Ongoing Status Epilepticus Research Articles

Prophylactic antiseizure medications for recurrent status epilepticus in nonsyndromic childhood epilepsy

PurposeThe management of status epilepticus (SE) has mainly focused on the termination of ongoing SE episodes. However, long-term therapeutic strategies for the prevention of SE are lacking. This study aimed to investigate the effectiveness of prophylactic antiseizure medications (ASMs) for SEs in nonsyndromic childhood epilepsy. MethodsThis retrospective study was conducted at Jikei University Hospital. Patients <18 years of age, diagnosed with epilepsy, and experiencing three or more SE episodes within 1 year between April 1, 2017, and October 1, 2021, were included. ASMs introduced for seizure types that developed into SE were evaluated. The effectiveness of ASMs was determined by using the “Rule of Three”: An ASM was determined effective if patients were free of SE for a duration at least three times that of their longest SE interval in 12 months prior to intervention. ResultsThe investigation included a total of 32 ASMs administered to 13 patients. The longest interval between SE episodes before ASM administration was 28–257 d. The first SE interval after ASM administration was 12–797 d. Levetiracetam (LEV) and clobazam (CLB) showed effectiveness in 2/10 and 5/6 patients, respectively. Other ASMs were ineffective. The leading etiology of epilepsy was perinatal brain injury, identified in four patients, and CLB was effective in all of them. ConclusionsThe present study suggests that CLB and LEV may prolong the SE interval in some cases of nonsyndromic childhood epilepsy. CLB may be beneficial, particularly in patients with perinatal brain injury.

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.

Indications for the use of intravenous second-line antiseizure medications in an emergency room setting

BackgroundSecond-line iv antiseizure medications (ASMs) are used to treat status epilepticus (SE), but in the emergency room setting, there might be other intended and unintended indications for administration. We wanted to explore these different indications and assess the actual usage of first- and second-line ASMs for SE with reference to other uses, such as for SE mimics. MethodsIn this retrospective study, we searched the electronic patient registry with the following terms: “epilepsy”, “SE”, and “seizure”, during 2015. Patients at least 16 years old and treated with iv second-line ASMs were further analysed. We reassessed the indications for the use of iv ASMs based on clinical features and examinations performed. ResultsA total of 166 episodes from 136 patients with a median age of 66 years were evaluated, constituting the following indication categories: ongoing SE (48.2%), recurrent seizures (19.3%), postictal (12.1%), seizure mimics (10.2%) and prophylactic use of ASMs (10.2%). Ongoing SE included the following subgroups: convulsive SE, focal aware SE, nonconvulsive SE (NCSE) and NCSE with coma. The seizure mimics group had a preexisting epilepsy diagnosis more often than the ongoing SE group (73% vs. 44%, p = 0.039). Ischaemic stroke was the most frequent seizure mimic. EEG was performed during hospital admission in 78% of patients with ongoing SE, 50% of patients with recurrent seizures, 75% of patients with postictal state, 53% of seizure mimic episodes and 12% of the prophylactic group. In NCSE and comatose NCSE, the diagnosis was made, and treatment was initiated only after an EEG in 52% and 30% of cases, respectively. The use of newer second-line ASMs (levetiracetam and lacosamide) was frequent in our study population. Immediate side effects of ASMs were infrequent. ConclusionsEven though most of the use of ASMs was justified and administered for SE, it is a diagnostic challenge where a prior diagnosis of epilepsy can be a misleading factor, and EEG is an essential tool when clinical features are often overlapping with other acute seizure disorders. Side effects of the newer second-line ASMs after a single dose are infrequent.

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

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

Isoflurane in (Super-) Refractory Status Epilepticus: A Multicenter Evaluation

BackgroundWe aimed to determine the association between seizure termination and side effects of isoflurane for the treatment of refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) in neurointensive care units (neuro-ICUs).MethodsThis was a multicenter retrospective study of patients with RSE/SRSE treated with isoflurane for status epilepticus termination admitted to the neuro-ICUs of nine German university centers during 2011–2018.ResultsWe identified 45 patients who received isoflurane for the treatment of RSE/SRSE. During isoflurane treatment, electroencephalograms showed no epileptiform discharges in 33 of 41 (80%) patients, and burst suppression pattern was achieved in 29 of 41 patients (71%). RSE/SRSE was finally terminated after treatment with isoflurane in 23 of 45 patients (51%) for the entire group and in 13 of 45 patients (29%) without additional therapy. Lengths of stay in the hospital and in the neuro-ICU were significantly extended in cases of ongoing status epilepticus under isoflurane treatment (p = 0.01 for length of stay in the hospital, p = 0.049 for length in the neuro-ICU). During isoflurane treatment, side effects were reported in 40 of 45 patients (89%) and mainly included hypotension (n = 40, 89%) and/or infection (n = 20, 44%). Whether side effects occurred did not affect the outcome at discharge. Of 22 patients with follow-up magnetic resonance imaging, 2 patients (9%) showed progressive magnetic resonance imaging alterations that were considered to be potentially associated with RSE/SRSE itself or with isoflurane therapy.ConclusionsIsoflurane was associated with a good effect in stopping RSE/SRSE. Nevertheless, establishing remission remained difficult. Side effects were common but without effect on the outcome at discharge.

SENSE registry for status epilepticus.

Evidence is scarce regarding the treatment of status epilepticus (SE). Only a few large randomized controlled trials have been published. Therefore, we set up a multicenter registry to prospectively document treatment practice in several different large hospitals in German-speaking countries. Over a period of more than 4years, we were able to document 1179 episodes of 1049 patients who were treated for SE in 1 of the 8 participating centers in Germany, Austria, and Switzerland. Median age was 70years. The most frequent etiology was remote (32%), followed by acute (31%), or a mixture of acute and remote factors (10%). Semiology was generalized convulsive in 44%, focal motor in 27%, and nonconvulsive in 30%. Only a few patients did not have relevant comorbidities. Median latency between SE onset and first treatment was 1hour (median). Three hundred ninety-three (32%) of the patients were treated within 30minutes after onset. The first treatment step consisted of benzodiazepines in more than 80%, and in levetiracetam in 15%. Five hundred eleven patients (49%) were refractory (defined as ongoing SE after application of benzodiazepine and 1 intravenous anticonvulsant). Further analysis of these registry data may be important for hypothesis generation and trial design for treatment of status epilepticus.

Pre- and post-exposure talampanel (GYKI 53773) against kainic acid seizures in neonatal rats.

AMPA receptors play an important role in the neurobiology of neonatal epilepsy. The present study evaluated the effect of talampanel, a potent and selective non-competitive antagonist of AMPA receptors, against kainic acid-induced continuous seizures (status epilepticus) and other behavioral abnormalities in neonatal rats. Kainic acid was administered at doses of 2 or 4mg/kg, ip to induce seizures and status epilepticus in postnatal 7 days old rat neonates in pre- and post-exposure studies, respectively. Intraperitoneal administration of kainic acid (2 or 4mg/kg) resulted in forelimb/hind-limb scratching defined as automatism, continuous generalized tonic-clonic seizures with loss of righting reflex suggesting status epilepticus and tonic extension. Pre-exposure of talampanel (2.5-10mg/kg, ip) 30min before kainic acid did not affect the onset of kainic acid convulsions. Talampanel at 20mg/kg, ip delayed the commencement of tonic extension, but not status-induced by kainic acid. In contrast, talampanel (5 and 10mg/kg, ip) when administered 5min after kainic acid (4mg/kg, ip) postponed the onset of status epilepticus and tonic extension compared to vehicle treated group. Furthermore, talampanel (10mg/kg, ip) but not GYKI 52466 (20 or 50mg/kg, ip; a non-competitive AMPA/kainate receptor antagonist) stopped the ongoing status epilepticus when administered 10min after the administration of kainic acid. However, seizures re-occurred after 35.98±2.36min. The present results suggested that talampanel is protective in kainic acid-induced neonatal status epilepticus model; however, the time of administration is a crucial factor in determining its effectiveness.

Status Epilepticus: Immunologic and Inflammatory Mechanisms

Status epilepticus (SE) can be difficult to treat, particularly if refractory, and lead to significant morbidity and mortality. Prolonged seizures are also a risk factor for the subsequent diagnosis of epilepsy. Activation of the immune system and inflammation are areas of recent interest in the field of epilepsy, and there is growing evidence that these may be involved in the pathogenesis of ongoing SE and subsequent epileptogenesis. We review the current data on this topic in both animal models and human disease. We conclude that there is evidence suggesting a role for immunologic and inflammatory mechanisms in SE. Further research, especially human studies, is necessary to determine whether targeting the immune system would improve control of SE and prevent sequelae such as epileptogenesis.

Surgical treatment of status epilepticus: A palliative approach

Although status epilepticus (SE) does not resemble a domain for neurosurgical indications in single occasions, a microneurosurgical procedure in patients with catastrophic epilepsy and status epilepticus should be considered as an ultimate ratio-choice in these patients. From a personal series of >600 epilepsy surgery procedures in a period from August 1, 1993 until March 13, 2013, 22 patients were identified with catastrophic epilepsy and all of them with at least one episode of status epilepticus. Five of the patients had surgery under ongoing status epilepticus. Twelve patients became seizure-free, two patients had >90% seizure reduction, seven patients >50% seizure reduction, and one patient was unchanged. No surgery-related complications in terms of permanent morbidity were ascertained in the presented series. In the subgroup of the five patients operated in the acute phase of SE one patient became seizure-free (Engel class. I), one showed Engel class II, two Engel class III, and one Engel class IV with no worthwhile improvement. Patients with catastrophic epilepsy including status epilepticus can benefit from resective epilepsy surgery, even with incomplete resection of the epileptogenic lesion.

Electroencephalography in the Pediatric Emergency Department

This study aimed to identify the indications in which electroencephalography in the pediatric emergency department is most useful. We retrospectively reviewed the influence that the results of the emergent electroencephalogram had on the eventual disposition of patients at our pediatric emergency department. Sixty-eight children (mean age, 7.3 years; 32 males) underwent 70 emergent electroencephalograms. Fifty-seven emergent electroencephalograms were performed for the suspicion of ongoing seizures or status epilepticus. Thirteen of the 22 children (59.1%) discharged from the emergency department were sent home mainly based on the results of the emergent electroencephalogram, which prevented an admission. In particular, 11 of 38 children with frequent and recurrent paroxysmal events concerning for seizures and 2 of 19 children with suspected ongoing status epilepticus were discharged after excluding an epileptic disturbance. The emergent electroencephalogram provided meaningful clinical information that influenced disposition, especially in patients with ongoing events in which the clinical picture was clarified by a rapidly acquired electroencephalogram.

What is the value of hypothermia in acute neurologic diseases and status epilepticus?

Patients with status epilepticus that proves refractory to anesthetic agents represent a daunting challenge for treating clinicians. Animal data support the neuroprotective action of brain hypothermia, and its efficacy in status epilepticus models. This approach, targeting a core temperature of about 33°C for at least 24 hours together with pharmacological sedation, has been described in adults and children. However, although relatively safe if concomitant barbiturates are avoided, it seems that mild hypothermia rarely allows a sustained control of ongoing status epilepticus, since seizures tend to recur in normothermia. Conversely, mild hypothermia has a high-evidence level and is increasingly used in postanoxic encephalopathy, both in newborns and adults. Due to the paucity of available clinical data, prospective studies are needed to assess the value of hypothermia in status epilepticus.

Molecular mechanisms of drug resistance in status epilepticus

Molecular mechanisms of drug resistance in status epilepticus

Why is the developing brain more susceptible to status epilepticus?

Why is the developing brain more susceptible to status epilepticus?

Management of and prophylaxis against status epilepticus in children with severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome) – A nationwide questionnaire survey in Japan

The aim of this study was to establish strategies for prophylaxis against status epilepticus (SE) associated with high fever and for management of ongoing SE in children with severe myoclonic epilepsy in infancy (SMEI). Methods: The investigation was performed retrospectively using a questionnaire, asking about medications, which was distributed to epilepsy specialists throughout Japan. All respondents were members of the Japan Epilepsy Society (JES) and/or the Japanese Society of Child Neurology (JSCN). Data from 109 SMEI patients (51 males and 58 females), 1–37 (M ± SD, 10.7 ± 6.53) years old, were used for this study. Of these 109 patients, 10 were excluded because they had not experienced SE, such that data from 99 patients were analyzed. Results: Among the anti-epileptic drugs (AEDs) used daily, excellent efficacy against SE evolution was obtained with the following: potassium bromide (KBr) (41.7%), zonisamide (ZNS) (13.5%), clobazam (CLB) (10.0%), valproate (VPA) (8.0%), phenobarbital (PB) (6.7%), and phenytoin (PHT) (2.6%). Excellent efficacy was not obtained with either clonazepam (CZP) or carbamazepine (CBZ). The diazepam (DZP) suppository was the most frequently given drug for prophylaxis against SE triggered by fever, but only 2 (2.4%) cases showed excellent results. Excellent efficacy in terminating ongoing SE was obtained with the following medications; intravenous barbiturates (75–100%), intravenous midazolam (MDZ) (68.8%), intravenous DZP (54.3%), intravenous lidocaine (Lid) (21.4%), and intravenous PHT (15.4%). Conclusions: Daily KBr was most efficacious for controlling seizures in SMEI patients. Early use of intravenous barbiturates is the most effective strategy in stopping SE in a subset of patients. Reliable efficacy in SE was not obtained with prophylactic DZP, intravenous benzodiazepines (BZPs), PHT and Lid.

Is Tolerance to Antiepileptic Drugs Clinically Relevant?

Is Tolerance to Antiepileptic Drugs Clinically Relevant?

Transient loss of inhibition precedes spontaneous seizures after experimental status epilepticus

The pathophysiological mechanisms that cause spontaneous seizures following status epilepticus are largely unknown. Erosion of inhibition is regarded as an important pathophysiological hallmark of ongoing status epilepticus. Therefore, we investigated if loss of inhibitory functions also plays an important role in the development of spontaneous seizures after status epilepticus. Furthermore, we analyzed possible changes in excitation that might contribute to epileptogenesis. Finally, neuronal cell loss in the dentate gyrus granule cell layer was analyzed. In rats, inhibition and excitation in the dentate gyrus were monitored 1, 4, and 8 weeks after electrically induced self-sustaining status epilepticus (SSSE). Control animals had electrodes implanted either without subsequent stimulation or with stimulation but under barbiturate anesthesia, neither of which resulted in subsequent spontaneous seizures or impairment of inhibition. Following SSSE 80% of animals developed seizures after 8 weeks. A pronounced impairment of inhibition 1 week after SSSE was followed by gradual recovery over 8 weeks. In the dentate gyrus, cell damage was highly variable most likely explaining the heterogeneity of changes in excitatory parameters. Loss of GABAergic inhibition in the dentate gyrus may facilitate initiation of epileptogenesis but impaired inhibition is not required for the process of epileptogenesis to be maintained.

Effect of an adenosine antagonist and an adenosine agonist on status entry and severity in a model of limbic status epilepticus

Adenosine is an endogenous neuromodulator that suppresses excitatory neurotransmission. We postulated that adenosine-mediated mechanisms resist status epilepticus (SE) entry and limit SE severity. In the first experiment rats were given an adenosine agonist (2-chloroadenosine), an adenosine antagonist (aminophylline), or saline vehicle, prior to SE induction with pulsed-train current delivered to amygdala in successive 5-min current-on sessions. Saline-treated animals entered limbic SE, with predominantly exploratory behavior, after 6.0 ± 0.9 current-on sessions. Aminophylline increased major convulsive activity during stimulation and resulted in entry into convulsive SE after only 2.1±0.1 sessions. 2-Chloroadenosine, in contrast, suppressed major convulsive activity during stimulation, and blocked (in 3 7 ) or delayed ( 4 7 ) SE entry, with successes requiring 12.8± 0.9 stimulation sessions. In a second experiment, animals already in exploratory SE were administered a single injection of saline vehicle, aminophylline, or 2-chloroadenosine. Aminophylline converted exploratory SE into lethally severe convulsive SE. 2-Chloroadenosine suppressed SE behaviorally and electrographically, and protected recipients from the seizure-associated cerebral damage seen in saline-administered SE controls. These results support the hypothesis that endogenous adenosine mechanisms resist SE entry, modulate the severity of ongoing SE, and limit the anatomic spread of seizure activity.

Anticonvulsant actions of MK-801 on the lithium-pilocarpine model of status epilepticus in rats

MK-801, a noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist, was tested for anticonvulsant effects in rats using two seizure models, coadministration of lithium and pilocarpine and administration of a high dose of pilocarpine alone. Three major results are reported. First, pretreatment with MK-801 produced an effective and dose-dependent anticonvulsant action with the lithium-pilocarpine model but not with rats treated with pilocarpine alone, suggesting that different biochemical mechanisms control seizures in these two models. Second, the anticonvulsant effect of MK-801 in the lithium-pilocarpine model only occurred after initial periods of seizure activity. This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that MK-801 binding requires agonist-induced opening of the channel sites of the NMDA receptor. Third, although it is relatively easy to block seizures induced by lithium and pilocarpine by administration of anticonvulsants prior to pilocarpine, it is more difficult to terminate ongoing status epilepticus and block the lethality of the seizures. Administration of MK-801 30 or 60 min after pilocarpine, i.e., during status epilepticus, gradually reduced electrical and behavioral seizure activity and greatly enhanced the survival rate. These results suggest that activation of NMDA receptors plays an important role in status epilepticus and brain damage in the lithium-pilocarpine model. This was further supported by results showing that nonconvulsive doses of NMDA and pilocarpine were synergistic, resulting in status epilepticus and subsequent mortality.