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General anesthesia (GA) earlier than recommended (as first‐ or second‐line treatment) was recently described to improve status epilepticus (SE) outcome. We aimed to assess the impact of early GA on outcome in matched groups. Data from a multicenter, prospective cohort of 1179 SE episodes in 1049 adults were retrospectively analyzed. Incident SE episodes were categorized as “early anesthesia” (eGA; GA as first‐ or second‐line treatment) or “non‐early anesthesia” (neGA; GA after second‐line treatment or not at all). Using propensity score matching, eGA episodes were paired 1:4 with neGA episodes. We assessed survival, functional outcomes at discharge (good: modified Rankin Scale = 0–2 or no worsening), SE cessation rate, SE duration, and hospital stay. Among 1049 SE episodes, 55 (5.2%) received eGA, and 994 constituted the neGA group; 220 represented the matched controls. Patients receiving eGA were younger (median = 63, interquartile range [IQR] = 56–76 vs. median = 70, IQR = 54–80 years, p = .004), had deeper consciousness impairment (80% vs. 40% stuporous/comatose, p < .001), and had more severe SE forms (89% vs. 54% generalized convulsive SE/nonconvulsive SE in coma, p < .001). Mortality, functional outcome, SE cessation rate, and duration of SE and hospital stay were similar between the eGA group and matched controls. We conclude that early anesthesia for SE treatment did not influence prognosis. [ABSTRACT FROM AUTHOR]

Abstract Background Treating refractory status epilepticus (RSE) remains a challenge. Thiamylal can be used as a second- or third-line treatment; however, its potential to induce cytochrome P450 (CYP) activity may reduce the concentration of antiepileptic drugs (AEDs) administered prior to thiamylal. This report details a case of RSE patient treated with thiamylal, with monitored concentrations of thiamylal and other AEDs. Case presentation A 72-year-old healthy man developed RSE. Despite the administration of various AEDs, his seizures were not resolved. Thiamylal was then administered at an initial bolus dose of 2.1 mg/kg, followed by a continuous infusion of 4.2–5.2 mg/kg/h. The initial thiamylal concentration was observed at 7.8 μg/mL, increasing to 35.2 μg/mL before decreasing after dose reduction and cessation. Concurrently, the concentration of concomitant carbamazepine decreased from 5.59 μg/mL to 2.1 μg/mL and recovered as thiamylal concentration decreased. Lesser impacts were noted for other AEDs. Conclusions This case report underscored the efficacy of thiamylal in treating RSE. However, it also highlighted the need for clinicians to closely monitor the concentrations of concurrent AEDs, especially carbamazepine, during thiamylal therapy.

Abstract Status Epilepticus (SE), unresponsive to medical management, is associated with high morbidity and mortality. Surgical management is typically considered in these refractory cases. The best surgical approach for affected patients remains unclear; however, given the lack of controlled trials exploring the role of surgery. We performed a systematic review according to PRIMSA guidelines, including case reports and series describing surgical interventions for patients in SE. Cases (157 patients, median age 12.9 years) were followed for a median of 12 months. Patients were in SE for a median of 21 days before undergoing procedures including: focal resection (36.9%), functional hemispherectomy (21%), lobar resection (12.7%), vagus nerve stimulation (VNS) (12.7%), deep brain stimulation (DBS) (6.4%), multiple subpial transection (MST) (3.8%), responsive neurostimulation (RNS) (1.9%), and cortical stimulator placement (1.27%), with 24 patients undergoing multiple procedures. Multiple SE semiologies were identified. 47.8% of patients had focal seizures, and 65% of patients had focal structural abnormalities on MRI. SE persisted for 36.8 ± 47.7 days prior to surgical intervention. SE terminated following surgery in 81.5%, terminated with additional adjuncts in 10.2%, continued in 1.9%, and was not specified in 6.4% of patients. Long‐term seizure outcomes were favorable, with the majority improved and 51% seizure‐free. Eight patients passed away in follow‐up, of which three were in SE. Seizures emerging from one hemisphere were both more likely to immediately terminate (OR 4.7) and lead to long‐term seizure‐free status (OR 3.9) compared to nonunilateral seizures. No other predictors, including seizure focality, SE duration, or choice of surgical procedure, were predictors of SE termination. Surgical treatment of SE can be effective in terminating SE and leading to sustained seizure freedom, with many different procedures showing efficacy if matched appropriately with SE semiology and etiology. Plain Language Summary Patients with persistent seizures (Status Epilepticus) that do not stop following medications can be treated effectively with surgery. Here, we systematically review the entirety of existing literature on surgery for treating status epilepticus to better identify how and when surgery is used and what patients do after surgery.

Background: Treating refractory status epilepticus (RSE) remains a challenge. Thiamylal can be used as a second- or third-line treatment; however, its potential to induce cytochrome P450 (CYP) activity may reduce the concentration of antiepileptic drugs (AEDs) administered prior to thiamylal. This report details a case of RSE patient treated with thiamylal, with monitored concentrations of thiamylal and other AEDs. Case presentation: A 72-year-old healthy man developed RSE. Despite the administration of various AEDs, his seizures were not resolved. Thiamylal was then administered at an initial bolus dose of 2.1 mg/kg, followed by a continuous infusion of 4.2–5.2 mg/kg/h. The initial thiamylal concentration was observed at 7.8 μg/mL, increasing to 35.2 μg/mL before decreasing after dose reduction and cessation. Concurrently, the concentration of concomitant carbamazepine decreased from 5.59 μg/mL to 2.1 μg/mL and recovered as thiamylal concentration decreased. Lesser impacts were noted for other AEDs. Conclusions: This case report underscored the efficacy of thiamylal in treating RSE. However, it also highlighted the need for clinicians to closely monitor the concentrations of concurrent AEDs, especially carbamazepine, during thiamylal therapy. [ABSTRACT FROM AUTHOR]

Super refractory status epilepticus (SRSE) is a condition associated with high rates of mortality and morbidity. We report the treatment protocol of magnesium sulphate infusion adapted for the management of a case of super refractory status epilepticus that lasted for 4 weeks. A young lady presented in altered sensorium with a history of fever followed by uncontrolled seizures of 2 weeks duration. Her serum tested weakly positive for GABA-B receptor antibody. Her seizures were not controlled despite being on multiple antiepileptics and anesthetic induction. Intravenous magnesium infusion was initiated and serum magnesium was titrated up to a final target concentration of 3.8–6.5 mg/dl. Seizure control was achieved after 11 days of the infusion. This case is the longest reported successful use of magnesium sulfate infusion for control of super refractory status epileptics. [ABSTRACT FROM AUTHOR]

Status Epilepticus (SE), unresponsive to medical management, is associated with high morbidity and mortality. Surgical management is typically considered in these refractory cases. The best surgical approach for affected patients remains unclear; however, given the lack of controlled trials exploring the role of surgery. We performed a systematic review according to PRIMSA guidelines, including case reports and series describing surgical interventions for patients in SE. Cases (157 patients, median age 12.9 years) were followed for a median of 12 months. Patients were in SE for a median of 21 days before undergoing procedures including: focal resection (36.9%), functional hemispherectomy (21%), lobar resection (12.7%), vagus nerve stimulation (VNS) (12.7%), deep brain stimulation (DBS) (6.4%), multiple subpial transection (MST) (3.8%), responsive neurostimulation (RNS) (1.9%), and cortical stimulator placement (1.27%), with 24 patients undergoing multiple procedures. Multiple SE semiologies were identified. 47.8% of patients had focal seizures, and 65% of patients had focal structural abnormalities on MRI. SE persisted for 36.8 ± 47.7 days prior to surgical intervention. SE terminated following surgery in 81.5%, terminated with additional adjuncts in 10.2%, continued in 1.9%, and was not specified in 6.4% of patients. Long‐term seizure outcomes were favorable, with the majority improved and 51% seizure‐free. Eight patients passed away in follow‐up, of which three were in SE. Seizures emerging from one hemisphere were both more likely to immediately terminate (OR 4.7) and lead to long‐term seizure‐free status (OR 3.9) compared to nonunilateral seizures. No other predictors, including seizure focality, SE duration, or choice of surgical procedure, were predictors of SE termination. Surgical treatment of SE can be effective in terminating SE and leading to sustained seizure freedom, with many different procedures showing efficacy if matched appropriately with SE semiology and etiology. Plain Language Summary: Patients with persistent seizures (Status Epilepticus) that do not stop following medications can be treated effectively with surgery. Here, we systematically review the entirety of existing literature on surgery for treating status epilepticus to better identify how and when surgery is used and what patients do after surgery. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to review the demographic characteristics, type, and etiology of status epilepticus (SE) cases followed in our hospital for a period of 1 year and to reveal the factors affecting the prognosis of the patients. Methods: Patients diagnosed with SE among the patients who applied to the emergency department of our hospital within a 1-year period (August 2018 and August 2019) and who were consulted to us because of epileptic seizures or changes in consciousness and behavior while being followed up in the services or intensive care unit were retrospectively screened. Results: A total of 51 patients, 28 female (54.9%) and 23 male (45.1%), were included in our study. Twenty-eight patients were under or equal to the age of 60, and 23 patients were over the age of 60. Twenty-one patients had convulsive SE, 18 patients had non-convulsive SE (NCSE), and 14 patients were transitioning from convulsive SE to NCSE. Causes of SE were; lack of anti-seizure drugs (ASD) in 9 patients, intracranial mass in 9 patients, infection in 8 patients, and cerebrovascular event in 6 patients. Refractory SE cases were mostly observed in patients who developed SE due to lack of ASD and infection. In addition to first-line treatment with benzodiazepines, intravenous (IV) phenytoin, levetiracetam, valproic acid, and oral topiramate and lacosamide treatments were used. It was observed that 26 patients who developed refractory SE were treated with IV midazolam, propofol, or thiopental infusion. It was observed that 2 patients died because of refractory seizures. Conclusion: SE is an important condition that requires rapid treatment and can be fatal. In this cross-sectional study, the demographic characteristics and etiological causes of SE cases registered in our center were presented, and the characteristics of refractory SE cases were also mentioned.

Abstract Focal cortical dysplasia (FCD) represents the most common cause of drug‐resistant epilepsy in adult and pediatric surgical series. However, genetic factors contributing to severe phenotypes of FCD remain unknown. We present a patient with an exceptionally rapid development of drug‐resistant epilepsy evolving in super‐refractory status epilepticus. We performed multiple clinical (serial EEG, MRI), biochemical (metabolic and immunological screening), genetic (WES from blood‐ and brain‐derived DNA), and histopathological investigations. The patient presented 1 month after an uncomplicated varicella infection. MRI was negative, as well as other biochemical and immunological examinations. Whole‐exome sequencing of blood‐derived DNA detected a heterozygous paternally inherited variant NM_006267.4(RANBP2):c.5233A>G p.(Ile1745Val) (Chr2[GRCh37]:g.109382228A>G), a gene associated with a susceptibility to infection‐induced acute necrotizing encephalopathy. No combination of anti‐seizure medication led to a sustained seizure freedom and the patient warranted induction of propofol anesthesia with high‐dose intravenous midazolam and continuous respiratory support that however failed to abort seizure activity. Brain biopsy revealed FCD type IIa; this finding led to the indication of an emergency right‐sided hemispherotomy that rendered the patient temporarily seizure‐free. Postsurgically, he remains on antiseizure medication and experiences rare nondisabling seizures. This report highlights a uniquely severe clinical course of FCD putatively modified by the RANBP2 variant. Plain Language Summary We report a case summary of a patient who came to our attention for epilepsy that could not be controlled with medication. His clinical course progressed rapidly to life‐threatening status epilepticus with other unusual neurological findings. Therefore, we decided to surgically remove a piece of brain tissue in order to clarify the diagnosis that showed features of a structural brain abnormality associated with severe epilepsy, the focal cortical dysplasia. Later, a genetic variant in a gene associated with another condition, was found, and we hypothesize that this genetic variant could have contributed to this severe clinical course of our patient.

Focal cortical dysplasia (FCD) represents the most common cause of drug‐resistant epilepsy in adult and pediatric surgical series. However, genetic factors contributing to severe phenotypes of FCD remain unknown. We present a patient with an exceptionally rapid development of drug‐resistant epilepsy evolving in super‐refractory status epilepticus. We performed multiple clinical (serial EEG, MRI), biochemical (metabolic and immunological screening), genetic (WES from blood‐ and brain‐derived DNA), and histopathological investigations. The patient presented 1 month after an uncomplicated varicella infection. MRI was negative, as well as other biochemical and immunological examinations. Whole‐exome sequencing of blood‐derived DNA detected a heterozygous paternally inherited variant NM_006267.4(RANBP2):c.5233A>G p.(Ile1745Val) (Chr2[GRCh37]:g.109382228A>G), a gene associated with a susceptibility to infection‐induced acute necrotizing encephalopathy. No combination of anti‐seizure medication led to a sustained seizure freedom and the patient warranted induction of propofol anesthesia with high‐dose intravenous midazolam and continuous respiratory support that however failed to abort seizure activity. Brain biopsy revealed FCD type IIa; this finding led to the indication of an emergency right‐sided hemispherotomy that rendered the patient temporarily seizure‐free. Postsurgically, he remains on antiseizure medication and experiences rare nondisabling seizures. This report highlights a uniquely severe clinical course of FCD putatively modified by the RANBP2 variant. Plain Language Summary: We report a case summary of a patient who came to our attention for epilepsy that could not be controlled with medication. His clinical course progressed rapidly to life‐threatening status epilepticus with other unusual neurological findings. Therefore, we decided to surgically remove a piece of brain tissue in order to clarify the diagnosis that showed features of a structural brain abnormality associated with severe epilepsy, the focal cortical dysplasia. Later, a genetic variant in a gene associated with another condition, was found, and we hypothesize that this genetic variant could have contributed to this severe clinical course of our patient. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to review the demographic characteristics, type, and etiology of status epilepticus (SE) cases followed in our hospital for a period of 1 year and to reveal the factors affecting the prognosis of the patients. Methods: Patients diagnosed with SE among the patients who applied to the emergency department of our hospital within a 1-year period (August 2018 and August 2019) and who were consulted to us because of epileptic seizures or changes in consciousness and behavior while being followed up in the services or intensive care unit were retrospectively screened. Results: A total of 51 patients, 28 female (54.9%) and 23 male (45.1%), were included in our study. Twenty-eight patients were under or equal to the age of 60, and 23 patients were over the age of 60. Twenty-one patients had convulsive SE, 18 patients had non-convulsive SE (NCSE), and 14 patients were transitioning from convulsive SE to NCSE. Causes of SE were; lack of anti-seizure drugs (ASD) in 9 patients, intracranial mass in 9 patients, infection in 8 patients, and cerebrovascular event in 6 patients. Refractory SE cases were mostly observed in patients who developed SE due to lack of ASD and infection. In addition to first-line treatment with benzodiazepines, intravenous (IV) phenytoin, levetiracetam, valproic acid, and oral topiramate and lacosamide treatments were used. It was observed that 26 patients who developed refractory SE were treated with IV midazolam, propofol, or thiopental infusion. It was observed that 2 patients died because of refractory seizures. Conclusion: SE is an important condition that requires rapid treatment and can be fatal. In this cross-sectional study, the demographic characteristics and etiological causes of SE cases registered in our center were presented, and the characteristics of refractory SE cases were also mentioned. [ABSTRACT FROM AUTHOR]

Refractory status epilepticus (RSE) is a diagnosis that can be made when tonic-clonic status epilepticus (SE) and focal SE cannot be stopped by at least two anti-seizure medications after 30 and 60 minutes, respectively, from the time of commencement. It could result in mortality, loss of functionality, neurological deficiency, and other serious short- and long-term effects. This narrative review covers original clinical studies of any design and case series investigating long-term outcomes of RSE recorded after at least a year from the SE onset. The future of a patient with RSE rests mostly on the long-term effects of this severe pathological condition, which may be accompanied with systemic complications like hyperthermia, hyperkalemia, acidosis, and/or stress cardiomyopathy. Younger patients with less severe RSE of shorter duration, particularly of the convulsive kind, are reported to have better long-term outcomes. Previous studies on the factors influencing the long-term outcomes of RSE, however, did not link the outcomes to treatment options for the condition. Such circumstances currently prevent making any definitive recommendations on the treatment of RSE until future research with adequate statistical power is completed. [ABSTRACT FROM AUTHOR]

Endotracheal intubation, frequently required during management of refractory status epilepticus (RSE), can be facilitated by anesthetic medications; however, their effectiveness for RSE control is unknown. We performed a single-center retrospective review of patients admitted to a neurocritical care unit (NCCU) who underwent in-hospital intubation during RSE management. Patients intubated with propofol, ketamine, or benzodiazepines, termed anti-seizure induction (ASI), were compared to patients who received etomidate induction (EI). The primary endpoint was clinical or electrographic seizures within 12 h post-intubation. We estimated the association of ASI on post-intubation seizure using logistic regression. A sub-group of patients undergoing electroencephalography during intubation was identified to evaluate the immediate effect of ASI on RSE. We screened 697 patients admitted to the NCCU for RSE and identified 148 intubated in-hospital (n = 90 ASI, n = 58 EI). There was no difference in post-intubation seizure (26 % (n = 23) ASI, 29 % (n = 17) EI) in the cohort, however, there was increased RSE resolution with ASI in 24 patients with electrographic RSE during intubation (ASI: 61 % (n = 11/18) vs EI: 0 % (n = 0/6), p =.016). While anti-seizure induction did not appear to affect post-intubation seizure occurrence overall, a sub-group of patients undergoing electroencephalography during intubation had a higher incidence of seizure cessation, suggesting potential benefit in an enriched population.

OBJECTIVE: Examine the association of duration of therapeutic coma (TC) with seizure recurrence, morbidity, and mortality in refractory status epilepticus (RSE). Define an optimal window for TC that provides sustained seizure control and minimizes complications. METHODS: Retrospective, observational cohort study involving patients who presented with RSE to the University of Alabama at Birmingham or the University of California at San Francisco from 2010 to 2016. Relationship of duration of TC with primary and secondary outcomes was evaluated using two-sample t tests, simple linear regression, and chi-square tests. Multivariable linear and logistic regression models were used to identify independent predictors. Predictive ability of TC for seizure recurrence was quantified using a receiver-operating characteristic curve. Youden index was used to determine an optimal cutoff value. RESULTS: Multivariable analysis of clinical and treatment characteristics of 182 patients who were treated predominantly with propofol as anesthetic agent showed that longer duration of the first trial of TC (27.2 vs 15.6 hours) was independently associated with a higher chance of seizure recurrence following the first weaning attempt (P = 0.038) but not with poor functional neurologic outcome upon discharge, in-hospital complications, or mortality. Furthermore, higher doses of anesthetic utilized during the first trial of TC were independently associated with fewer in-hospital complications (P = 0.003) and associated with a shorter duration of mechanical ventilation and total length of stay. Duration of TC was identified as an independent predictor of seizure recurrence with an optimal cutoff point at 35 hours. SIGNIFICANCE: This study suggests that a shorter duration yet deeper TC as treatment for RSE may be more effective and safer than the currently recommended TC duration of 24-48 hours. Prospective and randomized trials should be conducted to validate these assertions.

Abstract Objective To discuss the results of the KETASER01 trial and the reasons for its failure, particularly in view of future studies. Methods KETASER01 is a multicenter, randomized, controlled, open‐label, sequentially designed, non‐profit Italian study that aimed to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory convulsive status epilepticus (RCSE) in children. Results During the 5‐year recruitment phase, a total of 76 RCSEs treated with third‐line therapy were observed in five of the 10 participating Centers; only 10 individuals (five for each study arm; five females, mean age 6.5 ± 6.3 years) were enrolled in the KETASER01 study. Two of the five patients (40%) in the experimental arm were successfully treated with ketamine and two of the five (40%) children in the control arm, where successfully treated with thiopental. In the remaining six (60%) enrolled patients, RCSE was not controlled by the randomized anesthetic(s). Significance The KETASER01 study was prematurely halted due to low eligibility of patients and no successful recruitment. No conclusions can be drawn regarding the objectives of the study. Here, we discuss the KETASER01 results and critically analyze the reasons for its failure in view of future trials.

Introduction: Febrile infection-related epilepsy syndrome (FIRES) is a severe childhood epilepsy with refractory status epilepticus after a typically mild febrile infection. The etiology of FIRES is largely unknown, and outcomes in most individuals with FIRES are poor. Methods: Here, we reviewed the current state-of-the art genetic testing strategies in individuals with FIRES. We performed a systematic computational analysis to identify individuals with FIRES and characterize the clinical landscape using the Electronic Medical Records (EMR). Among 25 individuals with a confirmed FIRES diagnosis over the last decade, we performed a comprehensive review of genetic testing and other diagnostic testing. Results: Management included use of steroids and intravenous immunoglobulin (IVIG) in most individuals, with an increased use of immunomodulatory agents, including IVIG, plasma exchange (PLEX) and immunosuppressants such as cytokine inhibitors, and the ketogenic diet after 2014. Genetic testing was performed on a clinical basis in almost all individuals and was non-diagnostic in all patients. We compared FIRES with both status epilepticus (SE) and refractory status epilepticus (RSE) as a broader comparison cohort and identified genetic causes in 36% of patients with RSE. The difference in genetic signatures between FIRES and RSE suggest distinct underlying etiologies. In summary, despite the absence of any identifiable etiologies in FIRES, we performed an unbiased analysis of the clinical landscape, identifying a heterogeneous range of treatment strategies and characterized real-world clinical practice. Discussion: FIRES remains one of the most enigmatic conditions in child neurology without any known etiologies to date despite significant efforts in the field, suggesting a clear need for further studies and novel diagnostic and treatment approaches. [ABSTRACT FROM AUTHOR]

Continuous ketamine infusions have been studied as an adjunctive agent for refractory status epilepticus (RSE) and super refractory status epilepticus (SRSE) in older children and adults. However, minimal information exists on the efficacy, safety, and dosing for continuous ketamine in young infants. We present the clinical course of 3 young infants with RSE and SRSE who received continuous ketamine in conjunction with other antiseizure medications. The condition of these patients was refractory to an average of 6 antiseizure medications before initiation of continuous ketamine infusion. For each patient, a continuous ketamine infusion was initiated at a rate of 1 mg/kg/hr with 1 patient requiring titration to a maximum of 6 mg/ kg/hr. In 1 case, the concomitant use of continuous ketamine allowed for a reduction in the benzodiazepine continuous infusion rate. In all cases, ketamine was well tolerated especially in the setting of hemodynamic instability. Ketamine may provide a safe adjunct in the acute setting in severe RSE and SRSE. This is the first case series to document the use of continuous ketamine as a treatment modality in young infants with RSE or SRSE secondary to various underlying etiologies, without adverse events. Further studies are needed to evaluate the long-term safety and efficacy of continuous ketamine in this patient population. [ABSTRACT FROM AUTHOR]

IntroductionFebrile infection-related epilepsy syndrome (FIRES) is a severe childhood epilepsy with refractory status epilepticus after a typically mild febrile infection. The etiology of FIRES is largely unknown, and outcomes in most individuals with FIRES are poor.MethodsHere, we reviewed the current state-of-the art genetic testing strategies in individuals with FIRES. We performed a systematic computational analysis to identify individuals with FIRES and characterize the clinical landscape using the Electronic Medical Records (EMR). Among 25 individuals with a confirmed FIRES diagnosis over the last decade, we performed a comprehensive review of genetic testing and other diagnostic testing.ResultsManagement included use of steroids and intravenous immunoglobulin (IVIG) in most individuals, with an increased use of immunomodulatory agents, including IVIG, plasma exchange (PLEX) and immunosuppressants such as cytokine inhibitors, and the ketogenic diet after 2014. Genetic testing was performed on a clinical basis in almost all individuals and was non-diagnostic in all patients. We compared FIRES with both status epilepticus (SE) and refractory status epilepticus (RSE) as a broader comparison cohort and identified genetic causes in 36% of patients with RSE. The difference in genetic signatures between FIRES and RSE suggest distinct underlying etiologies. In summary, despite the absence of any identifiable etiologies in FIRES, we performed an unbiased analysis of the clinical landscape, identifying a heterogeneous range of treatment strategies and characterized real-world clinical practice.DiscussionFIRES remains one of the most enigmatic conditions in child neurology without any known etiologies to date despite significant efforts in the field, suggesting a clear need for further studies and novel diagnostic and treatment approaches.

Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA)A receptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The 2 neuroactive steroids are being investigated as treatments for SE, including as a treatment for SE induced by chemical threat agents. Intramuscular injection is the preferred route of administration in the prehospital treatment of SE. The objective of this study was to assess the efficacy of intramuscular allopregnanolone and ganaxolone in the treatment of SE induced by the chemical threat agent tetramethylenedisulfotetramine (TETS). The test agents were administered 40 minutes after the onset of SE when mice are refractory to treatment. Allopregnanolone and ganaxolone (each at 3 mg/kg) terminated SE in, respectively, 92% and 75% of animals, and prevented mortality in 85% and 50% of animals; the mean times to termination of behavioral seizures were, respectively, 172 ± 16 and 447 ± 52 seconds. In a separate series of experiments, mice were dosed with the neuroactive steroids by intramuscular injection, and plasma and brain levels were sampled at various time points following injection to estimate pharmacokinetic parameters. Plasma Cmax (maximum concentration) values for allopregnanolone and ganaxolone were 645 and 550 ng/mL, respectively. Brain exposure of both steroids was approximately 3-fold the plasma exposure. Two-compartment pharmacokinetic analysis revealed that the central compartment Vd (volume of distribution), CL (clearance), t½ (terminal half-life), and F (intramuscular bioavailability) values for allopregnanolone and ganaxolone were, respectively, 4.95 L/kg 12.88 L/kg/h,16 minutes, 97%, and 5.07 L/kg, 8.35 L/kg/h, 25 minutes, 95%. Allopregnanolone and ganaxolone are effective in the treatment of TETS-induced SE when administered by the intramuscular route. Allopregnanolone is more rapidly acting and modestly more effective, possibly because it has greater potency on GABAA receptors.

Background: Cryptogenic febrile infection-related epilepsy syndrome (FIRES) is a rare but catastrophic encephalopathic condition. We aimed to investigate the long-term outcome in adult cryptogenic FIRES. Methods: This was a retrospective study based on the prospective database in the neuro-intensive care unit of a tertiary hospital in China. Consecutive adult patients with cryptogenic FIRES between July 2007 to December 2021 were included. Long-term outcomes included function independence, the development of drug-resistant epilepsy (DRE), remote recurrent status epilepticus (SE), anti-seizure medications (ASMs), and changes in the brain Magnetic Resonance Imaging (MRI). Results: A total of 11 adult patients with cryptogenic FIRES were identified from 270 patients with SE. Four (36%) patients died in the hospital, with three of them withdrawing treatments, and one patient died 12 months after discharge. After the follow-up ranging from12 to 112months, 6 (55%) patients were still alive, and all of them achieved functional independence [modified Rankin Scale (mRS) 0-3]. 45% (5/11) patients developed DRE, 18% (2/11) had remote recurrent SE, and 55% (6/11) were on polytherapy with ASMs at the last follow-up. Most of the patients with initial normal or abnormal MRI had abnormalities in the hippocampus at follow-up, and most of the other MRI abnormalities found in the acute stage disappeared over time. Conclusion: The outcome of adult cryptogenic FIRES is daunting. More than one-third of patients die in the hospital. Survivors of cryptogenic FIRES may regain functional independence, but they usually develop DRE and receive polytherapy of ASMs for a long time. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to develop consensus‐based recommendations for the management of adult and pediatric patients with new onset refractory status epilepticus (NORSE)/febrile infection‐related epilepsy syndrome (FIRES) based on best evidence and experience. Methods: The Delphi methodology was followed. A facilitator group of nine experts was established, who defined the scope, users, and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment, and research directions were generated, which were then rated on a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was ≥7 and inappropriate if the median score was ≤3. The analysis of evidence was mapped to the results of each statement included in the Delphi survey. Results: Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: (1) disease characteristics; (2) diagnostic testing and sampling; (3) acute treatment; (4) treatment in the postacute phase; and (5) research, registries, and future directions in NORSE/FIRES. The detailed results and discussion of all 85 statements are outlined herein. A corresponding summary of findings and practical flowsheets are presented in a companion article. Significance: This detailed analysis offers insight into the supporting evidence and the current gaps in the literature that are associated with expert consensus statements related to NORSE/FIRES. The recommendations generated by this consensus can be used as a guide for the diagnosis, evaluation, and management of patients with NORSE/FIRES, and for planning of future research. [ABSTRACT FROM AUTHOR]

Introduction: Epidemiological data on childhood status epilepticus (SE) limited in India. This study depicts clinical profiles, etiology, and outcomes of convulsive refractory SE (RSE) and compares the results with cases of nonrefractory SE (NRSE). Subjects and Methods: This observational, cross-sectional study enrolled 300 children aged 1 month to 18 years, presenting with convulsive SE at a tertiary care hospital. Details of children who progressed to RSE were compared to those without RSE. Results: In the acute symptomatic etiology group, common causes for RSE were central nervous system infections (33.8%), cryptogenic etiology (13.8%), and remote symptomatic etiology (7%). RSE iwas associated with a higher rate of complications (58% Vs 24%) as compared to NRSE. Thirty percent of cases that progressed to RSE needed ventilator support as compared to only 8% of cases in the NRSE group. RSE was also associated with higher rates of shock (25%), AKI (16%), transaminitis (25%), acute liver failure (5.69%), multiple organ dysfunction score (12.6%), and acidosis (53%) as compared to NRSE. RSE was associated with higher mortality (28%) and morbidity (32%) as compared to NRSE cases. Cryptogenic etiology led to the highest mortality (33.3%) in cases of RSE while acute symptomology was associated with the highest morbidity (62%). Conclusions: RSE is a serious pediatric emergency that requires prompt recognition and management. Clinical knowledge and early administration of appropriate antiepileptic drugs at health-care facilities is the key to reduce morbidity and mortality. [ABSTRACT FROM AUTHOR]

Introduction: Epidemiological data on childhood status epilepticus (SE) limited in India. This study depicts clinical profiles, etiology, and outcomes of convulsive refractory SE (RSE) and compares the results with cases of nonrefractory SE (NRSE). Subjects and Methods: This observational, cross-sectional study enrolled 300 children aged 1 month to 18 years, presenting with convulsive SE at a tertiary care hospital. Details of children who progressed to RSE were compared to those without RSE. Results: In the acute symptomatic etiology group, common causes for RSE were central nervous system infections (33.8%), cryptogenic etiology (13.8%), and remote symptomatic etiology (7%). RSE iwas associated with a higher rate of complications (58% Vs 24%) as compared to NRSE. Thirty percent of cases that progressed to RSE needed ventilator support as compared to only 8% of cases in the NRSE group. RSE was also associated with higher rates of shock (25%), AKI (16%), transaminitis (25%), acute liver failure (5.69%), multiple organ dysfunction score (12.6%), and acidosis (53%) as compared to NRSE. RSE was associated with higher mortality (28%) and morbidity (32%) as compared to NRSE cases. Cryptogenic etiology led to the highest mortality (33.3%) in cases of RSE while acute symptomology was associated with the highest morbidity (62%). Conclusions: RSE is a serious pediatric emergency that requires prompt recognition and management. Clinical knowledge and early administration of appropriate antiepileptic drugs at health-care facilities is the key to reduce morbidity and mortality.

Abstract Objective Cholinergic‐induced status epilepticus (SE) is associated with a loss of synaptic gamma‐aminobutyric acid A receptors (GABAAR) and an increase in N‐methyl‐D‐aspartate receptors (NMDAR) and amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABAAR to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate‐induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman‐induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist. Methods We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABAAR modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA‐dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI‐6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset. Results The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman‐induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic‐induced toxicity. Significance Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine‐refractory cholinergic‐induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.

Abstract Febrile infection–related epilepsy syndrome (FIRES) is a devastating immune inflammatory–mediated epileptic encephalopathy. Herein, we discuss a previously healthy 8‐year‐old boy with FIRES in whom high dosages of conventional and nonconventional anesthetics were ineffective in treating SE, as were ketogenic diet, intravenous corticosteroids, and immunoglobulins. After 29 days of prolonged SRSE, the patient was successfully treated with sevoflurane paired with plasma exchange, for a total of five days, thus obtaining a stable EEG suppression burst pattern with no adverse events. Anakinra at the dosage of 100 mg b.i.d. was started seven days after sevoflurane and plasma exchange had been discontinued and was effective in ensuring non‐recurrence of SE. Sevoflurane as bridge therapy for immunosuppressive treatment could be considered an early, safe, and effective option in treating convulsive SE in which an autoimmune‐inflammatory etiology can reasonably be hypothesized.

Objective: To discuss the results of the KETASER01 trial and the reasons for its failure, particularly in view of future studies. Methods: KETASER01 is a multicenter, randomized, controlled, open‐label, sequentially designed, non‐profit Italian study that aimed to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory convulsive status epilepticus (RCSE) in children. Results: During the 5‐year recruitment phase, a total of 76 RCSEs treated with third‐line therapy were observed in five of the 10 participating Centers; only 10 individuals (five for each study arm; five females, mean age 6.5 ± 6.3 years) were enrolled in the KETASER01 study. Two of the five patients (40%) in the experimental arm were successfully treated with ketamine and two of the five (40%) children in the control arm, where successfully treated with thiopental. In the remaining six (60%) enrolled patients, RCSE was not controlled by the randomized anesthetic(s). Significance: The KETASER01 study was prematurely halted due to low eligibility of patients and no successful recruitment. No conclusions can be drawn regarding the objectives of the study. Here, we discuss the KETASER01 results and critically analyze the reasons for its failure in view of future trials. [ABSTRACT FROM AUTHOR]

Refractory status epilepticus (RSE) requires multimodal treatment approaches to achieve rapid seizure cessation and neuroprotection. A ketogenic diet (KD) has demonstrated efficacy as a nutritional therapeutic option for adult RSE. However, the group of adult RSE patients who would benefit from adopting a KD needs to be determined to appropriately select the patients indicated for a KD. Therefore, we conducted a nonrandomized retrospective cohort study to explore the therapeutic efficacy of a KD by investigating the moderation effect of a KD on the association between the clinical characteristics of RSE patients and their functional outcomes. This study investigated 140 RSE patients, including 32 patients treated with a KD; among these patients, 28 (81%) achieved seizure cessation. We found that KD moderated the reduction in the modified Rankin scale (mRS) score at discharge among patients who were older, had higher seizure severity scores, were under continuous intravenous anesthetic therapy (CIVAD), and had super-RSE. Age and seizure severity scores, but not CIVAD or super-RSE, were associated with a KD-moderated change in mRS score at 3 months. Thus, we consider that our study provides evidence of a neuroprotective effect of KD in the most severe RSE patients with very few remaining therapeutic options, but future randomized controlled trials in these subgroups of KD patients are necessary. [ABSTRACT FROM AUTHOR]

Early maladaptive internalization of synaptic GABAA receptors (GABAAR) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE-induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABAAR and NMDAR trafficking can reduce the severity of SE and its long-term consequences.

During status epilepticus (SE), synaptic γ-aminobutyric acid A receptors (GABAA Rs) become internalized and inactive, whereas spare N-methyl-d-aspartate receptors (NMDARs) assemble, move to the membrane, and become synaptically active. When treatment of SE is delayed, the number of synaptic GABAA Rs is drastically reduced, and a GABAA agonist cannot fully restore inhibition. We used a combination of low-dose diazepam (to stimulate the remaining GABAA Rs), ketamine (to mitigate the effect of the NMDAR increase), and valproate (to enhance inhibition at a nonbenzodiazepine site) to treat seizures in a model of severe cholinergic SE. High doses of diazepam failed to stop electrographic SE, showing that benzodiazepine pharmacoresistance had developed. The diazepam-ketamine-valproate combination was far more effective in stopping SE than triple-dose monotherapy using the same individual drugs. Isobolograms showed that this drug combination's therapeutic actions were synergistic, with positive cooperativity between drugs, whereas drug toxicity was simply additive, without positive or negative cooperativity. As a result, the therapeutic index was improved by this drug combination compared to monotherapy. These results suggest that synergistic drug combinations that target receptor changes can control benzodiazepine-refractory SE.

Background: Status epileptics are classically defined as seizures that are continuous for 30 minutes or longer or repetitive seizures between which the patient does not regain consciousness. This study reports a case of a boy with a 2-hour seizure. Case Presentation: We present the case of a 7-year-old boy, who is known to have tuberous sclerosis (TSC2 gene mutation). On the day of presentation, the seizure had started with aura (epigastric pain with weakness in the face), then started to seize in a form left focal jerky movement with generalization associated with rolling up of the eyes, and lasted for 5 minutes; it was aborted clinically by lorazepam 0.1 mg/kg IV. However, the electroencephalography (EEG) showed subclinical seizure. The patient received a loading dose of phenytoin, 20 mg/kg IV, with no changes in the EEG; then Keppra (three doses) with a total of 40 mg/kg IV was given, but subclinical seizure still persisted. The patient was given one dose of Ketamine IV of 1 mg/kg, which resulted in complete cessation of the seizure activity within 3 minutes after injection, which was confirmed by prolonged EEG monitoring. The total duration of the seizure was 2 hours. Conclusion: Ketamine can be considered as a third-line drug in refractory status epilepticus. [SJEMed 2021; 2(1.000): 92-95]

Introduction: Status epilepticus (SE) is a life-threatening neurological emergency requiring immediate medical intervention and is associated with high mortality and morbidity. The aim of this research was evaluation of clinical and etiological profile of refractory status epilepticus (RSE) among children aged between 1 month and 18 years. Material and methods: The study was done between January 1, 2017 and December 24, 2019. All children with the age limits mentioned above, who presented convulsive SE, subsequently with development in refractory status epileptic (RSE), were included in the study. Patients were investigated and evaluated according to a standard protocol. Subsequently, the characteristics of children with RSE and those without an evolution in RSE were compared. Results: 55 children, out of whom 32 boys with SE were enrolled in the study, of which 20 children (36%) developed RSE. Central nervous system (CNS) infections were the most common causes of SE and development of RSE (51% in SE and 53% in RSE, p > 0.05). Noncompliance of antiepileptic medication served as the second cause for evolution of RSE. The overall mortality rate was 10.9%, the chances of death in RSE (20%) being higher than in SE (5.7%). The unfavorable prognosis was seven times higher in children with RSE, compared to children who developed SE. Conclusions: In the management of CNS infections, pediatricians should be aware of the high risk of developing RSE. In addition, the possibility of developing RSE should be considered and promptly managed in an intensive care unit in order to reduce the risk of mortality and morbidity of this severe neurological condition.

Ketamine is one of the old anaesthetic agents which has regained popularity in analgesia, trauma, emergency medicine, neurology and psychiatry. Recently several cases were reported on ketamine induced seizures in otherwise healthy children despite its popularity in the treatment of refractory status epilepticus. We present an eight-year-old prematurely born healthy boy who developed two episodes of generalized tonic clonic seizures following administration of ketamine for a short ophthalmic procedure. This case and our comprehensive narrative review of literature on pro- and anti-epileptic effects of ketamine show that the debate continues and gaps on mechanism of action, etiology and risk factors for ketamine's epileptic activity remains. Due to the recent increase in its use further evaluation on ketamine's epileptic effects is warranted to ensure safe and effective use of ketamine. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nonconvulsive status epilepticus (NCSE) is a diagnosis that is often challenging and one that may progress to refractory NCSE. Ketamine is a noncompetitive N-methyl-d-aspartate antagonist that increasingly has been used to treat refractory status epilepticus. Current Neurocritical Care Society guidelines recommend intravenous (IV) ketamine infusion as an alternative treatment for refractory status epilepticus in adults. On the other hand, enteral ketamine use in NCSE has been reported in only 6 cases (1 adult and 5 pediatric) in the literature to date. CASE PRESENTATION: A 33-year-old woman with a history of poorly controlled epilepsy presented with generalized tonic-clonic seizures, followed by recurrent focal seizures that evolved into NCSE. This immediately recurred within 24 h of a prior episode of NCSE that was treated with IV ketamine. Considering her previous response, she was started again on an IV ketamine infusion, which successfully terminated NCSE. This time, enteral ketamine was gradually introduced while weaning off the IV formulation. Treatment with enteral ketamine was continued for 6 months and then tapered off. There was no recurrence of NCSE or seizures and no adverse events noted during the course of treatment. CONCLUSION: This case supports the use of enteral ketamine as a potential adjunct to IV ketamine in the treatment of NCSE, especially in cases without coma. Introduction of enteral ketamine may reduce seizure recurrence, duration of stay in ICU, and morbidity associated with intubation.

ObjectivePharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic γ-aminobutyric acid A (GABAA ) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences.MethodsA severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits.ResultsMidazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits.SignificanceThis study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.

Cholinergic status epilepticus (CSE) quickly becomes self-sustaining, independent of its initial trigger, and resistant to benzodiazepines and other antiepileptic drugs. We review a few of the many physiological changes associated with CSE, with an emphasis on receptor trafficking. Time-dependent internalization of synaptic γ-aminobutyric acid (GABA)A receptors explains, in part, the loss of inhibition and the loss of response to benzodiazepines in the early stages of CSE. The increase in N-methyl-d-aspartate receptors may contribute to the runaway excitation and excitotoxicity of CSE. These changes have therapeutic implications. The time-dependent increase in maladaptive changes points to the importance of early treatment. The involvement of both inhibitory and excitatory systems challenges current therapeutic guidelines, which recommend treating only one system, and questions the rationale for monotherapy. It suggests that polytherapy may be needed, especially when treatment is delayed, so that drugs can only reach a much reduced number of GABAA receptors. Finally, it raises the possibility that the current practice of waiting for one treatment to fail before starting the next drug may need to be reevaluated.

Introduction: Scoring systems to predict outcomes in pediatric status epilepticus (SE) are limited. We sought to assess usefulness of the END-IT score in pediatric SE. Methodology: We conducted a retrospective study at a tertiary hospital in New Delhi, India. Children aged 1 month–18 years who presented with seizure for ≥5 min/actively convulsing to emergency were enrolled. END-IT score was calculated and correlated with outcome at discharge using Pediatric Overall Performance Category (POPC) scale, in-hospital mortality, and progression to refractory and super-refractory SE (SRSE). Results: We enrolled 140 children (mean age 5.8 years; 67.1% males). Seven children died and 15 had unfavorable outcomes. The predictive accuracy of END-IT at a cutoff of > 2: for unfavorable outcome (POPC score ≥3) was: sensitivity 0.73 (95% CI: 0.45–0.92), specificity 0.94 (95% CI: 0.89–0.98), PPV 0.61 (95% CI: 0.36–0.83), NPV 0.97 (95% CI: 0.92–0.99), positive likelihood ratio (13.09), F1 score (0.666); for death: sensitivity 0.86 (95% CI: 0.42–0.99), specificity 0.91 (95% CI: 0.85–0.95), PPV 0.33 (95% CI: 0.13–0.59), NPV 0.99 (95% CI: 0.96–1.00), F1 score (0.48); for RSE: sensitivity 0.80 (95%CI: 0.28–0.99), specificity 0.90 (95% CI: 0.83–0.94), PPV 0.22 (95% CI: 0.06–0.48) NPV 0.99 (95% CI: 0.96–1.00), F1 score (0.35); for SRSE: sensitivity 0.67 (95% CI: 0.22–0.96) specificity 0.75 (95% CI: 0.66–0.82), PPV 0.22 (95% CI: 0.06–0.48) NPV 0.98 (95% CI: 0.94–0.99), F1 score (0.33). Conclusion: We demonstrate utility of the END-IT score to predict short-term outcomes as well as progression to refractory and SRSE for the first time among children with SE.

Objectives: In refractory status epilepticus (RSE), the optimal degree of suppression (EEG burst suppression or merely suppressing seizures) remains unknown. Many centers lacking continuous EEG must default to serial intermittent recordings where uncertainty from lack of data may prompt more aggressive suppression. In this study, we sought to determine whether the quantitative burst suppression ratio (QBSR) from serial intermittent EEG recording is associated with RSE patient outcome. Methods: We screened the EEG database to identify non-anoxic adult RSE patients for EEG and chart review. QBSR was calculated per 10-second EEG epoch as the percentage of time during which EEG amplitude was

Status epilepticus (SE) is a serious complication of epilepsy that warrants both rapid and appropriate emergency management for better outcomes in terms of mortality and morbidity. The initial management of SE in emergency department (ED) involves a rapid neurological assessment and initiation of supportive therapy. Benzodiazepines are the recommended first-line treatment based on high-quality evidence, among them intramuscular (IM) midazolam IM was found to be as effective as intravenous lorazepam. However, it is important to understand that speedy drug delivery and adequate initial dose are of prime importance than selection of drug. Recent evidence shows all three second-line drugs, namely, valproate, fosphenytoin, and levetiracetam are alike in cessation of SE with similar incidence of adverse events. In refractory SE, the therapeutic options include the use of bolus dose followed by infusion of propofol, midazolam, ketamine, lacosamide, and phenobarbital. Magnesium sulfate is safe and superior in the management of eclamptic SE prompt and appropriate management in ED is the key to early cessation of SE, leading to better outcomes.

Abstract Objective Refractory status epilepticus is a serious condition in which seizure continues despite use of two antiepileptic medications. Retrospective studies have shown that 29%‐43% of SE patients progress into RSE despite treatment. Mortality following RSE is high. We aimed to evaluate the predictors of outcome in patients with RSE at a tertiary care center. Methods Sixty‐eight consecutive patients with RSE who presented to our hospital between February 2018 and January 2020 were evaluated for outcome. Result In our study 28(41.2%), patients who failed to respond to first‐ and second‐line antiepileptic drug responded to the third‐line antiepileptic drug thus avoiding mechanical ventilation and intravenous anesthesia. Low GCS at admission (P

Objective: Alpers Huttenlocher disease although is a rare mitochondrial disease, but is still present in different nervous systems and other system's features. Seizures and neurodegeneration are one of the early pictures encountered. Case: A case of 11-month-old girl with acute onset of epileptic seizures has been reported along with her brother who died two years before this event following the same disease and symptoms. Her lab work values were normal for which she was planned for MRI. However, because of her general condition, only CT scan of brain was done which showed normal study. Results: The electroencephalographic findings show a pattern of continuous, anterior, high-voltage, l-to-3-Hz spike-and-wave like activity that persists despite intermittent focal seizures. Death is not unusual in the setting of persistent seizures, and valproic acid should be avoided unless polymerase gamma γ level in genetic testing produces normal level. Whole exome sequencing identified the homozygous missense mutation c.3286C>T in POLG gene which corresponds to the p.R1096C amino acid change. Conclusion: Alpers Huttenlocher disease should be considered in different diagnosis of refractory status epilepticus in infants even in absence of liver disease signs. [ABSTRACT FROM AUTHOR]

Objective: Cholinergic‐induced status epilepticus (SE) is associated with a loss of synaptic gamma‐aminobutyric acid A receptors (GABAAR) and an increase in N‐methyl‐D‐aspartate receptors (NMDAR) and amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABAAR to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate‐induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman‐induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist. Methods: We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABAAR modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA‐dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI‐6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset. Results: The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman‐induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic‐induced toxicity. Significance: Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine‐refractory cholinergic‐induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy. [ABSTRACT FROM AUTHOR]

Febrile infection–related epilepsy syndrome (FIRES) is a devastating immune inflammatory–mediated epileptic encephalopathy. Herein, we discuss a previously healthy 8‐year‐old boy with FIRES in whom high dosages of conventional and nonconventional anesthetics were ineffective in treating SE, as were ketogenic diet, intravenous corticosteroids, and immunoglobulins. After 29 days of prolonged SRSE, the patient was successfully treated with sevoflurane paired with plasma exchange, for a total of five days, thus obtaining a stable EEG suppression burst pattern with no adverse events. Anakinra at the dosage of 100 mg b.i.d. was started seven days after sevoflurane and plasma exchange had been discontinued and was effective in ensuring non‐recurrence of SE. Sevoflurane as bridge therapy for immunosuppressive treatment could be considered an early, safe, and effective option in treating convulsive SE in which an autoimmune‐inflammatory etiology can reasonably be hypothesized. [ABSTRACT FROM AUTHOR]

Early use of the ketogenic diet (KD) is described as having a particular interest for super‐refractory status epilepticus and febrile infection-related epilepsy syndrome. The authors conducted a systematic review of the available data on the KD for refractory and super-refractory status epilepticus. Following a systematic bibliographic search, the authors found 15 published papers: 2 prospective and 13 retrospective studies. Most often, the primary aim of the retrospective studies was the efficacy evaluation of the KD for refractory or super-refractory status epilepticus. Four studies focused on the use of KD for NORSE/FIRES. These initial studies suggested that KD was effective in these conditions, and that it showed mild and manageable side effects. The published studies provided enough preliminary data to validate the feasibility and safety of the use of KD for refractory and super-refractory status epilepticus. Further studies demonstrating the efficacy of the KD in these indications are needed. Possible design and endpoints are discussed. [ABSTRACT FROM AUTHOR]

Purpose: Processed electroencephalogram (EEG) is used peri-operatively for monitoring depth of anaesthesia. Because these utilise EEG data, attempts have been made to investigate their use in diagnosing and monitoring seizures. This is important as formal EEG monitoring can be hard to obtain in many critical care environments. We undertook a scoping review of the evidence for using processed EEG (pEEG) from depth of anaesthesia monitors for this indication.Methods: Medline, Psych INFO, and Embase were searched for peer-reviewed journals until 20 March 2021. Data and conclusions taken from the study of pEEG in both critical care and peri-operative settings have been included in a qualitative synthesis about the current evidence for the use of pEEG in the detection and monitoring of seizures.Results: Searches yielded 8 observational studies, 1 randomised trial and 15 case reports in which the use of pEEG in critical care and peri-operative medicine was described. Most concerned the Bispectral Index (BIS) device. The majority of observational studies reported the use of BIS for optimisation of burst suppression in patients with refractory status-epilepticus (RSE), or in the comparison of pEEG data with conventional EEG during epileptic activity. Multiple case reports describe the application of pEEG in the presence of disorders of consciousness as a tool for detection of non-convulsive status-epilepticus, finding variable trends in the pEEG output.Conclusions: Processed EEG may be helpful in monitoring pharmacologically induced burst suppression. Despite this, its use in the diagnosing or monitoring seizure activity is controversial and currently not evidenced, with numerous confounding variables that requires systematic assessment in future studies. [ABSTRACT FROM AUTHOR]

New-onset refractory status epilepticus (NORSE) describes prolonged or recurring new onset seizures which fail to respond to antiseizure medications. NORSE poses a challenge in diagnosis and treatment, and limited high-quality evidence exists to guide management. The efficacy of Electroconvulsive therapy (ECT) in aborting refractory status epilepticus has been described in case reports, but its application remains uncommon, particularly in young children. We describe a case of NORSE in a 3-year old child in which ECT played an important role in aborting status epilepticus, facilitating the diagnosis and surgical excision of an underlying focal cortical dysplasia. Although further research is needed, our case suggests that ECT can be a valuable tool in the treatment of refractory status epilepticus in children. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) is a life-threatening neurologic condition that requires immediate assessment and intervention. Over the past few decades, the duration of seizure required to define status epilepticus has shortened, reflecting the need to start therapy without the slightest delay. The focus of this review is on the management of convulsive and nonconvulsive status epilepticus in critically ill patients. Initial treatment of both forms of status epilepticus includes immediate assessment and stabilization, and administration of rapidly acting benzodiazepine therapy followed by nonbenzodiazepine antiepileptic drug. Refractory and super-refractory status epilepticus (RSE and SRSE) pose a lot of therapeutic problems, necessitating the administration of continuous infusion of high doses of anesthetic agents, and carry a high risk of debilitating morbidity as well as mortality.

Abstract Objective Our objective was to evaluate the protective efficacy of the neurosteroid pregnanolone (3α‐hydroxy‐5β pregnan‐20‐one), a GABAA receptor‐positive allosteric modulator, as an adjunct to benzodiazepine therapy against the chemical warfare nerve agent (CWNA) sarin (GB), using whole‐body exposure, an operationally relevant route of exposure to volatile GB. Methods Rats implanted with telemetry transmitters for the continuous measurement of cortical electroencephalographic (EEG) activity were exposed for 60 minutes to 3.0 LCt50 of GB via whole‐body exposure. At the onset of toxic signs, rats were administered an intramuscular injection of atropine sulfate (2 mg/kg) and the oxime HI‐6 (93.6 mg/kg) to increase survival rate and, 30 minutes after seizure onset, treated subcutaneously with diazepam (10 mg/kg) and intravenously with pregnanolone (4 mg/kg) or vehicle. Animals were evaluated for GB‐induced status epilepticus (SE), spontaneous recurrent seizures (SRS), impairment in spatial memory acquisition, and brain pathology, and treatment groups were compared. Results Delayed dual therapy with pregnanolone and diazepam reduced time in SE in GB‐exposed rats compared to those treated with delayed diazepam monotherapy. The combination therapy of pregnanolone with diazepam also prevented impairment in the Morris water maze and reduced the neuronal loss and neuronal degeneration, evaluated at one and three months after exposure. Significance Neurosteroid administration as an adjunct to benzodiazepine therapy offers an effective means to treat benzodiazepine‐refractory SE, such as occurs following delayed treatment of GB exposure. This study is the first to present data on the efficacy of delayed pregnanolone and diazepam dual therapy in reducing seizure activity, performance deficits and brain pathology following an operationally relevant route of exposure to GB and supports the use of a neurosteroid as an adjunct to standard anticonvulsant therapy for the treatment of CWNA‐induced SE.

Abstract Background Several studies have compared the efficacy and safety of propofol and barbiturates in the treatment of refractory status epilepticus (RSE). This study aims to quantitatively assess the advantages and disadvantages of propofol and barbiturates in controlling RSE. Methods We searched for studies with relevant data from the PubMed, Embase, Ovid, Cochrane Library, Springer Link, Web of Science, and China National Knowledge Infrastructure databases. By calculating odds ratios and standardized mean differences with 95% confidence intervals, we assessed the disease control rate (DCR), case fatality rate (CFR), average control time (ACT), average tracheal intubation placement time (ATIPT), and incidence of hypotension between propofol and barbiturates in treating RSE. Results Seven studies with 261 patients were included in this analysis. Meta-analysis revealed that the DCR of propofol was higher than that of barbiturates (p

Objective: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE). Methods: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks–24 h), and without fever. Results: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function. Significance: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection‐related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes. [ABSTRACT FROM AUTHOR]