Treatment Of Status Epilepticus Research Articles

Advances in the management of generalized convulsive status epilepticus: what have we learned?

Convulsive status epilepticus is the most serious manifestation of an epileptic diathesis. In the early stages (5-30 min), there exists class A evidence to support the efficacy of benzodiazepines as first-line treatment. As status epilepticus progresses into the later stages, the evidence for treatment becomes less robust until we are depending upon short case series and case reports for the treatment of refractory status epilepticus. However, the past year saw the publication of three randomized controlled trials in the setting of benzodiazepine-resistant established convulsive status epilepticus: the EcLiPSE and ConSEPT studies, compared levetiracetam to phenytoin in children; and the ESETT study compared fosphenytoin, levetiracetam and sodium valproate in adults and children. In addition, the emergence of data from the SENSE study, a multicentre multinational prospective cohort study and the publication of a systematic review and meta-analysis of the mortality of status epilepticus over the past 30 years, has brought the treatment of status epilepticus into sharp focus. In this update we provide a detailed analysis of these studies and their impact on clinical practice. We review contentious areas of management in status epilepticus where a consensus is lacking and advance the case for more research on existing and alternative treatment strategies.

Time to Treatment in Pediatric Convulsive Refractory Status Epilepticus: The Weekend Effect

BackgroundTime to treatment in pediatric refractory status epilepticus is delayed. We aimed to evaluate the influence of weekends and holidays on time to treatment of this pediatric emergency. MethodsWe performed a retrospective analysis of prospectively collected observational data of pediatric patients with refractory status epilepticus. ResultsWe included 329 patients (56% males) with a median (p25 to p75) age of 3.8 (1.3 to 9) years. The median (p25 to p75) time to first BZD on weekdays and weekends/holidays was 20 (6.8 to 48.3) minutes versus 11 (5 to 35) minutes, P = 0.01; adjusted hazard ratio (HR) = 1.20 (95% confidence interval [CI]: 0.95 to 1.55), P = 0.12. The time to first non-BZD ASM was longer on weekdays than on weekends/holidays (68 [42.8 to 153.5] minutes versus 59 [27 to 120] minutes, P = 0.006; adjusted HR = 1.38 [95% CI: 1.08 to 1.76], P = 0.009). However, this difference was mainly driven by status epilepticus with in-hospital onset: among 108 patients, the time to first non-BZD ASM was longer during weekdays than during weekends/holidays (55.5 [28.8 to 103.5] minutes versus 28 [15.8 to 66.3] minutes, P = 0.003; adjusted HR = 1.65 [95% CI: 1.08 to 2.51], P = 0.01). ConclusionsThe time to first non-BZD ASM in pediatric refractory status epilepticus is shorter on weekends/holidays than on weekdays, mainly driven by in-hospital onset status epilepticus. Data on what might be causing this difference may help tailor policies to improve medication application timing.

TRPV4 Regulates Soman-Induced Status Epilepticus and Secondary Brain Injury via NMDA Receptor and NLRP3 Inflammasome.

Nerve agents are used in civil wars and terrorist attacks, posing a threat to public safety. Acute exposure to nerve agents such as soman (GD) causes serious brain damage, leading to death due to intense seizures induced by acetylcholinesterase inhibition and neuronal injury resulting from increased excitatory amino-acid levels and neuroinflammation. However, data on the anticonvulsant and neuroprotective efficacies of currently-used countermeasures are limited. Here, we evaluated the potential effects of transient receptor vanilloid 4 (TRPV4) in the treatment of soman-induced status epilepticus (SE) and secondary brain injury. We demonstrated that TRPV4 expression was markedly up-regulated in rat hippocampus after soman-induced seizures. Administration of the TRPV4 antagonist GSK2193874 prior to soman exposure significantly decreased the mortality rate in rats and reduced SE intensity. TRPV4-knockout mice also showed lower incidence of seizures and higher survival rates than wild-type mice following soman exposure. Further in vivo and in vitro experiments demonstrated that blocking TRPV4 prevented NMDA receptor-mediated glutamate excitotoxicity. The protein levels of the NLRP3 inflammasome complex and its downstream cytokines IL-1β and IL-18 increased in soman-exposed rat hippocampus. However, TRPV4 inhibition or deletion markedly reversed the activation of the NLRP3 inflammasome pathway. In conclusion, our study suggests that the blockade of TRPV4 protects against soman exposure and reduces brain injury following SE by decreasing NMDA receptor-mediated excitotoxicity and NLRP3-mediated neuroinflammation. To our knowledge, this is the first study regarding the "dual-switch" function of TRPV4 in the treatment of soman intoxication.

Early Neurologic Recovery, Practice Pattern Variation, and the Risk of Endotracheal Intubation Following Established Status Epilepticus.

To quantify the association between early neurologic recovery, practice pattern variation, and endotracheal intubation during established status epilepticus, we performed a secondary analysis within the cohort of patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT). We evaluated factors associated with the endpoint of endotracheal intubation occurring within 120 minutes of ESETT study drug initiation. We defined a blocked, stepwise multivariate regression, examining 4 phases during status epilepticus management: (1) baseline characteristics, (2) acute treatment, (3) 20-minute neurologic recovery, and (4) 60-minute recovery, including seizure cessation and improving responsiveness. Of 478 patients, 117 (24.5%) were intubated within 120 minutes. Among high-enrolling sites, intubation rates ranged from 4% to 32% at pediatric sites and 19% to 39% at adult sites. Baseline characteristics, including seizure precipitant, benzodiazepine dosing, and admission vital signs, provided limited discrimination for predicting intubation (area under the curve [AUC] 0.63). However, treatment at sites with an intubation rate in the highest (vs lowest) quartile strongly predicted endotracheal intubation independently of other treatment variables (adjusted odds ratio [aOR] 8.12, 95% confidence interval [CI] 3.08-21.4, model AUC 0.70). Site-specific variation was the factor most strongly associated with endotracheal intubation after adjustment for 20-minute (aOR 23.4, 95% CI 6.99-78.3, model AUC 0.88) and 60-minute (aOR 14.7, 95% CI 3.20-67.5, model AUC 0.98) neurologic recovery. Endotracheal intubation after established status epilepticus is strongly associated with site-specific practice pattern variation, independently of baseline characteristics, and early neurologic recovery and should not alone serve as a clinical trial endpoint in established status epilepticus. ClinicalTrials.gov Identifier: NCT01960075.

S2k guidelines: status epilepticus in adulthood

Diese S2k-Leitlinie (LL) zum Status epilepticus (SE) im Erwachsenenalter schreibt die letzte DGN-LL zum SE von 2012 fort. Neue Definitionen und Evidenz wurden bei der Erstellung der LL und des Clinical Pathway berücksichtigt. Jeder epileptische Anfall, der länger als 5 Minuten anhält (oder ≥ 2 Anfälle über einen Zeitraum von mehr als 5 Minuten ohne Wiedererlangen des neurologischen Ausgangsstatus), soll als SE behandelt werden.In der Diagnostik sollte initial eine CCT oder, wenn möglich, eine MRT erfolgen. Das EEG spielt bei der Diagnosestellung und beim Therapiemonitoring von non-konvulsiven SE und zum Ausschluss bzw. Nachweis psychogener nichtepileptischer Anfälle eine wesentliche Rolle. Der prognostische Einfluss von insbesondere entzündlichen Begleiterkrankungen (z. B. Pneumonie) wurde besser belegt, weshalb entsprechende Laborparameter auch im Verlauf kontrolliert werden sollten und ggf. frühzeitig eine antibiotische Therapie initiiert werden sollte.Die Therapie erfolgt in 4 Stufen: 1. Initialer SE: Gabe eines ausreichend hoch dosierten Benzodiazepins i. m., i. v. oder i. n.; 2. Benzodiazepin-refraktärer SE: 1. Wahl ist die i.v. Gabe von Levetiracetam oder Valproat; 3. Refraktärer SE (RSE) und 4. Superrefraktärer SE (SRSE): I.v. Propofol oder Midazolam alleine oder in Kombination oder Thiopental in anästhetischen Dosen. Beim fokalen non-konvulsiven RSE kann unter Umständen auf die Einleitung eines therapeutischen Komas verzichtet werden. Bei SRSE sollte die ketogene Diät zum Einsatz kommen. I.v. Ketamin oder inhalatives Isofluran kann erwogen werden. In Einzelfällen kann die elektrokonvulsive Therapie und, bei resektabler epileptogener Zone, ein Epilepsie chirurgischer Eingriff erwogen werden. I.v. Allopregnanolon oder die Hyperthermie sollen nicht eingesetzt werden.

Treatment of Super-Refractory Status Epilepticus: A Review.

Purpose:Super-refractory status epilepticus (SRSE) presents management challenges due to the absence of randomized controlled trials and a plethora of potential medical therapies. The literature on treatment options for SRSE reports variable success and quality of evidence. This review is a sequel to the 2020 American Epilepsy Society (AES) comprehensive review of the treatment of convulsive refractory status epilepticus (RSE).Methods:We sought to determine the effectiveness of treatment options for SRSE. We performed a structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) for studies on reported treatments of SRSE. We excluded antiseizure medications (ASMs) covered in the 2016 AES guideline on the treatment of established SE and the convulsive RSE comprehensive review of the 2020 AES. Literature was reviewed on the effectiveness of vagus nerve stimulation, ketogenic diet (KD), lidocaine, inhalation anesthetics, brain surgery, therapeutic hypothermia, perampanel, pregabalin (PGB), and topiramate in the treatment of SRSE. Two authors reviewed each therapeutic intervention. We graded the level of the evidence according to the 2017 classification scheme of the American Academy of Neurology.Results:For SRSE (level U; 39 class IV studies total), insufficient evidence exists to support that perampanel, PGB, lidocaine, or acute vagus nerve stimulation (VNS) is effective. For children and adults with SRSE, insufficient evidence exists to support that the KD is effective (level U; 5 class IV studies). For adults with SRSE, insufficient evidence exists that brain surgery is effective (level U, 7 class IV studies). For adults with SRSE insufficient, evidence exists that therapeutic hypothermia is effective (level C, 1 class II and 4 class IV studies). For neonates with hypoxic-ischemic encephalopathy, insufficient evidence exists that therapeutic hypothermia reduces seizure burden (level U; 1 class IV study). For adults with SRSE, insufficient evidence exists that inhalation anesthetics are effective (level U, 1 class IV study) and that there is a potential risk of neurotoxicity.Conclusion:For patients with SRSE insufficient, evidence exists that any of the ASMs reviewed, inhalational anesthetics, ketogenic diet, acute VNS, brain surgery, and therapeutic hypothermia are effective treatments. Data supporting the use of these treatments for SRSE are scarce and limited mainly to small case series and case reports and are confounded by differences in patients’ population, and comedications, among other factors.

Editors' Note: Association of Guideline Publication and Delays to Treatment in Pediatric Status Epilepticus

In “Association of guideline publication and delays to treatment in pediatric status epilepticus,” Fernandez et al. reported that despite publication of evidence of delays in treatment of refractory status epilepticus (SE) in the Pediatric Status Epilepticus Research Group (pSERG) at the end of 2014, there was no difference in time to initiation of benzodiazepines, nonbenzodiazepine antiepileptic drugs (AEDs), and continuous infusions to patients with refractory SE in pSERG in the hospital between 2011–2014 and 2015–2019. The authors identified a number of proposed actions to overcome potential barriers to the timely initiation of AEDs. Albuja et al. commented that they improved the time to administration of second-line AEDs at their institution by creating a SE alert system to contact neurology, pharmacy, the rapid response team, and the bed manager simultaneously when an inpatient is suspected to be in SE. Amengual-Gual et al. applauded them for implementing this initiative. It is imperative to continue to identify quality improvement measures to identify SE and ensure that AEDs are given in a timely fashion to patients with SE because it becomes more resistant over time, which may lead to increased morbidity and mortality.[1][1],[2][2] In “Association of guideline publication and delays to treatment in pediatric status epilepticus,” Fernandez et al. reported that despite publication of evidence of delays in treatment of refractory status epilepticus (SE) in the Pediatric Status Epilepticus Research Group (pSERG) at the end of 2014, there was no difference in time to initiation of benzodiazepines, nonbenzodiazepine antiepileptic drugs (AEDs), and continuous infusions to patients with refractory SE in pSERG in the hospital between 2011–2014 and 2015–2019. The authors identified a number of proposed actions to overcome potential barriers to the timely initiation of AEDs. Albuja et al. commented that they improved the time to administration of second-line AEDs at their institution by creating a SE alert system to contact neurology, pharmacy, the rapid response team, and the bed manager simultaneously when an inpatient is suspected to be in SE. Amengual-Gual et al. applauded them for implementing this initiative. It is imperative to continue to identify quality improvement measures to identify SE and ensure that AEDs are given in a timely fashion to patients with SE because it becomes more resistant over time, which may lead to increased morbidity and mortality.1,2 [1]: #ref-1 [2]: #ref-2

Reader Response: Association of Guideline Publication and Delays to Treatment in Pediatric Status Epilepticus.

Sánchez Fernández et al.1 reported that the publication of evidence on delays in treatment of pediatric refractory convulsive status epilepticus (rSE) was not associated with improvement in time to treatment of rSE (TTTSE). They propose interventions to reduce TTTSE. We would like to share a successful model that we implemented. In 2013, we identified delays in TTTSE in our institution.2 We saw no improvement in TTTSE after a dual intervention consisting of educational programs for healthcare professionals and the development of an electronic SE order set.3 This prompted us to develop an SE alert system that was modeled after our “code stroke” protocol.4 When an inpatient is suspected to have SE, the SE alert is activated by calling an operator who simultaneously pages the neurology and pharmacy house staff, the rapid response team, and the manager responsible for bed assignment. Use of this alert system led to considerable reduction in time to administration of second-line antiseizure medications (22.21 ± 3.44 minutes) compared with standard care (58.30 ± 6.72 minutes; p < 0.0001).4 Because many hospitals have alert protocols for management of acute stroke, SE alert systems could be replicated with local resources to facilitate timely management and coordinated care of SE in adults and children.

Author Response: Association of Guideline Publication and Delays to Treatment in Pediatric Status Epilepticus.

We thank Drs. Albuja, Bensalem-Owen, and Villamar for their comment on our study1 and for their crucial contribution, highlighting the developments toward improving status epilepticus treatment in this pilot study in 19 adult patients during inpatient care at a single center2 and our publication. We are entirely aligned with these essential suggestions and applaud the authors for their crucial contribution. Similarly—and simultaneously to the authors' accomplishment—pediatric investigators were able to improve inpatient treatment times in children at a single center.3 Most ongoing delays continue to occur in patients with intermittent refractory status epilepticus—related to difficulties in assessment whether convulsive status epilepticus persists—and in the outpatient setting.4 Our group is actively working on measures that can identify ongoing seizures—not only at a single center but also for larger populations in multicenter settings and in the outpatient setting.5 We agree that—among other approaches such as implementing novel technologies and quality improvement techniques—learning from previous stroke treatment efforts will play an important role.6 We are grateful for the chance to add this outlook to our current article and congratulate Drs. Albuja, Bensalem-Owen, and Villamar on this innovative milestone toward our shared goal of implementing improved status epilepticus care for our patients.

A case of juvenile CLN1– challenge in diagnosis and epilepsy treatment

ABSTRACT Introduction Classic onset of CLN1 disease is within the first year of life with developmental arrest, epilepsy and rapid progression. In an atypical variant of CLN1 disease onset is later in the juvenile epoch. Although epilepsy in the juvenile form of CLN1 often is less severe than in typical CLN1, treatment of seizures and status epilepticus may be challenging. Case presentation The clinical course, misdiagnosis and epilepsy phenotype are presented in a girl with juvenile CLN1. Cognitive and neurologic regression started at age 5.5 years. Epilepsy was a major clinical issue as the patient suffered from focal seizures, recurrent status epilepticus and epilepsia partialis continua. In one episode of refractory status epilepticus, the patient had significant bradycardia associated with the intravenous infusion of levetiracetam. Diagnosis was made at the age of 12 years, based on palmitoyl protein-thioesterase (PPT) enzyme deficiency and genetic testing that documented a homozygous exon missense mutation in the CLN1 gene (PPT1, c.541G>A, p.Val181Met). Discussion Epilepsy in all NCL patients is a major clinical issue and presumed related to neuronal excitation and epileptogenesis. The treatment of status epilepticus, in juvenile CLN1 patients, presents a particular challenge and requires monitoring of potential serious pharmacologic side effects of therapy.

Febrile Seizures: Evidence for Evolution of an Operational Strategy from an Armed Forces Referral Hospital.

PurposeCurrent recommendations for ‘Febrile seizures’ management include emergency first aid and treatment along with intermittent prophylaxis. Evidence of practices, efficacy, side-effects, and complications should lead to refined and rational management strategies.Patients and MethodsStudy of cases referred and treated at a tertiary level hospital, providing referral services to a large state in India. Evidence sought for the research questions identified, these were (i) immediate treatment: First aid components and practices; response to drug treatment (ii) intermittent prophylaxis: effectiveness, compliance, and side-effects (iii) complications arising due to treatment side-effects: quantifying the number of cases of CNS infections missed as a result of alterations in consciousness levels due to benzodiazepines.ResultsA total of 85 febrile seizure cases were studied. Full correct “First Aid” was provided by only 13 parents. Total 35 cases (41.18%) had seizures lasting more than 05 minutes. Emergency treatment for these included rectal diazepam in 14 cases with 57.14% success in terminating seizure, and intranasal midazolam in 21 cases with 71.43% success. The cases with persisting seizures were managed as status epilepticus treatment algorithm. Intermittent prophylaxis prevented recurrence of seizures in 90%, however side-effects were reported in 36.36%. There was no case of CNS infection missed.ConclusionSafe and effective management strategy should include “Health education” for correct first aid and ‘Protocols’ for timely and correct emergency treatment by parents/pre-hospital teams/emergency duty doctors. Intermittent prophylaxis is effective but refinements needed to minimize side-effects. Vigilant clinical monitoring obviates the fear that treatment may mask CNS infection.

Establishing a learning healthcare system to improve health outcomes for people with epilepsy

ObjectiveTo describe the organization of the Epilepsy Learning Healthcare System (ELHS), a network that aims to improve care outcomes for people with epilepsy (PWE). Materials and MethodsPatients and family partners, providers, researchers, epidemiologists, and other leaders collaborated to recruit epilepsy centers and community services organizations into a novel learning network. A multidisciplinary Coordinating Committee developed ELHS governance and organizational structure, including four key planning Cores (Community, Clinical, Quality Improvement, and Data). Through Quality Improvement (QI) methodology grounded in the Institute for Healthcare Improvement (IHI) model, including iterative Plan-Do-Study-Act (PDSA) rapid learning cycles and other learning and sharing sessions, ELHS equipped epilepsy centers and community organizations with tools to standardize, measure, share, and improve key aspects of epilepsy care. The initial learning cycles addressed provider documentation of seizure frequency and type, and also screening for medication adherence barriers. Rapid learning cycles have been carried out on these initial measures in both clinical centers and community-based settings. Additional key measures have been defined for quality of life, screening, and treatment for mental health and behavioral comorbidities, transition from pediatric to adult care, counseling for women and girls living with epilepsy, referral for specialty care, and prevention and treatment of seizure clusters and status epilepticus. ResultsIt is feasible to adopt a learning healthcare system framework in epilepsy centers and community services organizations. Through structured collaboration between epilepsy care providers, community support organizations, PWE, and their families/caregivers we have identified new opportunities to improve outcomes that are not available in traditional care models.

Two Concomitant Cases with Febrile Infection-Related Epilepsy Syndrome (FIRES) treated with andldquo;3-Dimensional Combination Treatment Protocolandrdquo;

Objective: Febrile Infection-Related Epilepsy Syndrome (FIRES) is an immun-mediated epileptic encephalopathy presents as a febrile infection related super refractory status epilepticus with mortality rate of up to 30% in intensive care unit in spite of pharmacologically induced coma and immunotherapies. Early interventional ketogenic diet and cannabinoids are suggested for treatment with unknown mechanisms. Case presentation: Here we report two concomitant FIRES cases treated with a “3 dimensional combined treatment protocol“ for FIRES including (1); super refractory status epilepticus treatment protocol with intravenous infusion of antiepileptic and anesthetic drugs, (2) immunomodulatory therapies and (3) early interventional anti-epileptogenic therapy (ketogenic diet plus cannabinoids). The therapeutic intensity of the treatment protocol was monitored with serial EEG monitoring and Functional Independence Scores-WeeFIM. Two previously healthy school children manifesting super refractory status epilepticus were treated with moderate success. Both patients recovered with drug refractory epilepsy and neurocognitive impairments (patient 1; WeeFIM Scores were: self-care: 17, motor: 24, cognition: 10 and patient 2; WeeFIM score remained totally dependent: self-care: 8, motor: 5, cognition: 5) at the 12 months of follow-up. Conclusion: Febrile infection-related epilepsy syndrome is a devasting catastrophic epileptic encephalopathy. Early interventional treatment protocols should be applied in the early period of super refractory status epilepticus.

Drug Use Review of Intravenous Levetiracetam in Patients with Epilepsy, Tertiary Care Hospital

Background: Epilepsy is a current important health problem. Status epilepticus is a medical emergency condition which may be lifethreatening, increased mortality rate and hospitalization. However, some patients with epilepsy could not control their symptoms and anticonvulsant medications have some adverse effects. Intravenous levetiracetam (ivLEV) is a new antiepileptic drug which its use tends to be increased. Objective: To study the prescription pattern of ivLEV and its adverse drug reactions (ADRs) in hospitalized patients and to define the efficacy of iv LEV as first line treatment for status epilepticus. Materials and Methods: This was a descriptive retrospective study to review medical records of all inpatients receiving ivLEV at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University during January 1st 2010 to December 31st 2014. Results: During the study period, there were 406 hospital visits that met the study criteria. The average age of the patients was 54.32+20.36 years with nearly equal sex distribution. The indications of ivLEV were status epilepticus (22.4%), previous treatment with oral levetiracetam (9.6%), perioperative craniectomy/craniotomy (8.6%), and acute seizure with non-status epilepticus (59%). Most of the patients (63.3%) received ivLEV as first line treatment antiepileptic drug and the most loading dose range of ivLEV that the patients received was 500 to 1,000 mg/day (78.3%). All of the patients had been followed vital signs and plasma electrolytes. 98.5% and 45.8% of hospital visits had been monitored liver/kidney function and electroencephalogram (EEG), respectively. Adverse effects during the treatment of ivLEV occurred 0.98%, which were hypotension, drowsiness, and maculopapular rash. No major ADRs were detected in any patients after the ivLEV treatment. Regarding process indicators, overall seizure control rate was 76.4%, of which 35.2% and 85.9% were for the patients with status epilepticus and acute seizure with non-status epilepticus, respectively. ivLEV could be used as first line treatment effectively in patients with status epilepticus (80.2%). In the patients with renal impairment receiving adjusted dosage regimen ivLEV could be control seizure 73.1%. Conclusion: The treatment of ivLEV was effective and safe for control seizure, including status epilepticus and acute seizure with non-status epilepticus. Thus, ivLEV could be the first line antiepileptic drug for the treatment of status epilepticus and brain surgery prevention. However, due to the high cost of the drug and the treatment course, there would be further study of cost-effectiveness. Keywords: Levetiracetam, Epilepsy, Acute seizure, Status epilepticus, Drug use review, Inpatient

Effects of sulthiame on seizure frequency and EEG in children with electrical status epilepticus during slow sleep

ObjectiveIt is argued that early and adequate treatment of electrical status epilepticus in sleep (ESES) is essential to preserve cognitive functions and possibly recovering lost skills. Although antiepileptic drugs (AEDs) are effective in ESES, there is not much experience in the use of sulthiame. In this study, we aimed to examine the efficiency and tolerability of sulthiame in ESES. MethodsThe data of 39 patients diagnosed as ESES and who received sulthiame as an additional treatment between 2016 and 2020 were reviewed retrospectively. Electroencephalographic (EEG) findings and seizure rates were compared before and after the sulthiame treatment. ResultsThe mean age was 8.5 ± 4.1 (1.5–16 years). Nine out of 39 patients had benign childhood focal epilepsies. Structural causes were identified in 13 patients. The mean duration of sulthiame use was 32.5 ± 13.7 months. After sulthiame treatment, 25 patients (64.1%) were seizure free, and 8 (20.5%) had more than a 50% decrease in seizure frequency. The mean seizure-free time after the sulthiame treatment was 27.8 ± 17.9 months. Nineteen patients (48.7%) had complete, and nine patients (23.1%) had partial EEG improvement. Complete seizure control was significantly higher in benign focal epilepsy of childhood (p = 0.01). Significant neurocognitive and behavioral recovery, improvement in school performance was observed following sulthiame treatment (p < 0.001). ConclusionSulthiame was found to be effective in seizure control and EEG improvement in ESES. We think that the use of sulthiame alone can be a good choice with high efficacy and tolerability in ESES.

Intravenous brivaracetam in status epilepticus: A multicentric retrospective study in Italy

Purposeto evaluate the use, effectiveness, and adverse events of intravenous brivaracetam (BRV) in status epilepticus (SE). Methodsa retrospective multicentric study involving 24 Italian neurology units was performed from March 2018 to June 2020. A shared case report form was used across participating centres to limit biases of retrospective data collection. Diagnosis and classification of SE followed the 2015 ILAE proposal. We considered a trial with BRV a success when it was the last administered drug prior the clinical and/or EEG resolution of seizures, and the SE did not recur during hospital observation. In addition, we considered cases with early response, defined as SE resolved within 6 h after BRV administration. Results56 patients were included (mean age 62 years; 57 % male). A previous diagnosis of epilepsy was present in 21 (38 %). Regarding SE etiology classification 46 % were acute symptomatic, 18 % remote and 16 % progressive symptomatic. SE episodes with prominent motor features were the majority (80 %). BRV was administered as first drug after benzodiazepine failure in 21 % episodes, while it was used as the second or the third (or more) drug in the 38 % and 38 % of episodes respectively. The median loading dose was 100 mg (range 50−300 mg). BRV was effective in 32 cases (57 %). An early response was documented in 22 patients (39 % of the whole sample). The use of the BRV within 6 h from SE onset was independently associated to an early SE resolution (OR 32; 95 % CI 3.39–202; p = 0.002). No severe treatment emergent adverse events were observed. ConclusionBRV proved to be useful and safe for the treatment of SE. Time to seizures resolution appears shorter when it is administered in the early phases of SE.

Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice

Organophosphate pesticides and nerve agents (OPs), are characterized by cholinesterase inhibition. In addition to severe peripheral symptoms, high doses of OPs can lead to seizures and status epilepticus (SE). Long lasting seizure activity and subsequent neurodegeneration promote neuroinflammation leading to profound pathological alterations of the brain.The aim of this study was to characterize neuroinflammatory responses at key time points after SE induced by the OP, diisopropylfluorophosphate (DFP). Immunohistochemistry (IHC) analysis and RT-qPCR on cerebral tissue are often insufficient to identity and quantify precise neuroinflammatory alterations. To address these needs, we performed RT-qPCR quantification after whole brain magnetic-activated cell-sorting (MACS) of CD11B (microglia/infiltrated macrophages) and GLAST (astrocytes)-positive cells at 1, 4, 24 h and 3 days post-SE. In order to compare these results to those obtained by IHC, we performed, classical Iba1 (microglia/infiltrated macrophages) and GFAP (astrocytes) IHC analysis in parallel, focusing on the hippocampus, a brain region affected by seizure activity and neurodegeneration.Shortly after SE (1–4 h), an increase in pro-inflammatory (M1-like) markers and A2-specific markers, proposed as neurotrophic, were observed in CD11B and GLAST-positive isolated cells, respectively. Microglial cells successively expressed immuno-regulatory (M2b-like) and anti-inflammatory (M2a-like) at 4 h and 24 h post-SE induction. At 24 h and 3 days, A1-specific markers, proposed as neurotoxic, were increased in isolated astrocytes. Although IHC analysis presented no modification in terms of percentage of marked area and cell number at 1 and 4 h after SE, at 24 h and 3 days after SE, microglial and astrocytic activation was visible by IHC as an increase in Iba1 and GFAP-positive area and Iba1-positive cells in DFP animals when compared to the control.Our work identified sequential microglial and astrocytic phenotype activation. Although the role of each phenotype in SE cerebral outcomes requires further study, targeting specific markers at specific time point could be a beneficial strategy for DFP-induced SE treatment.

Recognition and treatment of status epilepticus in the prehospital setting

PurposeWe performed this retrospective data bank analysis to evaluate the management of status epilepticus (SE) in the prehospital setting and the possible association of treatment delay or insufficient treatment approach with outcome. MethodWe evaluated all treatment episodes of a prehospital SE according to our hospital record system between January 1st 2014 and December 31st 2018. Classification according to the ILAE classification of 2015, Status Epilepticus Severity Score (STESS), Charlson Comorbidity Index (CCI) at admission and the Modified Rankin Scale (mRS) at discharge or in hospital death were recorded or calculated. Statistical analysis was performed with the Mann-Withney-U test, the Chi-Square test and corrections of Yates and Bonferroni-Holmes where appropriate. ResultsThere were 331 treatment episodes in 282 patients with a fatality rate of 7.6 %. Median age at treatment was 72 years. Patients who died were significantly older and had a higher STESS and CCI than patients who survived. SE was recognised in the prehospital setting in only 56.8 % of treatment episodes. Patients in treatment episodes with recognized SE were significantly younger than the others. Status epilepticus was more often recognized, when epilepsy was known. Overall in 48 % of treatment episodes with another SE type than generalized convulsive SE the diagnosis was missed. CCI was significantly higher in the episodes without recognized SE. Patients were more often discharged from hospital with a new deficit, when the SE was not recognized in the prehospital setting. In treatment episodes with initiation of a benzodiazepine (BZD) the patients were more likely to be discharged without a new deficit than others. After excluding cases with insufficient documentation of treatment steps 273 treatment episodes remained. In 178 of these treatment episodes epilepsy was known before, but in only 11.2 % of them a rescue medication was given by bystanders. In only 6.7 % of treatment episodes of SE in patients with known epilepsy a BZD was given in an appropriate way by bystanders. In nearly all treatment episodes with lorazepam (88.9 %) or midazolam (97.8 %) the dosage was below the recommended level. ConclusionsMissing the SE in the prehospital setting was frequent and associated with a higher risk of developing a new neurological deficit. Treatment with BZD was associated with a lower risk of developing a new neurological deficit, but was underdosed in the vast majority of situations.

Update on the management of status epilepticus.

Randomized controlled trials investigating the initial pharmacological treatment of status epilepticus have been recently published. Furthermore, status epilepticus arising in comatose survivors after cardiac arrest has received increasing attention in the last years. This review offers an updated assessment of status epilepticus treatment in these different scenarios. Initial benzodiazepines underdosing is common and correlates with development of status epilepticus refractoriness. The recently published ESETT trial provides high-level evidence regarding the equivalence of fosphenytoin, valproate, and levetiracetam as a second-line option. Myoclonus or epileptiform transients on electroencephalography occur in up to 1/3 of patients surviving a cardiac arrest. Contrary to previous assumptions regarding an almost invariable association with death, at least 1/10 of them may awaken with reasonably good prognosis, if treated. Multimodal prognostication including clinical examination, EEG, somatosensory evoked potentials, biochemical markers, and neuroimaging help identifying patients with a chance to recover consciousness, in whom a trial with antimyoclonic compounds and at times general anesthetics is indicated. There is a continuous, albeit relatively slow progress in knowledge regarding different aspect of status epilepticus; recent findings refine some treatment strategies and help improving patients' outcomes. Further high-quality studies are clearly needed to further improve the management of these patients, especially those with severe, refractory status epilepticus forms.

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High‐Dose Intravenous Administration in Young Children With Benzodiazepine‐Refractory Status Epilepticus

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.