Duration Of Status Epilepticus Research Articles

Trends in management of patients with new-onset refractory status epilepticus (NORSE) from 2016 to 2023: An interim analysis.

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

Status epilepticus in Auckland, New Zealand: Treatment patterns and determinants of outcome in a prospective population-based cohort.

Determination of the real-world performance of a health care system in the treatment of status epilepticus (SE). Prospective, multicenter population-based study of SE in Auckland, New Zealand (NZ) over 1 year, with data recorded in the EpiNet database. Focus on treatment patterns and determinants of SE duration and 30-day mortality. The incidence, etiology, ethnic discrepancies, and seizure characteristics of this cohort have been published previously. A total of 365 patients were included in this treatment cohort; 326 patients (89.3%) were brought to hospital because of SE, whereas 39 patients (10.7%) developed SE during a hospital admission for another reason. Overall, 190 (52.1%) had a known history of epilepsy and 254 (70.0%) presented with SE with prominent motor activity. The mean Status Epilepticus Severity Score (STESS) was 2.15 and the mean SE duration of all patients was 44 min. SE self-terminated without any treatment in 84 patients (22.7%). Earlier administration of appropriately dosed benzodiazepine in the pre-hospital setting was a major determinant of SE duration. Univariate analysis demonstrated that mortality was significantly higher in older patients, patients with longer durations of SE, higher STESS, and patients who developed SE in hospital, but these did not maintain significance with multivariate analysis. There was no difference in the performance of the health care system in the treatment of SE across ethnic groups. When SE was defined as 10 continuous minutes of seizure, overall mortality was lower than expected and many patients had self-limited presentations for which no treatment was required. Although there were disparities in the incidence of SE across ethnic groups there was no difference in treatment or outcome. The finding highlights the benefit of a health care system designed to deliver universal health care.

Hydrogen gas can ameliorate seizure burden during therapeutic hypothermia in asphyxiated newborn piglets.

We previously reported that hydrogen (H2) gas combined with therapeutic hypothermia (TH) improved short-term neurological outcomes in asphyxiated piglets. However, the effect on seizure burden was unclear. Using amplitude-integrated electroencephalography (aEEG), we compared TH + H2 with TH alone in piglets 24 h after hypoxic-ischemic (HI) insult. After a 40-min insult and resuscitation, 36 piglets ≤24 h old were divided into three groups: normothermia (NT, n = 14), TH alone (33.5 ± 0.5 °C, 24 h, n = 13), and TH + H2 (2.1-2.7% H2 gas, 24 h, n = 9). aEEG was recorded for 24 h post-insult and its background pattern, status epilepticus (SE; recurrent seizures lasting >5 min), and seizure occurrence (Sz; occurring at least once but not fitting the definition of SE) were evaluated. Background findings with a continuous low voltage and burst suppression were considered abnormal. The percentage of piglets with an abnormal aEEG background (aEEG-BG), abnormal aEEG-BG+Sz and SE was lower with TH + H2 than with TH at 24 h after HI insult. The duration of SE was shorter with TH + H2 and significantly shorter than with NT. H2 gas combined with TH ameliorated seizure burden 24 h after HI insult. In this asphyxiated piglet model, there was a high percentage of animals with an abnormal amplitude-integrated electroencephalography background (aEEG-BG) after hypoxic-ischemic (HI) insult, which may correspond to moderateand severe hypoxic-ischemic encephalopathy (HIE). Therapeutic hypothermia (TH) was associated with a low percentage of piglets with EEG abnormalities up to 6 h after HI insult but this percentage increased greatly after 12 h, and TH was not effective in attenuating seizure development. H2 gas combined with TH was associated with a low percentage of piglets with an abnormal aEEG-BG and with a shorter duration of status epilepticus at 24 h after HI insult.

PICU Admission of Children for Status Epilepticus: Is There a Different Approach Between Referral and Second-Level Hospitals in an Italian Region?

Appropriate status epilepticus (SE) management is key to minimize admission to the pediatric intensive care unit (PICU). We retrospectively describe 115 children admitted to the PICU of the tertiary-care referral hospital of Padova for seizures, SE, and SE-related complications (59% from second-level hospitals, 41% from the referral hospital) and compare SE management among hospitals. Compared with the referral center, in second-level hospitals, anesthetics were more often administered as first/second drug (P < .001), and intubation was more frequent (P < .001). Intubation was significantly associated with SE onset at home (P = .045) and benzodiazepine-associated respiratory depression (P = .044). There was no association between intubation and SE duration, etiology, PICU length of stay, and morbidity at discharge. In conclusion, adherence to treatment protocols on SE management after the first-line drug differs between referral center and second-level hospitals. Lack of association with SE characteristics and patient's outcome suggests PICU admission could be due to inappropriate invasive management.

Postictal Encephalopathy After Status Epilepticus: Outcome and Risk Factors

BackgroundPostictal encephalopathy is well known after status epilepticus (SE), but its prognostic impact and triggers are unknown. Here, we aimed to establish risk factors for the development of postictal encephalopathy and to study its impact on survival after discharge.MethodsThis retrospective cohort study comprised adult patients diagnosed with first nonanoxic SE at Odense University Hospital between January 2008 and December 2017. Patients with ongoing SE at discharge or unknown treatment success were excluded. Postictal symptoms of encephalopathy were estimated retrospectively using the West Haven Criteria (WHC). WHC grade was determined for postictal day 1 to 14 or until the patient died or was discharged from the hospital. Cumulative postictal WHC during 14 days after SE-cessation was used to quantify postictal encephalopathy. Clinical characteristics, patient demographics, electroencephalographic and imaging features, and details on intensive care treatment were assessed from medical records.ResultsOf all eligible patients (n = 232), 198 (85.3%) had at least WHC grade 2 postictal encephalopathy that lasted for > 14 days in 24.5% of the surviving patients. WHC grade at discharge was strongly associated with poor long-term survival (p < 0.001). Postictal encephalopathy was not associated with nonconvulsive SE, postictal changes on magnetic resonance imaging, or distinct ictal patterns on electroencephalography. Although duration of SE and treatment in the intensive care unit showed an association with cumulative postictal WHC grade, they were not independently associated with the degree of encephalopathy when controlling for confounders. In a linear regression model, etiology, duration of sedation, age, and premorbid modified Rankin Scale were significant and consistent predictors for higher cumulative postictal WHC grade. Exploratory analyses showed an association of a cumulative midazolam dosage (mg/kg/h) with higher cumulative postictal WHC grade.DiscussionIn this cohort, postictal encephalopathy after SE was common and associated with poor long-term survival. Seizure characteristics were not independently associated with postictal encephalopathy; the underlying etiology, long (high-dose midazolam) sedation, high age, and poor premorbid condition were the major risk factors for its development.

Preventing Long-Term Brain Damage by Nerve Agent-Induced Status Epilepticus in Rat Models Applicable to Infants: Significant Neuroprotection by Tezampanel Combined with Caramiphen but Not by Midazolam Treatment.

Acute exposure to nerve agents induces a peripheral cholinergic crisis and prolonged status epilepticus (SE), causing death or long-term brain damage. To provide preclinical data pertinent to the protection of infants and newborns, we compared the antiseizure and neuroprotective effects of treating soman-induced SE with midazolam (MDZ) versus tezampanel (LY293558) in combination with caramiphen (CRM) in 12- and 7-day-old rats. The anticonvulsants were administered 1 hour after soman exposure; neuropathology data were collected up to 6 months postexposure. In both ages, the total duration of SE within 24 hours after soman exposure was significantly shorter in the LY293558 plus CRM groups compared with the MDZ groups. Neuronal degeneration was substantial in the MDZ-treated groups but absent or minimal in the groups treated with LY293558 plus CRM. Loss of neurons and interneurons in the basolateral amygdala and CA1 hippocampal area was significant in the MDZ-treated groups but virtually absent in the LY293558 plus CRM groups. Atrophy of the amygdala and hippocampus occurred only in MDZ-treated groups. Neuronal/interneuronal loss and atrophy of the amygdala and hippocampus deteriorated over time. Reduction of inhibitory activity in the basolateral amygdala and increased anxiety were found only in MDZ groups. Spontaneous recurrent seizures developed in the MDZ groups, deteriorating over time; a small percentage of rats from the LY293558 plus CRM groups also developed seizures. These results suggest that brain damage can be long lasting or permanent if nerve agent-induced SE in infant victims is treated with midazolam at a delayed timepoint after SE onset, whereas antiglutamatergic treatment with tezampanel and caramiphen provides significant neuroprotection. SIGNIFICANCE STATEMENT: To protect the brain and the lives of infants in a mass exposure to nerve agents, an anticonvulsant treatment must be administered that will effectively stop seizures and prevent neuropathology, even if offered with a relative delay after seizure onset. The present study shows that midazolam, which was recently approved by the Food and Drug Administration for the treatment of nerve agent-induced status epilepticus, is not an effective neuroprotectant, whereas brain damage can be prevented by targeting glutamate receptors.

Sex-related differences in adult patients with status epilepticus: a seven-year two-center observation

BackgroundConflicting findings exist regarding the influence of sex on the development, treatment, course, and outcome of status epilepticus (SE). Our study aimed to investigate sex-related disparities in adult SE patients, focusing on treatment, disease course, and outcome at two Swiss academic medical centers.MethodsIn this retrospective study, patients treated for SE at two Swiss academic care centers from Basel and Geneva from 2015 to 2021 were included. Primary outcomes were return to premorbid neurologic function, death during hospital stay and at 30 days. Secondary outcomes included characteristics of treatment and disease course. Associations with primary and secondary outcomes were assessed using multivariable logistic regression. Analysis using propensity score matching was performed to account for the imbalances regarding age between men and women.ResultsAmong 762 SE patients, 45.9% were women. No sex-related differences were found between men and women, except for older age and lower frequency of intracranial hemorrhages in women. Compared to men, women had a higher median age (70 vs. 66, p = 0.003), had focal nonconvulsive SE without coma more (34.9% vs. 25.5%; p = 0.005) and SE with motor symptoms less often (52.3% vs. 63.6%, p = 0.002). With longer SE duration (1 day vs. 0.5 days, p = 0.011) and a similar proportion of refractory SE compared to men (36.9% vs. 36.4%, p = 0.898), women were anesthetized and mechanically ventilated less often (30.6% vs. 42%, p = 0.001). Age was associated with all primary outcomes in the unmatched multivariable analyses, but not female sex. In contrast, propensity score-matched multivariable analyses revealed decreased odds for return to premorbid neurologic function for women independent of potential confounders. At hospital discharge, women were sent home less (29.7% vs. 43.7%, p < 0.001) and to nursing homes more often (17.1% vs. 10.0%, p = 0.004).ConclusionsThis study identified sex-related disparities in the clinical features, treatment modalities, and outcome of adult patients with SE with women being at a disadvantage, implying that sex-based factors must be considered when formulating strategies for managing SE and forecasting outcomes.

Prediction of long-term unprovoked seizures after status epilepticus.

Possible long-term consequences of status epilepticus (SE) include cognitive and behavioral impairment and the development of chronic epilepsy. However, these aspects have not been systematically studied in clinical practice. We aimed to evaluate long-term seizure recurrence after SE and the potential risk factors for their development. Data were obtained from a prospective registry of all SE episodes occurring in adult patients who attended our center from February 2011 to April 2022. Clinical data, electroencephalographic findings, treatment, and long-term data were prospectively recorded. We performed a cross-sectional study of consecutive SE patients without previous epilepsy diagnosis, and analyzed the development of unprovoked remote seizures. A total of 849 patients were registered in the database. After excluding in-hospital mortality (198/849, 23.3%) and patients with prior epilepsy history (291/849, 44.7%), 360 patients (42.4%) with a first SE episode were included. The median age was 68 years (interquartile range [IQR] = 56-79), and 176 patients (48.9%) were women. The median time to first-line treatment initiation was 2 h (IQR = .7-7.4), and it was correlated with SE duration (R = .375, p < .001). One hundred nine patients (30.3%) presented unprovoked seizures during a median follow-up of 1.8 years (IQR = .5-4.3). After adjusting for identifiable confounders in a multivariable Cox regression analysis, progressive symptomatic etiology (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.17-3.33, p = .011), time to first-line treatment initiation > 1.5 h (HR = 1.89, 95% CI = 1.25-2.87, p = .003), and superrefractory SE (HR = 2.34, 95% CI = 1.26-4.33, p = .007) were independently associated with a greater risk of unprovoked seizure recurrence. In contrast, older patients (HR = .99, 95% CI = .97-.99, p = .021) and an acute symptomatic etiology (HR = .44, 95% CI .28-.68, p < .001) were at lower risk of unprovoked seizure recurrence. The etiology of SE, the delay in initiating SE treatment, and the presence of superrefractoriness have been identified as potentials factors associated with unprovoked remote seizures following a new onset SE. Therefore, prompt and appropriate management should be applied to avoid seizure recurrence.

Effects of losartan and enalapril on lithium-pilocarpine-induced status epilepticus, spontaneous convulsive seizures, and cardiac changes in rats

Modulating the brain renin-angiotensin system presents an innovative pathway for exploring newer treatment approaches in epilepsy. The current study aimed to evaluate the influence of losartan (LOS) and enalapril (ENP), which are angiotensin receptor blocker and angiotensin-converting enzyme inhibitor, respectively, on the incidence, initiation, and duration of status epilepticus (SE), spontaneous convulsive seizures (SCS), survival, and cardiac alterations in rats subjected to lithium-pilocarpine (LiP)-induced SE. Lithium (127 mg/kg, i.p.) pretreated male Wistar rats were administered pilocarpine (30 mg/kg, i.p.) after 24 h to induce SE, which was terminated after 90 min of onset. Daily 10-h video monitoring was carried out for examining onset, frequency, duration of SCS, and mortality till 18 days. The administration of LOS (10 mg/kg, i.p.), ENP (20 mg/kg, i.p.) and atenolol (AT; 50 mg/kg, p.o.) was started before lithium in pre-SE protocol and for post-SE protocol these drugs were administered 1 h after terminating SE and continued for 7 days’ post-SE. Cardiac pathology, echocardiography, heart weight/body weight ratio, and histopathology were evaluated. None of the drugs used (LOS/ENP/AT) offered protection against SE. Administration before SE decreased and post-SE administration increased the latency of SCS, and the overall duration of seizures remained short in both cases as compared to untreated rats. The heart weight/body weight ratio decreased in rats that did not survive. No echocardiographic changes were observed in any of the groups. Untreated SE rats showed myocyte ischemic changes, which were not present in any treated rats. In conclusion, LOS may reduce cardiac complications in SE rats. Hence, further evaluation of LOS as an add-on in epilepsy treatment should be performed.

Transcutaneous electrical stimulation of auricular branch of the vagus nerve effectively and rapidly modulates the EEG patterns in patients with possible electrographic status epilepticus.

Invasive vagal nerve stimulation (iVNS) is a known treatment approach for patients with refractory epilepsy. Transcutaneous auricular vagus nerve stimulation (tVNS) was developed to overcome the side effects and surgical complications of iVNS. tVNS is proven beneficial in refractory epilepsy. The effectiveness of tVNS, however, has never been studied in patients with Status Epilepticus. In this study, we explored the effect of tVNS in three patients with possible electrographic status epilepticus. To compare the EEG pattern before, during and after tVNS in three patients with possible electrographic status epilepticus. Three consecutive patients with possible electrographic status epilepticus were included after due consenting process. In addition to the standard care, tVNS was applied on the left ear over the cymba concha in two sessions, 6 h apart, with each session for 45 min. Continuous EEG monitoring was performed as standard of care and the findings before, during and after tVNS were documented. The duration of status epilepticus at the time of inclusion of Patients 1, 2, and 3 was 6 weeks, 7 days, and 5 days respectively. All were in coma and on multiple antiseizure medications. Patient 1 and 3 were on anesthetic infusions. Before stimulation, one patient had burst suppression pattern and two had generalized periodic discharges at 1 Hz frequency. We observed a significant reduction/resolution of ongoing EEG patterns in all three patients during the stimulation. The abnormal patterns re-emerged approximately 20 min post cessation of tVNS. No stimulation-related side effects were detected. There was no change in clinical status, but all three patients had severe underlying conditions. Transcutaneous auricular Vagus Nerve Stimulation (tVNS) is a potential noninvasive adjuvant therapy that can modulate EEG patterns in patients with Status epilepticus. Larger studies in early SE are needed to assess its clinical benefits.

Early timing of anesthesia in status epilepticus is associated with complete recovery: A 7-year retrospective two-center study.

This study was undertaken to investigate the efficacy, tolerability, and outcome of different timing of anesthesia in adult patients with status epilepticus (SE). Patients with anesthesia for SE from 2015 to 2021 at two Swiss academic medical centers were categorized as anesthetized as recommended third-line treatment, earlier (as first- or second-line treatment), and delayed (later as third-line treatment). Associations between timing of anesthesia and in-hospital outcomes were estimated by logistic regression. Of 762 patients, 246 received anesthesia; 21% were anesthetized as recommended, 55% earlier, and 24% delayed. Propofol was preferably used for earlier (86% vs. 55.5% for recommended/delayed anesthesia) and midazolam for later anesthesia (17.2% vs. 15.9% for earlier anesthesia). Earlier anesthesia was statistically significantly associated with fewer infections (17% vs. 32.7%), shorter median SE duration (.5 vs. 1.5 days), and more returns to premorbid neurologic function (52.9% vs. 35.5%). Multivariable analyses revealed decreasing odds for return to premorbid function with every additional nonanesthetic antiseizure medication given prior to anesthesia (odds ratio [OR] = .71, 95% confidence interval [CI] = .53-.94) independent of confounders. Subgroup analyses revealed decreased odds for return to premorbid function with increasing delay of anesthesia independent of the Status Epilepticus Severity Score (STESS; STESS = 1-2: OR = .45, 95% CI = .27-.74; STESS > 2: OR = .53, 95% CI = .34-.85), especially in patients without potentially fatal etiology (OR = .5, 95% CI = .35-.73) and in patients experiencing motor symptoms (OR = .67, 95% CI = .48-.93). In this SE cohort, anesthetics were administered as recommended third-line therapy in only every fifth patient and earlier in every second. Increasing delay of anesthesia was associated with decreased odds for return to premorbid function, especially in patients with motor symptoms and no potentially fatal etiology.

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

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

Understanding the Influence of Hospital Volume on Inpatient Outcomes Following Hospitalization for Status Epilepticus.

Prior studies show hospital admission volume to be associated with poor outcomes following elective procedures and inpatient medical hospitalizations. However, it is unknown whether hospital volume impacts Inpatient outcomes for status epilepticus (SE) hospitalizations. In this study, we aimed to assess the impact of hospital volume on the outcome of patients with SE and related inpatient medical complications. The 2005 to 2013 National Inpatient Sample database was queried using International Classification of Diseases 9th Edition diagnosis code 345.3 to identify patients undergoing acute hospitalization for SE. The National Inpatient Sample hospital identifier was used as a unique facility identifier to calculate the average volume of patients with SE seen in a year. The study cohort was divided into three groups: low volume (0-7 patients with SE per year), medium volume (8-22 patients with SE per year), and high volume (> 22 patients with SE per year). Multivariate logistic regression analyses were used to assess whether medium or high hospital volume had lower rates of inpatient medical complications compared with low-volume hospitals. A total of 137,410 patients with SE were included in the analysis. Most patients (n = 50,939; 37%) were treated in a low-volume hospital, 31% (n = 42,724) were treated in a medium-volume facility, and 18% (n = 25,207) were treated in a high-volume hospital. Patients undergoing treatment at medium-volume hospitals (vs. low-volume hospitals) had higher odds of pulmonary complications (odds ratio [OR] 1.18 [95% confidence interval {CI} 1.12-1.25]; p < 0.001), sepsis (OR 1.24 [95% CI 1.08-1.43] p = 0.002), and length of stay (OR 1.13 [95% CI 1.0 -1.19] p < 0.001). High-volume hospitals had significantly higher odds of urinary tract infections (OR 1.21 [95% CI 1.11-1.33] p < 0.001), pulmonary complications (OR 1.19 [95% CI 1.10-1.28], p < 0.001), thrombosis (OR 2.13 [95% CI 1.44-3.14], p < 0.001), and renal complications (OR 1.21 [95% CI 1.07-1.37], p = 0.002). In addition, high-volume hospitals had lower odds of metabolic (OR 0.81 [95% CI 0.72-0.91], p < 0.001), neurological complications (OR 0.80 [95% CI 0.69-0.93], p = 0.004), and disposition to a facility (OR 0.89 [95% CI 0.82-0.96], p < 0.001) compared with lower-volume hospitals. Our study demonstrates certain associations between hospital volume and outcomes for SE hospitalizations. Further studies using more granular data about the type, severity, and duration of SE and types of treatment are warranted to better understand how hospital volume may impact care and prognosis of patients.

Balancing the risks and benefits of anesthetics in status epilepticus

PurposeAccording to international guidelines, status epilepticus refractory to first- and second-line antiseizure medication should be treated with anesthetics. Therefore, continuously delivered intravenous midazolam, propofol, or barbiturates are recommended as third-line therapy. While electroencephalographically (EEG)-controlled titration of anesthetics to seizure termination or to the emergence of an EEG burst-suppression pattern makes sense, evidence of the efficacy and tolerability of such third-line treatment is limited and concerns regarding the risks of anesthesia remain. The lack of treatment alternatives and persistent international discord reflecting contradictory results from some studies leave clinicians on their own when deciding to escalate treatment.In this conference-accompanying narrative review, we highlight the challenges of EEG-monitored third-line treatment and discuss recent studies that examined earlier administration of anesthetics. ResultsBased on the literature, maintaining continuous burst suppression is difficult despite the constant administration of anesthetics, and the evidence for burst suppression as an adequate surrogate target is limited by methodological shortcomings as acknowledged by international guidelines. In our Swiss cohort including 102 patients with refractory status epilepticus, burst suppression as defined by the American Clinical Neurophysiology Society's Critical Care EEG Terminology 2021 was established in only 21%. Besides case reports suggesting that rapid but short-termed anesthesia can be sufficient to permanently stop seizures, a study including 205 patients revealed that anesthesia as second-line treatment was associated with a shorter median duration of status epilepticus (0.5 versus 12.5 days, p < 0.001), median ICU (2 versus 5.5 days, p < 0.001) and hospital stay (8 versus 17 days, p < 0.001) with equal rates of complications when compared to anesthesia as third-line treatment. ConclusionsRecent investigations have led to important findings and new insights regarding the use of anesthetics in refractory status epilepticus. However, numerous methodological limitations and remaining questions need to be considered when it comes to the translation into clinical practice, and, in consequence, call for prospective randomized studies.This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Anticonvulsant and antioxidant effects of lamotrigine on pilocarpine-induced status epilepticus in mice.

The anticonvulsant and antioxidant effects of lamotrigine on status epilepticus (SE) are incompletely understood. We assessed these effects of lamotrigine on pilocarpine (Pilo)-induced SE in mice. Male C57BL/J6 mice were assigned to three groups: the control group, Pilo (400 mg/kg, s.c.)-induced SE (Pilo group) and lamotrigine (20 mg/kg, i.p.) treated (Pilo/lamotrigine group). The latency to SE of Racine's stage 3 or higher, the mortality rate within 2 h of Pilo administration, and the duration of SE until sacrifice were examined. Nitric oxide (NO), malondialdehyde and glutathione of oxidative stress biomarkers were detected in the hippocampus of the sacrificed animals in the above groups. NO was also detected in the cultured rat hippocampal neurons treated with 4 μM Pilo, Pilo+100 μM lamotrigine (Pilo/lamotrigine) and Pilo/lamotrigine+ N-methyl-D-aspartic acid (NMDA) receptor antagonist (10 μM MK-801, 3 μM ifenprodil) to examine the antioxidant effects of lamotrigine via non-NMDA-related pathways. lamotrigine prolonged the latency to SE, the SE duration until sacrifice, and decreased the mortality rate in mice with Pilo-induced SE. Lamotrigine also decreased hippocampal concentrations of NO and malondialdehyde and increased the concentrations of glutathione in the SE model. Furthermore, there were significant differences in NO concentrations between groups of cultured rat hippocampal neurons treated with Pilo and Pilo/lamotrigine, and with Pilo/lamotrigine and Pilo/lamotrigine+MK-801. Our findings suggest that lamotrigine exerts anticonvulsant and antioxidant effects on SE, but its antioxidant activity may not be fully exerted via NMDA-related pathways.

Association of ictal imaging changes in status epilepticus and neurological deterioration.

In patients with status epilepticus (SE), the clinical significance of ictal changes on magnetic resonance imaging (MRI) is insufficiently understood. We here studied whether the presence of ictal MRI changes was associated with neurological deterioration at discharge. The retrospective cohort comprised all identifiable patients treated at Odense University Hospital in the period 2008-2017. All amenable MRIs were systemically screened for ictal changes. Patient demographics, electroencephalography, seizure characteristics, treatment, and SE duration were assessed. Neurological status was estimated before and after SE. The predefined endpoint was the association of neurological deterioration and ictal MRI changes. Of 261 eligible patients, 101 received at least one MRI during SE or within 7 days after cessation; 43.6% (44/101) had SE due to non- or less brain-damaging etiologies. Patients who received MRI had a longer duration of SE, less frequently had a history of epilepsy, and were more likely to have SE due to unknown causes. Basic characteristics (including electroencephalographic features defined by the Salzburg criteria) did not differ between patients with (n= 20) and without (n= 81) ictal MRI changes. Timing of MRI was important; postictal changes were rare within the first 24 h and hardly seen >5 days after cessation of SE. Ictal MRI changes were associated with a higher risk of neurological deterioration at discharge irrespective of etiology. Furthermore, they were associated with a longer duration of SE and higher long-term mortality that reached statistical significance in patients with non- or less brain-damaging etiologies. In this retrospective cohort, ictal changes on MRI were associated with a higher risk of neurological deterioration at discharge and, possibly, with a longer duration of SE and poorer survival.

Timing matters: there are significant differences in short-term outcomes between two time points of status epilepticus

BackgroundIn 2015, the International League Against Epilepsy proposed a new conceptual definition of status epilepticus (SE) with two operational dimensions (t1 and t2) to guide emergency treatment. The purpose of this study was to compare clinical characteristics and prognoses of patients at these two different time points.MethodsWe conducted a prospective observational cohort study of consecutive adults diagnosed with SE. In case of convulsive SE, t1 is 5 min and t2 is 30 min, whereas in case of focal SE with impaired consciousness, t1 is 10 min, t2 is 60 min. Data on clinical characteristics, including age, gender, history of prior seizures, neuroimaging, semiology, duration, and etiology of SE, were collected. The primary outcome was mortality, with seizure recurrence as a secondary measure, and functional status as tertiary outcome of enrolled patients at 3 months after SE onset.ResultsWe screened one hundred patients with SE, with a median age of 66 years and 61% were male. Fifty-six (56.0%) patients reached t1 of SE, while 44 (44.0%) reached t2 of SE. Convulsive SE (52.0%, n = 52) was more common than focal SE with impaired consciousness (48.0%, n = 48). Status epilepticus secondary to an acute symptomatic process was the most common (50%, n = 50). Patients meeting t2 of SE demonstrated a remarkably increased risk of mortality (unadjusted analysis-RR 3.606, 95%CI 1.552–8.376, p = 0.003; adjusted analysis-RR 2.924, 95%CI 1.221–7.003, p = 0.016) and unfavorable functional status (unadjusted analysis-RR 1.803, 95%CI 1.280–2.539, p = 0.001; adjusted analysis-RR 1.664, 95%CI 1.184–2.340, p = 0.003) at 3 months compared to those who only reached t1 of SE. Patients reaching t2 of SE were more likely to experience seizure recurrence, however, there was no significant difference between the two cohorts.ConclusionsOur study provides strong support for the new definition of SE. Patients meeting t2 of SE tend to have a remarkably increased risk of mortality and unfavorable functional outcomes compared to those who only reached t1 of SE. Furthermore, patients were likely to experience seizure recurrence after undergoing an episode of SE. Physicians must be educated about prompt recognition and appropriate management of SE.

Antiseizure and Neuroprotective Efficacy of Midazolam in Comparison with Tezampanel (LY293558) against Soman-Induced Status Epilepticus.

Acute exposure to nerve agents induces status epilepticus (SE), which can cause death or long-term brain damage. Diazepam is approved by the FDA for the treatment of nerve agent-induced SE, and midazolam (MDZ) is currently under consideration to replace diazepam. However, animal studies have raised questions about the neuroprotective efficacy of benzodiazepines. Here, we compared the antiseizure and neuroprotective efficacy of MDZ (5 mg/kg) with that of tezampanel (LY293558; 10 mg/kg), an AMPA/GluK1 receptor antagonist, administered 1 h after injection of the nerve agent, soman (1.2 × LD50), in adult male rats. Both of the anticonvulsants promptly stopped SE, with MDZ having a more rapid effect. However, SE reoccurred to a greater extent in the MDZ-treated group, resulting in a significantly longer total duration of SE within 24 h post-exposure compared with the LY293558-treated group. The neuroprotective efficacy of the two drugs was studied in the basolateral amygdala, 30 days post-exposure. Significant neuronal and inter-neuronal loss, reduced ratio of interneurons to the total number of neurons, and reduction in spontaneous inhibitory postsynaptic currents accompanied by increased anxiety were found in the MDZ-treated group. The rats treated with LY293558 did not differ from the control rats (not exposed to soman) in any of these measurements. Thus, LY293558 has significantly greater efficacy than midazolam in protecting against prolonged seizures and brain damage caused by acute nerve agent exposure.

Clinico-biological markers for the prognosis of status epilepticus in adults

Prediction of mortality, functional outcome and recovery after status epilepticus (SE) is a challenge. Biological and clinical markers have been proposed to reflect the brain injury or to monitor critical ill patients' severity. The aim of this study was to characterize short-term and long-term prognostic factors for SE patients hospitalized in intensive care unit. Patient's outcome was assessed using the modified Rankin Scale at discharge and after 6-12months. We first assessed the univariate prognosis significance of 51 clinical, demographic or biochemical markers. Next, we built multivariate clinico-biological models by combining most important factors. Statistical models' performances were compared to those of two previous published scales STESS and mSTESS. Eighty-one patients were enrolled. Thirty-five patients showed a steady state while 46 patients clinically worsened at discharge: 14 died, 14 had persistent disability at 6-12months and 18 recovered. Logistic regression analysis revealed that clinical markers (SE refractoriness, SE duration, de novo SE) were significant independent predictors of worsening while lipids markers and progranulin better predicted mortality. The association of clinico-biological variables allowed to accurately predict worsening at discharge (AUC > 0.72), mortality at discharge (AUC 0.83) and recovery at long-term (AUC 0.89). Previous scales provided lower prediction for worsening (AUC 0.63, STESS; 0.53, mSTESS) and mortality (AUC 0.56, STESS; 0.62, mSTESS) (p < 0.001). We proposed new clinico-biological models with a strong discrimination power for prediction of short- and long-term outcome of hospitalized status epilepticus patients. Their implementation in electronic devices may enhance their clinical liability.

Disease progression and brain atrophy in NMDAR encephalitis: Associated factor &amp; clinical implication

ObjectiveWe investigated the longitudinal pattern, determining factors, and clinical implications of brain volume changes in N‐methyl d‐aspartate receptor‐antibody (NMDAR) encephalitis.MethodsBaseline clinical profiles, treatment profiles, and outcome measured using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) and modified Rankin scale (mRS) were obtained from a long‐term clinical database documenting an NMDAR encephalitis cohort. In serial MRI, the change in the normalized volume of different brain regions from the baseline evaluation was measured. At each MRI evaluation time point, the cumulative disease burden (CASE score × months) and the cumulative duration of status epilepticus were also evaluated.ResultsThirty‐six patients were followed‐up for 28.5 months (range 12–63 months). The volume ratio at last MRI to baseline was the lowest in the cerebellum (94.4 ± 5.7%, p < 0.001). Once developed, cerebellar volume reduction followed a progressive course until 2 years from disease onset. The degree of cerebellar volume reduction was positively correlated with mRS and total CASE scores (all, p < 0.001), and CASE scores in the domains of memory, language, and psychiatric problems, gait instability/ataxia, and weakness (all, p < 0.01). In linear mixed model analyses, the degree of cerebellar volume reduction was associated with cumulative disease burden up to 2 years (p < 0.001) and duration of status epilepticus (p < 0.001), and delayed removal of teratoma for ≥1 month (p = 0.006).InterpretationIn NMDAR encephalitis, cerebellar volume reduction was progressive once developed. Cerebellar volume reduction might reflect disease burden and extent of progression and be associated with poor outcomes in multiple functional domains.