pharmacokinetics in the treatment of status epilepticus.

OBJECTIVES: Refractory status epilepticus (RSE) is often treated with midazolam boluses and continuous infusions, but there is considerable variability in dosing and efficacy. We aimed to evaluate the performance of a clinical midazolam dose escalation pathway for the treatment of pediatric RSE that was designed based on a novel midazolam pharmacokinetic model. DESIGN: Prospective pharmacokinetic study of midazolam bolus and escalation of continuous midazolam infusion. SETTING: Pediatric Intensive Care Unit in quaternary-care academic hospital. SUBJECTS: Children between two months to seventeen years of age who received clinically-indicated midazolam infusion for treatment of RSE. INTERVENTION: Blood sampled at regular intervals during treatment. Main study outcome measure was the accuracy of a pharmacokinetic model to predict serum midazolam concentrations. MEASUREMENTS AND MAIN RESULTS: We analysed data from six subjects. Three subjects had serum midazolam concentrations close to those predicted by our initial model (accuracy 88.9-170.2 %) which incorporates body weight, hepatic function, and renal function. For the other three subjects, all of whom were receiving pre-existing chronic benzodiazepine therapy prior to the RSE episode, the model grossly overestimated serum concentrations (predictive error 420.3-722.5 %). Once the model was corrected for the impact of pre-existing chronic benzodiazepine use on clearance, predicted concentrations more closely reflected those measured in subjects. CONCLUSION: We evaluated a clinical midazolam RSE treatment pathway but discovered that the model on which the pathway was based was not accurate for all patients. We therefore developed a novel pharmacokinetic midazolam model in children with RSE treated with continuous midazolam infusion. This model incorporates body weight, hepatic and renal function, and importantly, a correction factor for pre-existing chronic benzodiazepine use. Once validated, this model may guide dosing and drive the development of more effective treatment pathways for continuous midazolam in RSE.

The burden of decisional uncertainty in the treatment of status epilepticus.

OBJECTIVE: Treatments for convulsive status epilepticus (SE) have a wide range of effectiveness. The estimated effectiveness of non-intravenous benzodiazepines (non-IV BZDs) ranges from approximately 70% to 90% and the estimated effectiveness of non-benzodiazepine antiseizure medications (non-BZD ASMs) ranges from approximately 50% to 80%. This study aimed to quantify the clinical and economic burden of decisional uncertainty in the treatment of SE. METHODS: We performed a decision analysis that evaluates how decisional uncertainty on treatment choices for SE impacts hospital admissions, intensive care unit (ICU) admissions, and costs in the United States. We evaluated treatment effectiveness based on the available literature. RESULTS: Use of a non-IV BZD with high estimated effectiveness, like intranasal midazolam, rather than one with low estimated effectiveness, like rectal diazepam, would result in a median (p25 -p75 ) reduction in hospital admissions from 6 (3.9-8.8) to 1.1 (0.7-1.8) per 100 cases and associated cost reductions of $638 ($289-$1064) per pediatric patient and $1107 ($972-$1281) per adult patient. For BZD-resistant SE, use of a non-BZD ASM with high estimated effectiveness, like phenobarbital, rather than one with low estimated effectiveness, like phenytoin/fosphenytoin, would result in a reduction in ICU admissions from 9.1 (7.3-11.2) to 3.9 (2.6-5.5) per 100 cases and associated cost reduction of $1261 ($445-$2223) per pediatric patient and $319 ($-93-$806) per adult patient. Sensitivity analyses showed that relatively minor improvements in effectiveness may lead to substantial reductions in downstream hospital admissions, ICU admissions, and costs. SIGNIFICANCE: Decreasing decisional uncertainty and using the most effective treatments for SE may substantially decrease hospital admissions, ICU admissions, and costs.

Arterial Spin Labeling Magnetic Resonance Imaging in the Assessment of Non-Convulsive Status Epilepticus in Alzheimer's Disease: A Report of Two Cases.

BACKGROUND The diagnosis of early non-convulsant status epilepticus (NCSE) can be challenging and can overlap with other critical conditions. Two patients with Alzheimer's disease are reported with clinically suspected NCSE presenting in the emergency setting who were diagnosed using arterial spin-labeling magnetic resonance imaging (ASL-MRI) sequences. CASE REPORT In Case 1, a 69-year-old woman with mild Alzheimer's disease and diabetes presented with acute worsening of cognitive status and fluctuating level of consciousness. In Case 2, a 70-year-old man with mild cognitive impairment due to Alzheimer's disease and hypertension presented with acute loss of consciousness and left hemiparesis, without evidence of hypoglycemia or a hypertensive crisis. In both cases, ASL-MRI perfusion images showed focal cerebral hyperperfusion in the posterior cingulate and parietal associative cortex, which involved neurodegenerative areas associated with epilepsy in early Alzheimer's disease. In both cases, the patients developed generalized tonic-clonic epileptic seizures that lasted for 5 minutes or more, which indicated the emergence of status epilepticus that developed from the initial presentation of NCSE. In both cases, electroencephalogram (EEG) findings confirmed that the seizures were controlled by intravenous administration of antiepileptic drugs. Both patients discharged home from the hospital without recurrence of seizures, between 10-12 days after the onset of symptoms. CONCLUSIONS These two cases have demonstrated that ASL-MRI is feasible as an emergency diagnostic tool in clinically suspected NCSE in patients with Alzheimer's disease.

Meta-analysis and cost-effectiveness of second-line antiepileptic drugs for status epilepticus.

OBJECTIVE: Compare the cost and effectiveness of nonbenzodiazepine antiepileptic drugs (non-BZD AEDs) for treatment of BZD-resistant convulsive status epilepticus (SE). METHODS: Decision analysis model populated with effectiveness data from a systematic review and meta-analysis of the literature, and cost data from publicly available prices. The primary outcome was cost per seizure stopped ($/SS). Sensitivity analyses evaluated the robustness of the results across a wide variation of the input parameters. RESULTS: We included 24 studies with 1,185 SE episodes. The most effective non-BZD AED was phenobarbital (PB) with a probability of SS of 0.8 (95% confidence interval [CI]: 0.69-0.88), followed by valproate (VPA) (0.71 [95% CI: 0.61-0.79]), lacosamide (0.66 [95% CI: 0.51-0.79]), levetiracetam (LEV) (0.62 [95% CI: 0.5-0.73]), and phenytoin/fosphenytoin (PHT) (0.53 [95% CI: 0.39-0.67]). In pairwise comparisons, PB was more effective than PHT (p = 0.002), VPA was more effective than PHT (p = 0.043), and PB was more effective than LEV (p = 0.018). The most cost-effective non-BZD AED was LEV (incremental cost-effectiveness ratio [ICER]: $18.55/SS), followed by VPA (ICER: $94.44/SS), and lastly PB (ICER: $847.22/SS). PHT and lacosamide were not cost-effective compared to the other options. Sensitivity analyses showed marked overlap in cost-effectiveness, but PHT was consistently less cost-effective than LEV, VPA, and PB. CONCLUSION: VPA and PB were more effective than PHT for SE. There is substantial overlap in the cost-effectiveness of non-BZD AEDs for SE, but available evidence does not support the preeminence of PHT, neither in terms of effectiveness nor in terms of cost-effectiveness.

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial.

BACKGROUND: Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus. METHODS: This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894. FINDINGS: Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91-1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). INTERPRETATION: Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Cost of status epilepticus (SE): Effects of delayed treatment and SE duration.

BACKGROUND: The health expenditure related to status epilepticus (SE) is high because of lengthy hospitalization requirements and possible sequelae. We aimed to study the factors associated with this cost including the different timings of the treatment and SE duration. METHODS: We evaluated retrospectively all SE recorded in 2 hospitals. The factors studied included the mean cost of hospitalization, demographics, clinical data, duration of hospitalization, in-hospital/out-of-hospital debut, time from onset to treatment, duration of SE, and destination at discharge. RESULTS: Three hundred five patients were evaluated (December/2012-July/2017), 195 with out-of hospital and 110 with in-hospital debut. The cost of SE with out-of-hospital onset was significantly lower (6559€ vs 15,174€; p = 0.0001). In out-of-hospital cases, the factors independently related to expenditure were the level of consciousness (p < 0.001), presence of complications (p = 0.005), a potentially fatal etiology (p = 0.008), and duration of the episode (p = 0.003). Duration was significantly higher in patients discharged to a convalescence center (p = 0.006); this variable was significantly related to the time SE onset-arrival to hospital, and SE onset-administration of the treatment. In the in-hospital cases, cost was related to male sex (p = 0.002), the development of complications (p = 0.003), and the etiology (p = 0.016) but was not directly related to the SE duration or to the time onset-treatment. CONCLUSIONS: The duration of SE and the speed with which proper management is applied have a direct impact on the healthcare expenditure resulting from out-of-hospital SE. In contrast, the etiology and development of complications are the main factors responsible for expenditure related to in-hospital SE.

Nonintravenous rescue medications for pediatric status epilepticus: A cost-effectiveness analysis.

OBJECTIVE: To quantify the cost-effectiveness of rescue medications for pediatric status epilepticus: rectal diazepam, nasal midazolam, buccal midazolam, intramuscular midazolam, and nasal lorazepam. METHODS: Decision analysis model populated with effectiveness data from the literature and cost data from publicly available market prices. The primary outcome was cost per seizure stopped ($/SS). One-way sensitivity analyses and second-order Monte Carlo simulations evaluated the robustness of the results across wide variations of the input parameters. RESULTS: The most cost-effective rescue medication was buccal midazolam (incremental cost-effectiveness ratio ([ICER]: $13.16/SS) followed by nasal midazolam (ICER: $38.19/SS). Nasal lorazepam (ICER: -$3.8/SS), intramuscular midazolam (ICER: -$64/SS), and rectal diazepam (ICER: -$2,246.21/SS) are never more cost-effective than the other options at any willingness to pay. One-way sensitivity analysis showed the following: (1) at its current effectiveness, rectal diazepam would become the most cost-effective option only if its cost was $6 or less, and (2) at its current cost, rectal diazepam would become the most cost-effective option only if effectiveness was higher than 0.89 (and only with very high willingness to pay of $2,859/SS to $31,447/SS). Second-order Monte Carlo simulations showed the following: (1) nasal midazolam and intramuscular midazolam were the more effective options; (2) the more cost-effective option was buccal midazolam for a willingness to pay from $14/SS to $41/SS and nasal midazolam for a willingness to pay above $41/SS; (3) cost-effectiveness overlapped for buccal midazolam, nasal lorazepam, intramuscular midazolam, and nasal midazolam; and (4) rectal diazepam was not cost-effective at any willingness to pay, and this conclusion remained extremely robust to wide variations of the input parameters. SIGNIFICANCE: For pediatric status epilepticus, buccal midazolam and nasal midazolam are the most cost-effective nonintravenous rescue medications in the United States. Rectal diazepam is not a cost-effective alternative, and this conclusion remains extremely robust to wide variations of the input parameters.