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Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, there are limited data comparing the neuroprotective efficacy of diazepam versus midazolam following acute OP intoxication. To address this data gap, we used non-invasive imaging techniques to longitudinally quantify neuropathology in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) with and without post-exposure intervention with diazepam or midazolam. Magnetic resonance imaging (MRI) was used to monitor neuropathology and brain atrophy, while positron emission tomography (PET) with a radiotracer targeting translocator protein (TSPO) was utilized to assess neuroinflammation. Animals were scanned at 3, 7, 28, 65, 91, and 168 days post-DFP and imaging metrics were quantitated for the hippocampus, amygdala, piriform cortex, thalamus, cerebral cortex and lateral ventricles. In the DFP-intoxicated rat, neuroinflammation persisted for the duration of the study coincident with progressive atrophy and ongoing tissue remodeling. Benzodiazepines attenuated neuropathology in a region-dependent manner, but neither benzodiazepine was effective in attenuating long-term neuroinflammation as detected by TSPO PET. Diffusion MRI and TSPO PET metrics were highly correlated with seizure severity, and early MRI and PET metrics were positively correlated with long-term brain atrophy. Collectively, these results suggest that anti-seizure therapy alone is insufficient to prevent long-lasting neuroinflammation and tissue remodeling.

The mechanisms by which brain insults lead to subsequent epilepsy remain unclear. Insults including trauma, stroke, infections, and long seizures (status epilepticus, SE) increase the nuclear expression and chromatin binding of the neuron-restrictive silencing factor/RE-1 silencing transcription factor (NRSF/REST). REST/NRSF orchestrates major disruption of the expression of key neuronal genes, including ion channels and neurotransmitter receptors, potentially contributing to epileptogenesis. Accordingly, transient interference with REST/NRSF chromatin binding after an epilepsy-provoking SE suppressed spontaneous seizures for the 12 d duration of a prior study. However, whether the onset of epileptogenesis was suppressed or only delayed has remained unresolved. The current experiments determined if transient interference with REST/NRSF chromatin binding prevented epileptogenesis enduringly or, alternatively, slowed epilepsy onset. Epileptogenesis was elicited in adult male rats via systemic kainic acid-induced SE (KA-SE). We then determined if decoy, NRSF-binding-motif oligodeoxynucleotides (NRSE-ODNs), given twice following KA-SE (1) prevented REST/NRSF binding to chromatin, using chromatin immunoprecipitation, or (2) prevented the onset of spontaneous seizures, measured with chronic digital video-electroencephalogram. Blocking NRSF function transiently after KA-SE significantly lengthened the latent period to a first spontaneous seizure. Whereas this intervention did not influence the duration and severity of spontaneous seizures, total seizure number and seizure burden were lower in the NRSE-ODN compared with scrambled-ODN cohorts. Transient interference with REST/NRSF function after KA-SE delays and moderately attenuates insult-related hippocampal epilepsy, but does not abolish it. Thus, the anticonvulsant and antiepileptogenic actions of NRSF are but one of the multifactorial mechanisms generating epilepsy in the adult brain.

Status epilepticus (SE) is a life-threatening development of self-sustaining seizures that becomes resistant to benzodiazepines when treatment is delayed. Benzodiazepine pharmacoresistance is thought in part to result from internalization of synaptic GABAA receptors, which are the main target of the drug. The naturally occurring neurosteroid allopregnanolone is a therapy of interest against SE for its ability to modulate all isoforms of GABAA receptors. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been partially effective in combination with benzodiazepines in mitigating SE-associated neurotoxicity. In this study, allopregnanolone as an adjunct to midazolam or midazolam-ketamine combination therapy was evaluated for efficacy against cholinergic-induced SE. Adult male rats implanted with electroencephalographic (EEG) telemetry devices were exposed to the organophosphorus chemical (OP) soman (GD) and treated with an admix of atropine sulfate and HI-6 at 1 minute after exposure followed by midazolam, midazolam-allopregnanolone, or midazolam-ketamine-allopregnanolone 40 minutes after seizure onset. Neurodegeneration, neuronal loss, and neuroinflammation were assessed 2 weeks after GD exposure. Seizure activity, EEG power integral, and epileptogenesis were also compared among groups. Overall, midazolam-ketamine-allopregnanolone combination therapy was effective in reducing cholinergic-induced toxic signs and neuropathology, particularly in the thalamus and hippocampus. Higher dosage of allopregnanolone administered in combination with midazolam and ketamine was also effective in reducing EEG power integral and epileptogenesis. The current study reports that there is a promising potential of neurosteroids in combination with benzodiazepine and ketamine treatments in a GD model of SE. SIGNIFICANCE STATEMENT: Allopregnanolone, a naturally occurring neurosteroid, reduced pathologies associated with soman (GD) exposure such as epileptogenesis, neurodegeneration, and neuroinflammation, and suppressed GD-induced toxic signs when used as an adjunct to midazolam and ketamine in a delayed treatment model of soman-induced status epilepticus (SE) in rats. However, protection was incomplete, suggesting that further studies are needed to identify optimal combinations of antiseizure medications and routes of administration for maximal efficacy against cholinergic-induced SE.

OBJECTIVES: Continuous electroencephalogram (cEEG) monitoring is recommended for status epilepticus (SE) management in ICU but is still underused due to resource limitations and inconclusive evidence regarding its impact on outcome. Furthermore, the term "continuous monitoring" often implies continuous recording with variable intermittent review. The establishment of a dedicated ICUelectroencephalogram unit may fill this gap, allowing cEEG with nearly real-time review and multidisciplinary management collaboration. This study aimed to evaluate the effect of ICU-electroencephalogram unit establishing on SE outcome and management. DESIGN: Single-center retrospective before-after study. SETTING: Neuro-ICU of a Swiss academic tertiary medical care center. PATIENTS: Adult patients treated for nonhypoxic SE between November 1, 2015, and December 31, 2023. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Data from all SE patients were assessed, comparing those treated before and after ICU-electroencephalogram unit introduction. Primary outcomes were return to premorbid neurologic function, ICU mortality, SE duration, and ICU SE management. Secondary outcomes were SE type and etiology. Two hundred seven SE patients were included, 149 (72%) before and 58 (38%) after ICU-electroencephalogram unit establishment. ICUelectroencephalogram unit introduction was associated with increased detection of nonconvulsive SE (p = 0.003) and SE due to acute symptomatic etiology (p = 0.019). Regression analysis considering age, comorbidities, SE etiology, and SE semeiology revealed a higher chance of returning to premorbid neurologic function (p = 0.002), reduced SE duration (p = 0.024), and a shift in SE management with increased use of antiseizure medications (p = 0.007) after ICUelectroencephalogram unit introduction. CONCLUSIONS: Integrating neurology expertise in the ICU setting through the establishment of an ICU-electroencephalogram unit with nearly real-time cEEG review, shortened SE duration, and increased likelihood of returning to premorbid neurologic function, with an increased number of antiseizure medications used. Further studies are warranted to validate these findings and assess long-term prognosis. [ABSTRACT FROM AUTHOR]

Background: There is not a preferred medication for treating refractory status epilepticus (RSE) and intravenous ketamine is increasingly used. Ketamine efficacy, safety, dosage, and influence of other variables on seizure cessation while on ketamine infusions are not well studied. We aimed to characterize ketamine effect on RSE, including interictal activity on electroencephalogram (EEG) and when done by Teleneurocritical care (TNCC). Methods: We conducted a multicenter, retrospective study from August 2017 to October 2022. Patients 18 years or older who had RSE and received ketamine were included. The primary outcome was effect of ketamine on RSE including interictal activity; secondary outcomes were effect of other variables on RSE, care by TNCC, ketamine infusion dynamics, adverse events, and discharge outcomes. Logistic regression was used. Results: Fifty-one patients from five hospitals met inclusion criteria; 30 patients had RSE and interictal activity on EEG. Median age was 56.8 years (IQR 18.2) and 26% had previously diagnosed epilepsy. Sixteen (31%) patients were treated virtually by TNCC. In those with RSE on EEG, ketamine was added as the fourth antiseizure medication (mean 4.4, SD 1.6). An initial bolus of ketamine was used in 24% of patients (95 mg, IQR 47.5), the median infusion rate was 30.8 mcg/kg/min (IQR 40.4), and median infusion duration was 40 h (IQR 37). Ketamine was associated with 50% cessation of RSE and interictal activity at 24 h in 84% of patients, and complete seizure cessation in 43% of patients. In linear regression, ASMs prior to ketamine were associated with seizure cessation (OR 2.6, 95% CI 0.9–6.9, p = 0.05), while the inverse was seen with propofol infusions (OR 0.02, 95% CI 0.001–0.43, p = 0.01). RSE management by in-person NCC versus virtual by TNCC did not affect rates of seizure cessation. Conclusions: Ketamine infusions for RSE were associated with reduced seizure burden at 24 h, with 84% of patients having 50% seizure reduction. Similar efficacy and safety was observed irrespective of underlying RSE etiology or when done via TNCC vs in-person NCC. [ABSTRACT FROM AUTHOR]

Temporal Lobe Epilepsy (TLE) is a severe neurological condition characterized by recurrent seizures that often do not respond well to available anti-seizure medications. TLE has been associated with epileptogenesis, a process that starts during the latent period following a neurologic insult and is followed by chronic phase. Recent research has linked canonical Wnt signaling to the pathophysiology of epileptogenesis and TLE. Our previous study demonstrated differential regulation of canonical Wnt signaling during early and late stage post status epilepticus (SE) induction. Building on these findings, our current study utilized Wnt modulators: GSK-3β inhibitor 6-bromoindirubin-3'-oxime (6-Bio) and disheveled inhibitor niclosamide and investigated their impact on canonical Wnt signaling during the early (30 days) and later stages (60 days) following SE induction. We assessed several parameters, including seizure frequency, astrogliosis, synaptic density, and neuronal counts in hippocampal tissue. We used immunohistochemistry and Nissl staining to evaluate gliosis, synaptic density, and neuronal counts in micro-dissected hippocampi. Western blotting was used to examine the expression of proteins involved in canonical Wnt/β-catenin signaling, and real-time PCR was conducted to analyze their relative mRNA expression. Wnt modulators, 6-Bio and Niclosamide were found to reduce seizure frequency and various other parameters including behavioral parameters, hippocampal morphology, astrogliosis and synaptic density at different stages of TLE. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) is a neurologic emergency defined as continued seizure activity greater than five minutes or recurrent seizure activity without return to baseline. Benzodiazepine-refractory SE is continuous seizure activity despite treatment with a benzodiazepine. Treatment of benzodiazepine-refractory SE includes levetiracetam with loading doses ranging from 20 mg/kg to 60 mg/kg up to a maximum dose of 4500 mg. While levetiracetam has minimal adverse effects, there is currently a lack of studies directly comparing the safety and efficacy of various loading doses of levetiracetam. The objective of this study was to evaluate the safety and efficacy of three loading doses of levetiracetam in the setting of benzodiazepine-refractory SE. This was a single center, retrospective cohort study of adult patients with benzodiazepine-refractory SE who were treated with levetiracetam from April 1, 2016, to August 31, 2023. Patients with documented hypersensitivity to levetiracetam, those who were pregnant or incarcerated and patients who received an alternative antiepileptic drug (AED) prior to levetiracetam were excluded. Patients with other identifiable causes of SE including hyperglycemia, hypoglycemia, hyponatremia or who were post cardiac arrest were also excluded. Patients were divided into three arms based on loading dose of levetiracetam administered (≤20 mg/kg [LEVlow], 21‐–39 mg/kg [LEVmed] or ≥40 mg/kg [LEVhigh]). The primary endpoint was the rate of seizure termination, defined as the lack of need for an additional AED within 60 min following levetiracetam administration. Secondary outcomes included the rate of intubation, and recurrent seizure activity 60 min to 24 h post seizure termination as defined by positive EEG results or need for an additional AED. Subgroup analyses were performed to assess the influence of adequate loading doses of benzodiazepines, and outpatient levetiracetam use. Overall, 740 patients were screened for inclusion, with 218 patients being included in the primary analysis. Patients were divided into three groups with an average levetiracetam loading dose of 14.5 mg/kg in the LEVlow group, 28.8 mg/kg in the LEVmed group, and 48.8 mg/kg in the LEVhigh group. There was no difference in rates of seizure termination at 60 min (92.9% LEVlow vs 89.3% LEVmed vs 84.7% LEVhigh; p = 0.377). Additionally, no difference was found in rates of recurrent seizure activity between 60 min and 24 h post levetiracetam loading dose (32.1% LEVlow vs 32.0% LEVmed vs 28.8% LEVhigh; p = 0.899). However, the LEVhigh group did have a higher rate of intubation (45.8%) compared to the LEVmed (28.2%) and LEVlow (26.8%) group (p = 0.040). The loading of levetiracetam did not result in a statistically significant difference in rate of seizure termination at 60 min nor did it appear to impact the rate of recurrent seizures at 24 h. However, we did find higher rates of intubation in patients who received levetiracetam >40 mg/kg. Further research is warranted to determine the optimal loading dose of levetiracetam in benzodiazepine-refractory SE. [ABSTRACT FROM AUTHOR]

AbstractIntroductionMethodsResultsDiscussionConclusionsCarbon monoxide poisoning may result in various neurological injuries, including acute symptomatic seizures. We aimed to investigate the long-term risk of epilepsy and status epilepticus in patients with previous carbon monoxide poisoning.The study population was derived from the National Health Insurance Service database of the Republic of Korea between 1 January 2002 and 31 December 2021. We included adults with at least one documented visit to medical facilities because of carbon monoxide poisoning (International Classification of Diseases, Tenth Revision, code T58). Patients were matched, on the same index date, with controls, without a T58 code, for age, sex, insurance type, income level, and residence location in a 1:1 ratio. Follow-up continued until death, migration, or the end of the observation period (31 December 2021). The primary outcome was the incidence of epilepsy (codes G40 or R56) and status epilepticus (code G41).This study included 53,380 patients with carbon monoxide poisoning and 53,380 controls, with 44.2% women and a mean age of 45.7 years. The mean (±SD) follow-up period was 5.7 ± 4.3 years in the carbon monoxide poisoned group and 6.4 ± 4.4 years in controls. The overall risk of epilepsy (adjusted hazard ratio 2.60; 95% CI: 2.43–2.78; P < 0.001) and status epilepticus (adjusted hazard ratio 4.10; 95% CI: 2.84–5.92; P < 0.001) was significantly increased in the carbon monoxide poisoned group compared to controls. The risk of epilepsy and status epilepticus was increased in patients with previous carbon monoxide poisoning, regardless of sex, age or a history of stroke, neurodegenerative diseases, or central nervous system tumour or infection. However, in the subgroup analysis according to age, the highest risk of epilepsy and status epilepticus was observed in patients less than 40 years of age.In this population-based cohort study, previous carbon monoxide poisoning was associated with an increased risk of epilepsy and status epilepticus. The risk was more noticeable in patients aged less than 40 years. Further studies are needed to confirm such an association in other populations.Previous carbon monoxide poisoning was associated with an increased risk of epilepsy and status epilepticus, particularly in the younger population. The long-term management of survivors of carbon monoxide poisoning should include monitoring for epilepsy and status epilepticus. [ABSTRACT FROM AUTHOR]

Cryptogenic new‐onset refractory status epilepticus (cNORSE) is a devastating condition with unclear pathogenesis. Here, we analyzed the genetic underprints of 31 cNORSE patients from an autoimmune encephalitis observational cohort through whole‐genome sequencing. Compared to their controls, cNORSE patients exhibited elevated polygenic risk scores (PRS) for traits associated with autoimmune diseases. The individual PRS against these diseases were correlated with specific clinical phenotypes of cNORSE. The variants were enriched in genes expressed in the central nervous system and lymphocytes. These results suggest a shared genetic framework between cNORSE and other autoimmune/autoinflammatory diseases, and its involvement in the disease pathogenesis. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Background: Focal epilepsy is common in children and adults with mitochondrial disease. Seizures are often refractory to pharmacological treatment and, in this patient group, frequently evolve to refractory focal status epilepticus (also known as epilepsia partialis continua). Where this occurs, the long-term prognosis is poor. Transcranial DC stimulation (tDCS) is a promising, non-invasive, adjunctive treatment alternative to common surgical procedures. Limited recruitment of study participants with this rare disease and the ethical challenges of administering a treatment to one group and not another, while maintaining strict methodological rigour can pose challenges to the design of a clinical study. Method: We designed the first delayed start, double-blinded, sham-controlled study to evaluate the efficacy of tDCS as an adjunctive treatment for focal epilepsy. We will include participants with a genetically confirmed diagnosis of mitochondrial disease with drug-resistant focal epilepsy aged ≥ 2 years, aiming to collect 30 episodes of focal status epilepticus, each treated for a maximum period of 14 days. The early start intervention arm will receive tDCS from day 1. The delayed start intervention arm will receive sham stimulation until crossover on day 3. Our primary endpoint is a greater than 50% reduction from baseline (on day 0) in seizure frequency assessed by 3x daily reporting, accelerometery, and video monitoring. Changes in the underlying epileptogenic focus within the brain related to the tDCS intervention will be assessed by magnetic resonance imaging (MRI) and/or electroencephalography (EEG). Discussion: Study results in favour of treatment efficacy would support development of tDCS into a mainstream treatment option for focal epileptic seizures related to mitochondrial disease. Trials registration: ISRCTN: 18,241,112; registered on 16/11/2021. [ABSTRACT FROM AUTHOR]

Background: Status epilepticus (SE) is one of the most common neurological emergencies and an acutely life-threatening condition characterized by high mortality and morbidity. Despite the well-established staged therapy of status epilepticus, especially stages 1 and 2, more than one third of patients develop (super-) refractory SE. Despite a large variety of potential treatment options for super-refractory SE, there is an unmet clinical need of potential new treatment ideas in this often desperate clinical situation. A number of studies have demonstrated the safety and efficacy of stiripentol (STP) in patients with Dravet syndrome (DS) and in children with focal epilepsy and generalized epilepsies. Some smaller series and case reports have documented the use of STP in the treatment of status epilepticus in adult patients. Methods: We retrospectively analyzed all patients who were admitted to the Department of Neurology at Marburg University Hospital between 2013 and 2023 with a diagnosis of (super)-refractory status epilepticus and who received additional treatment of SE with STP. All patients who received STP during the SE were included, regardless of previous medication. Results: SE ceased in 64% of 25 patients (13 female and 12 male). The mean age was 58.6 ± 21.9 years (mean ± SD). 72% had a structural epilepsy. In 20% of patients, SE was terminated by the administration of STP alone in 32% of cases, while in a further 32% of patients, the simultaneous administration of multiple anti-seizure medications (ASMs) including STP was potentially responsible for the cessation of the SE, with valproic acid (VPA), benzodiazepines and STP, being the most frequently implicated ASMs. In 12% of patients, there was at least a temporary improvement in the electroencephalogram (EEG). Stiripentol had to be discontinued in three cases due to a reduction in vigilance or hypercalcemia. Conclusions: Stiripentol may represent a promising additional treatment option for refractory and super-refractory status epilepticus. The tolerability of this treatment has already been demonstrated in previous studies, and was also reflected in these data. Further prospective investigation in larger patient populations are necessary to ascertain the efficacy of stiripentol in SE. Trial registration: NCT06540378, retrospectively registered. [ABSTRACT FROM AUTHOR]

Time is critical in executing acute seizure treatment, and efforts to minimize operational delays with medication preparation confer potential logistical and practical advantages. Multiple studies have demonstrated the safety and tolerability of intravenous (IV) undiluted levetiracetam (LEV) in adults; however, published pediatric data are limited. This study aims to evaluate the safety and tolerability of IV undiluted LEV in pediatrics. This was a retrospective, dual‐center, observational cohort study evaluating concentration‐related adverse drug events with IV undiluted (100 mg/mL) LEV in pediatrics over a 3‐year 3‐month timespan. A total of 60 undiluted administrations in 52 patients were included in the study. The median age was 4 years; 58.3% of patients were younger than 5 years of age. All doses were administered via a peripheral IV line. The most common IV anatomic site and peripheral IV gauge (G) was the antecubital (66.6%) and 22G catheter (63.3%). There were no documented concentration‐related adverse drug events. Regardless of IV anatomic site, IV gauge, and administered dose there were no documented concentration‐related adverse effects with IV undiluted LEV in a pediatric population. IV undiluted LEV may be considered safe and tolerable in pediatrics. Prospective pediatric studies should assess the safety and tolerability of IV undiluted LEV. [ABSTRACT FROM AUTHOR]

Mitochondrial calcium overload plays an important role in the neurological insults in seizure. The Rab7 GTPase-activating protein, Tre-2/Bub2/Cdc16 domain family member 15 (TBC1D15), is involved in the regulation of mitochondrial calcium dynamics by mediating mitochondria–lysosome membrane contact. However, whether TBC1D15-regulated mitochondria–lysosome membrane contact and mitochondrial calcium participate in neuronal injury in seizure is unclear. We aimed to investigate the effect of TBC1D15-regulated mitochondria–lysosome membrane contact on epileptiform discharge-induced neuronal damage and further explore the underlying mechanism. Lentiviral vectors (Lv) infection and stereotaxic adeno-associated virus (AAV) injection were used to regulate TBC1D15 expression before establishing in vitro epileptiform discharge and in vivo status epilepticus (SE) models. TBC1D15's effect on inter-organellar interactions, mitochondrial calcium levels and neuronal injury in seizure was evaluated. The results showed that abnormalities in mitochondria–lysosome membrane contact, mitochondrial calcium overload, mitochondrial dysfunction, increased levels of reactive oxygen species, and prominent neuronal damage were partly relieved by TBC1D15 overexpression, whereas TBC1D15 knockdown markedly deteriorated these phenomena. Further examination revealed that epileptiform discharge-induced mitochondrial calcium overload in primary hippocampal neurons was closely associated with abnormal mitochondria–lysosome membrane contact. This study highlights the crucial role played by TBC1D15-regulated mitochondria–lysosome membrane contact in epileptiform discharge-induced neuronal injury by alleviating mitochondrial calcium overload. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS) is an infantile onset developmental and epileptic encephalopathy. Sodium channel blockers are known to exacerbate seizures in this syndrome. Due to its high incidence, the management of prolonged seizures is crucial for DS patients. There is still ambiguity regarding the use of intravenous phenytoin for prolonged seizure in DS patients mainly due to the lack of data, raising concern about the safety of it use. We conducted a retrospective study (from January 2009 to January 2020) aiming to assess the management of prolonged seizures in DS with a focus on the use of intravenous phenytoin. Data were collected for patients admitted to our hospital for seizures lasting >5 min. Among 52 identified patients in our database, 23 experienced 59 prolonged seizures managed in our hospital. Only four seizures ceased without rescue medication. Notably, the use of intravenous phenytoin was not associated with discernible adverse effects and was effective in stopping status epilepticus in 71% of cases. This study suggests the safety and efficacy of intravenous phenytoin for prolonged seizure in DS. There is a need for broader investigations of emergency treatments for evidence‐based recommendations for the emergency plan of each patient. [ABSTRACT FROM AUTHOR]

Objective: Intravenous (IV) push (IVP) is an alternative administration method for levetiracetam, but evidence evaluating it compared to IV piggyback (IVPB) for loading doses in acutely seizing patients is limited, particularly in patients with status epilepticus (SE). This study aimed to compare the efficiency and safety of IVP versus IVPB levetiracetam loading doses. Methods: This was a single‐center sequential retrospective study conducted in adult (≥18 years) patients who received an IV levetiracetam loading dose (>2000 mg or ≥20 mg/kg) for acute or suspected seizure. The primary outcome was time to administration, compared between doses given as IVP versus IVPB. Secondary outcomes included rates of adverse events (AEs), rescue benzodiazepine or antiseizure medication administration, intubation, and intensive care unit (ICU) admission between groups. Results: A total of 246 patients were included; 116 received IVP and 130 received IVPB loading doses. Median age was 56 years; most patients were male (62%) and White (60%) and had witnessed seizures (67%). Doses were administered for SE in 32 (27.5%) and 46 (35.4%) patients in the IVP and IVPB arms, respectively. Median time to administration was shorter in the IVP group (12 vs. 38 min, p <.001). Bradycardia (1.7% vs. 2.3%, p =.99), hypotension (7.8% vs. 12%, p =.30), sedation (6% vs. 12.3%, p =.09), intubation (10% vs. 8%, p =.37), ICU admission (32% vs. 39%, p =.31), and rescue medication administration (8.6% vs. 14.6% p =.10) were similar between groups. In SE patients, IVP was associated with shorter time to administration (12 vs. 44 min, p =.003) and lower odds of ICU admission after adjustment for age, dose, Status Epilepticus Severity Score, and seizure history (adjusted odds ratio =.23, 95% confidence interval =.06–.81). Significance: IVP reduced time to levetiracetam administration versus IVPB and was not associated with more AEs. Rescue agent use, intubation, and ICU admission were similar between arms, but IVP may reduce ICU admissions in SE patients. Prospective studies should assess the effectiveness of IVP versus IVPB. [ABSTRACT FROM AUTHOR]

Zusammenfassung: Einleitung: Wir berichten über einen herausfordernden Fall von Autoimmunenzephalitis bei einem Patienten mit einem Thymom, das Titin- und Acetylcholinrezeptor-Antikörper enthielt. Trotz Thymektomie und aggressiver Erstlinien-Immuntherapie erlitt er mehrere Schübe. Letztendlich wurden GABAA-Rezeptor-Antikörper identifiziert. Falldarstellung: Dieser 40-jährige Mann wurde mit Kopfschmerzen, Schwäche, Diplopie, Hörverlust und Anfällen, die bis zum Status epilepticus reichten, vorstellig. Eine Magnetresonanztomografie (MRT) des Gehirns zeigte multifokale kortikale und subkortikale, in der T2/Fluid-Attenuated-Inversion-Recovery-Bildgebung hyperintensive Läsionen ohne Verbesserung. Bei anfänglichen neuronalen Antikörpertests wurden nur Acetylcholinrezeptor- und Titin-Antikörper identifiziert. Der Patient zeigte mehrere schwere Schübe trotz vollständiger Thymomresektion, intravenöser Gabe von Methylprednisolon mit Immunglobulinen oder Plasmapherese und Mycophenolat-Mofetil. Die Zweitlinien-Immuntherapie mit Rituximab linderte die Symptome und normalisierte die Elektroenzephalografie (EEG)- und MRT-Befunde nach der Identifizierung von Anti-GABAA-Rezeptor-Antikörpern durch die umfassenderen neuronalen Antikörpertests auf Autoimmunenzephalitis. [ABSTRACT FROM AUTHOR]

Here we describe a pediatric patient with febrile infection–related epilepsy syndrome with a good functional and neurologic outcome after treatment with early and aggressive cytokine-directed immunomodulatory therapy and a seizure management strategy that intentionally avoided a barbiturate coma. A 5-year-old previously healthy male presented with staring, behavioral arrest, and encephalopathy evolving to super-refractory status epilepticus. He had had onset of fever 5 days prior. He was treated with early and aggressive immunomodulatory therapy targeted to his evolving cytokine profile. He was also treated with the ketogenic diet, antiseizure medications, and continuous anesthetic infusions. Pentobarbital was purposely avoided. Now, 2½ years later, he attends mainstream school, has attention-deficit hyperactivity disorder (ADHD), mild neurocognitive impairment, and well-controlled epilepsy. By using cytokine-directed immunotherapy and avoiding a barbiturate coma, we were able to successfully treat a pediatric patient with febrile infection-related epilepsy syndrome and achieve a good outcome. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Structural epilepsies can manifest months or years after the occurrence of an initial epileptogenic insult, making them amenable for secondary prevention. However, development of preventive treatments has been challenged by a lack of biomarkers for identifying the subset of individuals with the highest risk of epilepsy after the epileptogenic insult.Four different rat models of epileptogenesis were investigated to identify differentially expressed circulating microRNA (miRNA) and isomiR profiles as biomarkers for epileptogenesis. Plasma samples were collected on day 2 and day 9 during the latency period from animals that did or did not develop epilepsy during long‐term video‐electroencephalographic monitoring. miRNAs and isomiRs were identified and measured in an unsupervised manner, using a genome‐wide small RNA sequencing platform. Receiver operating characteristic analysis was performed to determine the performance of putative biomarkers.Two days after an epileptogenic insult, alterations in the levels of several plasma miRNAs and isomiRs predicted epileptogenesis in a model‐specific manner. One miRNA, miR‐3085, showed good sensitivity (but low specificity) as a prognostic biomarker for epileptogenesis in all four models (area under the curve = .729, sensitivity = 83%, specificity = 64%, p < .05).Identified plasma miRNAs and isomiRs are mostly etiology‐specific rather than common prognostic biomarkers of epileptogenesis. These data imply that in preclinical and clinical studies, it may be necessary to identify specific biomarkers for different epilepsy etiologies. Importantly, circulating miRNAs like miR‐3085 with high negative predictive value for epileptogenesis in different etiologies could be useful candidates for initial screening purposes of epileptogenesis risk. [ABSTRACT FROM AUTHOR]

Background: Status epilepticus (SE) imposes a significant burden in terms of in-hospital mortality and costs, but the relationship between SE causes, patient comorbidities, mortality, and cost remains insufficiently understood. We determined the in-hospital mortality and cost-driving factors of SE using a large and comprehensive database. Methods: We conducted a retrospective cohort study involving patients experiencing their first hospitalization with an ICD-10 code diagnosis of SE, spanning from January 1, 2015, to December 31, 2019, using the French health insurance database which covers 99% of population. Patient characteristics, SE causes, Intensive Care Unit (ICU) admissions, mechanical ventilation, discharge status, and health insurance costs were extracted for each hospitalization. Results: We identified 52,487 patients hospitalized for a first SE. In-hospital mortality occurred in 11,464 patients (21.8%), with associated factors including age (Odds Ratio [OR], 10.3, 95% Confidence Interval [CI] 7.87–13.8 for ages over 80 compared to 10–19), acute causes (OR, 15.3, 95% CI 13.9–16.8 for hypoxic cause), tumors (OR, 1.75, 95% CI 1.63–1.8), comorbidities (OR, 3.00, 95% CI 2.79–3.24 for 3 or more comorbidities compared to 0), and prolonged mechanical ventilation (OR, 2.61, 95% CI 2.42–2.82). The median reimbursed cost for each SE hospitalization was 6517€ (3364–13,354), with cost factors mirroring those of in-hospital mortality. Conclusion: Causes and co-morbidities are major determinants of mortality and hospital costs in status epilepticus, and factors associated with higher mortality are also often associated with higher costs. Further studies are needed to identify their long-term effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Epileptic seizures are frequently associated with liver dysfunction and alcoholism. Subacute encephalopathy with seizures in chronic alcoholics (SESA) is an underrecognized condition with peculiar clinical, EEG and neuroradiological features. We report the case of a 58-year-old man with previous alcohol use disorder (AUD) and acute-on chronic liver failure on alcohol-related cirrhosis, referred for urgent Orthotopic Liver Transplantation evaluation. The patient presented with delirium, aphasia and progressive deterioration of consciousness leading to intensive care unit admission. EEG showed slow activity with superimposed lateralized periodic discharges (LPDs) over the left temporo-occipital regions and ictal discharges with focal motor phenomena, consistent with focal status epilepticus. Antiseizure treatment with lacosamide and levetiracetam was administered with progressive improvement of consciousness. Brain MRI disclosed T2/FLAIR areas of hyperintensity in the left pulvinar and T2/FLAIR hyperintensity with corresponding DWI hyperintensity in the left hippocampal cortex, suggestive of post/peri-ictal excitotoxic changes with anatomical correspondence to focal LPDs distribution. SWI demonstrated decreased prominence of cortical veins in the left temporo-occipital region consistent with increased venous blood oxygenation in compensatory hyperperfusion. In conclusion, SESA should be suspected in the differential diagnosis of patients with AUD presenting with focal neurological deficits, seizures and focal EEG abnormalities. In this context, EEG and brain MRI represent useful tools with both diagnostic and prognostic value. [ABSTRACT FROM AUTHOR]

Background: Electroconvulsive therapy (ECT) has been suggested as a treatment option for refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE). Objective: The objective of this scoping review was to conduct an extensive literature review on the role of ECT as a treatment option for RSE and SRSE. Methods: We searched Ovid MEDLINE and Scopus for journal articles from database inception until February 2024. Articles were then selected based on predetermined inclusion and exclusion criteria. Results: We identified five retrospective case series with 28 adult patients receiving ECT for RSE or SRSE. ECT was administered within 3–70 days (mean 20 days) after the development of SE, and the mean number of ECT courses ranged from 1 to 12 sessions for each patient. ECT was administered in fixed or titrated doses. A total of 20 out of 28 patients (71%) showed clinical improvement, with two (7%) having complete cessation of seizures. It is essential to note that given the lack of control, there could be overreporting of clinical improvement in these studies. 11 patients (39%) were reported as deceased due to causes that were not directly related to ECT treatment. Four patients (14%) reported adverse effects of ECT, including memory, concentration, and/or cognitive impairment. Conclusions: There are level-4 Oxford Centre for Evidence-Based Medicine evidence and low-level Grading of Recommendations Assessment Development and Education evidence that suggest ECT as a treatment option for RSE and SRSE. In light of the limitations of the existing evidence, clinicians should carefully consider individual patients' clinical contexts when deciding on the appropriateness of ECT as a treatment option. Further research, including prospective studies with controlled designs, is needed to elucidate the efficacy, safety, and optimal regime of ECT in the management of RSE and SRSE. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to assess the efficacy and tolerability of intranasal midazolam (in-MDZ) administration for antiseizure treatment in adults. Methods: Embase and Medline literature databases were searched. We included randomized trials and cohort studies (excluding case series) of adult patients (≥ 18 years of age) examining in-MDZ administration for epilepsy, epileptic seizures, or status epilepticus published in English between 1985 and 2022. Studies were screened for eligibility based on predefined criteria. The primary outcome was the efficacy of in-MDZ administration, and the secondary outcome was its tolerability. Extracted data included study design, patient characteristics, intervention details, and outcomes. Risk of bias was assessed using the Cochrane Risk of Bias Tool. Results: A total of 12 studies with 929 individuals treated with in-MDZ were included. Most studies were retrospective, with their number increasing over time. Administered in-MDZ doses ranged from 2.5 to 20 mg per single dose. The mean proportion of successful seizure termination after first in-MDZ administration was 72.7% (standard deviation [SD] 18%), and the proportion of seizure recurrence or persistent seizures ranged from 61 to 75%. Most frequent adverse reactions to in-MDZ were dizziness (mean 23.5% [SD 38.6%]), confusion (one study; 17.4%), local irritation (mean 16.6% [SD 9.6%]), and sedation (mean 12.7% [SD 9.7%]). Conclusions: Administration of in-MDZ seems promising for the treatment of prolonged epileptic seizures and seizure clusters in adults. Limited evidence suggests that intranasal administration is safe. Further research is warranted because of the heterogeneity of cohorts, the variation in dosages, and the lack of uniformity in defining successful seizure termination. [ABSTRACT FROM AUTHOR]

A ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that exerts antiepileptic effects by attenuating spontaneous recurrent seizures, ameliorating learning and memory impairments, and modulating the gut microbiota composition. However, the role of the gut microbiome in the antiepileptic effects of a KD on temporal lobe epilepsy (TLE) induced by lithium-pilocarpine in adult rats is still unknown. Our study provides evidence demonstrating that a KD effectively mitigates seizure behavior and reduces acute-phase epileptic brain activity and that KD treatment alleviates hippocampal neuronal damage and improves cognitive impairment induced by TLE. We also observed that the beneficial effects of a KD are compromised when the gut microbiota is disrupted through antibiotic administration. Analysis of gut microbiota components via 16S rRNA gene sequencing in fecal samples collected from TLE rats fed either a KD or a normal diet. The Chao1 and ACE indices showed decreased species variety in KD-fed rats compared to TLE rats fed a normal diet. A KD increased the levels of Actinobacteriota, Verrucomicrobiota and Proteobacteria and decreased the level of Bacteroidetes. Interestingly, the abundances of Actinobacteriota and Verrucomicrobiota were positively correlated with learning and memory ability, and the abundance of Proteobacteria was positively correlated with seizure susceptibility. In conclusion, our study revealed the significant antiepileptic and neuroprotective effects of a KD on pilocarpine-induced epilepsy in rats, primarily mediated through the modulation of the gut microbiota. However, whether the gut microbiota mediates the antiseizure effects of a KD still needs to be better elucidated. [ABSTRACT FROM AUTHOR]

• Children with acute CNS complication during HCT have higher epilepsy risk. • Epilepsy rate is 9.6 %, 5-year cumulative incidence is 13.3 %. • Status epilepticus as CNS complication correlates with epilepsy development (OR=14). • Need for tailored neuro follow-up post-HCT in children with acute CNS complication. Acute central nervous system (CNS) complications are common and well described among pediatric patients undergoing haematopoietic cell transplantation (HCT). However, their long-term outcomes are not known. The aim of this study is to describe the incidence, characteristics, and risk factors of long-term epilepsy in pediatric patients with acute CNS complications of HCT. This retrospective study included pediatric patients who developed acute CNS complications from autologous or allogeneic HCT between 2000 and 2022. Clinical, therapeutic and prognostic data including long-term outcomes were analyzed. A diagnosis of epilepsy was provided if unprovoked seizures occurred during follow-up. Ninety-four patients (63 males, 31 females, median age 10 years, range 1–21 years) were included. The most common acute CNS complications were posterior reversible encephalopathy syndrome (n = 43, 46 %) and infections (n = 15, 16 %). Sixty-five patients (69 %) had acute symptomatic seizures, with 14 (16 %) having one or more episodes of status epilepticus (SE). Nine patients (9.6 %) were diagnosed with long-term focal epilepsy during the follow-up (5-year cumulative incidence from the acute complication, 13.3 %). Acute symptomatic SE during neurological complications of HCT was associated with an increased risk of long-term epilepsy (OR=14, 95 % CI 2.87–68.97). A higher occurrence of epilepsy has been observed in our cohort compared to the general population. Acute symptomatic SE during HCT was associated with a higher risk of long-term epilepsy. Pediatric patients with CNS complications during HCT could benefit from specific neurological follow-up. Further studies are needed to characterize mechanisms of epileptogenesis in pediatric patients undergoing HCT. [Display omitted] [ABSTRACT FROM AUTHOR]