First-in-man allopregnanolone use in super-refractory status epilepticus.
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SUBMITTER: Vaitkevicius H
PROVIDER: S-EPMC5454395 | biostudies-other | 2017 Jun
REPOSITORIES: biostudies-other
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First-in-man allopregnanolone use in super-refractory status epilepticus.
Vaitkevicius Henrikas H Husain Aatif M AM Rosenthal Eric S ES Rosand Jonathan J Bobb Wendell W Reddy Kiran K Rogawski Michael A MA Cole Andrew J AJ
Annals of clinical and translational neurology 20170426 6
Super-refractory status epilepticus (SRSE) is associated with high morbidity and mortality. Treatment of SRSE is complicated by progressive cortical hyperexcitability believed to result in part from synaptic GABA receptor internalization and desensitization. Allopregnanolone, a neurosteroid that positively modulates synaptic and extrasynaptic GABA<sub>A</sub> receptors, has been proposed as a novel treatment. We describe the first two patients with SRSE who were each successfully treated with a ...[more]
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Project description:Earlier definitions of status epilepticus (SE) were based on the duration of seizures, but newer definitions rely more on a pragmatic staging based on treatment failures (Table 23.1). Refractory status epilepticus (RSE) is defined as SE that continues despite administration of both benzodiazepines and an appropriately dosed second-line antiseizure drug. Depending on the semiology of the seizures and comorbidities of the patient, this stage may be treated with further antiseizure drugs or anesthesia. When seizures recur upon weaning the anesthetic agent, typically after 24 h of seizure suppression, or in the rare cases where seizure control cannot be achieved with anesthesia, status epilepticus is considered to be super refractory (SRSE). The incidence of status epilepticus has been increasing, from 3.5 to 12.5/100,000 population between 1979 and 2010. During this time hospital mortality has not changed [1].
| S-EPMC7123027 | biostudies-literature
Project description:IntroductionSuper-refractory status epilepticus (SRSE) represents the culmination of refractory status epilepticus (RSE) and carries a significant risk of poor neurological outcome and high mortality. RSE is not defined primarily by seizure duration, but by failure to respond to appropriate antiseizure treatment. SRSE is present when a RSE persists or recurs after more than 24 h of treatment with anesthetics. No evidence-based treatment algorithms can be provided for SRSE. Therefore, we propose a pragmatic standard operating procedure (SOP) for the management of SRSE that addresses the existing uncertainties in the treatment of SRSE and provides options for resolution and decision-making.CommentsFirst, we recommend the assessment of persistent seizure activity and the evaluation of differential diagnoses to confirm correct diagnosis. Relevant differential diagnoses include psychogenic non-epileptic seizures, hypoxic, metabolic, or toxic encephalopathies, and tetanus. During SE or in severe encephalopathies, a so-called electroclinical ictal-interictal continuum may occur, which denotes an intermediate stage that cannot be defined with certainty as ictal or interictal by EEG and should not lead to harmful overtreatment. Because both prognosis and specific treatment options depend crucially on the etiology of SRSE, the etiological evaluation should be performed rapidly. When SRSE is confirmed, various pharmacological and non-pharmacological treatment options are available.ConclusionWe provide a pragmatical SOP for adult people with SRSE.
| S-EPMC9394073 | biostudies-literature
Project description:Refractory and super-refractory status epilepticus (SE) are serious illnesses with a high risk of morbidity and even fatality. In the setting of refractory generalized convulsive SE (GCSE), there is ample justification to use continuous infusions of highly sedating medications-usually midazolam, pentobarbital, or propofol. Each of these medications has advantages and disadvantages, and the particulars of their use remain controversial. Continuous EEG monitoring is crucial in guiding the management of these critically ill patients: in diagnosis, in detecting relapse, and in adjusting medications. Forms of SE other than GCSE (and its continuation in a "subtle" or nonconvulsive form) should usually be treated far less aggressively, often with nonsedating anti-seizure drugs (ASDs). Management of "non-classic" NCSE in ICUs is very complicated and controversial, and some cases may require aggressive treatment. One of the largest problems in refractory SE (RSE) treatment is withdrawing coma-inducing drugs, as the prolonged ICU courses they prompt often lead to additional complications. In drug withdrawal after control of convulsive SE, nonsedating ASDs can assist; medical management is crucial; and some brief seizures may have to be tolerated. For the most refractory of cases, immunotherapy, ketamine, ketogenic diet, and focal surgery are among several newer or less standard treatments that can be considered. The morbidity and mortality of RSE is substantial, but many patients survive and even return to normal function, so RSE should be treated promptly and as aggressively as the individual patient and type of SE indicate.
| S-EPMC6095773 | biostudies-literature
Project description:ObjectiveTo test ketamine infusion efficacy in the treatment of super-refractory status epilepticus (SRSE), we studied patients with SRSE who were treated with ketamine retrospectively. We also studied the effect of high doses of ketamine on brain physiology as reflected by invasive multimodality monitoring (MMM).MethodsWe studied a consecutive series of 68 patients with SRSE who were admitted between 2009 and 2018, treated with ketamine, and monitored with scalp EEG. Eleven of these patients underwent MMM at the time of ketamine administration. We compared patients who had seizure cessation after ketamine initiation to those who did not.ResultsMean age was 53 ± 18 years and 46% of patients were female. Seizure burden decreased by at least 50% within 24 hours of starting ketamine in 55 (81%) patients, with complete cessation in 43 (63%). Average dose of ketamine infusion was 2.2 ± 1.8 mg/kg/h, with median duration of 2 (1-4) days. Average dose of midazolam was 1.0 ± 0.8 mg/kg/h at the time of ketamine initiation and was started at a median of 0.4 (0.1-1.0) days before ketamine. Using a generalized linear mixed effect model, ketamine was associated with stable mean arterial pressure (odds ratio 1.39, 95% confidence interval 1.38-1.40) and with decreased vasopressor requirements over time. We found no effect on intracranial pressure, cerebral blood flow, or cerebral perfusion pressure.ConclusionKetamine treatment was associated with a decrease in seizure burden in patients with SRSE. Our data support the notion that high-dose ketamine infusions are associated with decreased vasopressor requirements without increased intracranial pressure.Classification of evidenceThis study provides Class IV evidence that ketamine decreases seizures in patients with SRSE.
| S-EPMC7713785 | biostudies-literature
Project description:Super-refractory status epilepticus is a life-threatening condition. Resistance to benzodiazepine and barbiturate treatment for this disorder is thought to be due to internalization of synaptic ?-aminobutyric acid (GABA)A receptors, and withdrawal of benzodiazepines and barbiturates during treatment often triggers seizure recurrence. The neurosteroid allopregnanolone acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. Here we describe the use of allopregnanolone in 2 pediatric patients with super-refractory status epilepticus. This treatment allowed the general anesthetic infusions to be weaned with resolution of status epilepticus. This is the first report of allopregnanolone use to treat status epilepticus in children.
| S-EPMC4534165 | biostudies-other
Project description:Super-refractory status epilepticus (SRSE) is a life-threatening form of status epilepticus that continues or recurs despite 24 hours or more of anesthetic treatment. We conducted a multicenter, phase 1/2 study in SRSE patients to evaluate the safety and tolerability of brexanolone (USAN; formerly SAGE-547 Injection), a proprietary, aqueous formulation of the neuroactive steroid, allopregnanolone. Secondary objectives included pharmacokinetic assessment and open-label evaluation of brexanolone response during and after anesthetic third-line agent (TLA) weaning.Patients receiving TLAs for SRSE control were eligible for open-label, 1-hour brexanolone loading infusions, followed by maintenance infusion. After 48 hours of brexanolone infusion, TLAs were weaned during brexanolone maintenance. After 4 days, the brexanolone dose was tapered. Safety and functional status were assessed over 3 weeks of follow-up.Twenty-five patients received open-label study drug. No serious adverse events (SAEs) were attributable to study drug, as determined by the Safety Review Committee. Sixteen patients (64%) experienced ?1 SAE. Six patient deaths occurred, all deemed related to underlying medical conditions. Twenty-two patients underwent ?1 TLA wean attempt. Seventeen (77%) met the response endpoint of weaning successfully off TLAs before tapering brexanolone. Sixteen (73%) were successfully weaned off TLAs within 5 days of initiating brexanolone infusion without anesthetic agent reinstatement in the following 24 hours.In an open-label cohort of limited size, brexanolone demonstrated tolerability among SRSE patients of heterogeneous etiologies and was associated with a high rate of successful TLA weaning. The results suggest the possible development of brexanolone as an adjunctive therapy for SRSE requiring pharmacological coma for seizure control. Ann Neurol 2017;82:342-352.
| S-EPMC5639357 | biostudies-literature
Project description:BackgroundWe aimed to determine the association between seizure termination and side effects of isoflurane for the treatment of refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) in neurointensive care units (neuro-ICUs).MethodsThis was a multicenter retrospective study of patients with RSE/SRSE treated with isoflurane for status epilepticus termination admitted to the neuro-ICUs of nine German university centers during 2011-2018.ResultsWe identified 45 patients who received isoflurane for the treatment of RSE/SRSE. During isoflurane treatment, electroencephalograms showed no epileptiform discharges in 33 of 41 (80%) patients, and burst suppression pattern was achieved in 29 of 41 patients (71%). RSE/SRSE was finally terminated after treatment with isoflurane in 23 of 45 patients (51%) for the entire group and in 13 of 45 patients (29%) without additional therapy. Lengths of stay in the hospital and in the neuro-ICU were significantly extended in cases of ongoing status epilepticus under isoflurane treatment (p = 0.01 for length of stay in the hospital, p = 0.049 for length in the neuro-ICU). During isoflurane treatment, side effects were reported in 40 of 45 patients (89%) and mainly included hypotension (n = 40, 89%) and/or infection (n = 20, 44%). Whether side effects occurred did not affect the outcome at discharge. Of 22 patients with follow-up magnetic resonance imaging, 2 patients (9%) showed progressive magnetic resonance imaging alterations that were considered to be potentially associated with RSE/SRSE itself or with isoflurane therapy.ConclusionsIsoflurane was associated with a good effect in stopping RSE/SRSE. Nevertheless, establishing remission remained difficult. Side effects were common but without effect on the outcome at discharge.
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Project description:Objective: Status epilepticus (SE) is one of the most critical symptoms of encephalitis. Studies on early predictions of progression to super-refractory status epilepticus (SRSE) and poor outcome in SE due to acute encephalitis are scarce. We aimed to investigate the values of neuroimaging and continuous electroencephalogram (EEG) in the multimodal prediction. Methods: Consecutive patients with convulsive SE due to acute encephalitis were included in this study. Demographics, clinical features, neuro-imaging characteristics, medical interventions, and anti-epileptic treatment responses were collected. All the patients had EEG monitoring for at least 24 h. We determined the early predictors of SRSE and prognostic factors of 3-month outcome using multivariate logistic regression analyses. Results: From March 2008 to February 2018, 570 patients with acute encephalitis were admitted to neurological intensive care unit (N-ICU) of Xijing hospital. Among them, a total of 94 patients with SE were included in this study. The percentage of non-SRSE and SRSE were 76.6 and 23.4%. Cortical or hippocampal abnormality on neuroimaging (p = 0.002, OR 20.55, 95% CI 3.16-133.46) and END-IT score (p < 0.001, OR 4.07, 95% CI 1.91-8.67) were independent predictors of the progression to SRSE. At 3 months after N-ICU discharge, 56 (59.6%) patients attained good outcomes, and 38 (40.4%) patients had poor outcomes. The recurrence of clinical or EEG seizures within 2 h after the infusion rate of a single anesthetic drug >50% proposed maximal dose (p = 0.044, OR 4.52, 95% CI 1.04-19.68), tracheal intubation (p = 0.011, OR 4.99, 95% CI 1.37-11.69) and emergency resuscitation (p = 0.040, OR 9.80, 95% 1.11-86.47) predicted poor functional outcome. Interpretation: Initial neuro-imaging findings assist early identification of the progression to SRSE. Continuous EEG monitoring contributes to outcome prediction in SE due to acute encephalitis.
| S-EPMC6186801 | biostudies-literature
Project description:Super-refractory status epilepticus (SRSE) is a critical condition in which seizures persist despite anesthetic use for 24 h or longer. High mortality has been reported in patients with SRSE, but the cause of death remains unclear. We investigated the factors associated with mortality, including clinical characteristics, SE etiologies and severities, treatments, and responses in patients with SRSE in a 13-year tertiary hospital-based retrospective cohort study comparing these parameters between deceased and surviving patients. SRSE accounted for 14.2% of patients with status epilepticus, and 28.6% of SRSE patients died. Deceased patients were mostly young or middle-aged without known systemic diseases or epilepsy. All deceased patients experienced generalized convulsive status epilepticus and failure of anesthetic tapering-off, significantly higher than survivors. An increased number of second-line anesthetics besides midazolam was observed in the deceased (median, 3, interquartile range 2-3) compared to surviving (1, 1-1; p = 0.0006) patients with prolonged use durations (p = 0.047). For mortality, the cut-off number of second-line anesthetics was 1.5 (AUC = 0.906, p = 0.004). Deceased patients had significantly higher renal and cardiac complications and metabolic acidosis than survivors. In SRSE management, multi-anesthetic use should be carefully controlled to avoid systemic complications and mortality.
| S-EPMC9188563 | biostudies-literature
Project description:Super-refractory status epilepticus (SRSE) represents a neurological emergency that is characterized by a lack of response to the third line of antiepileptic treatment, including intravenous general anesthetics. It is a medical challenge with high morbidity and mortality. Electroconvulsive therapy (ECT) has been recommended as a nonpharmacologic option of treatment after other alternatives are unsuccessful. Its effect on the cessation of SRSE has been minimally investigated. The objective of this article is to analyze the effect of ECT on SRSE. For this purpose, a multidisciplinary team created a protocol based on clinical guidelines similar to those described previously by Ray et al. (2017). ECT was applied to six patients with SRSE after the failure of antiepileptic treatment and pharmacologic coma.The objective of each ECT session was to elicit a motor seizure for at least 20 s. SRSE was resolved in all patients after several days of treatment, including ECT as a therapy, without relevant adverse effects. Thus, ECT is an effective and feasible option in the treatment of SRSE, and its place in the algorithm in treatment should be studied due to the uncommon adverse effects and the noninvasive character of the therapy.
| S-EPMC7312395 | biostudies-literature