Pediatric super-refractory status epilepticus treated with allopregnanolone.
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ABSTRACT:
SUBMITTER: Broomall E
PROVIDER: S-EPMC4534165 | biostudies-other | 2014 Dec
REPOSITORIES: biostudies-other
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Pediatric super-refractory status epilepticus treated with allopregnanolone.
Broomall Eileen E Natale JoAnne E JE Grimason Michele M Goldstein Joshua J Smith Craig M CM Chang Celia C Kanes Stephen S Rogawski Michael A MA Wainwright Mark S MS
Annals of neurology 20141111 6
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 γ-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 allopregnanolon ...[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].
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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.
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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.
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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.
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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:BackgroundTo compare the clinical characteristics and outcomes of pediatric patients with refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) who received therapeutic hypothermia (TH) plus anticonvulsants or anticonvulsants alone.MethodsTwo-medical referral centers, retrospective cohort study. Pediatric Intensive Care Unit (PICU) at Taoyuan Chang Gung Children's hospital and Kaohsiung Chang Gung Memorial Hospital. We reviewed the medical records of 23 patients with RSE/SRSE who were admitted to PICU from January 2014 to December 2017. Of these, 11 patients received TH (TH group) and 12 patients did not (control group).ResultsThe selective endpoints were RSE/SRSE duration, length of PICU stay, and Glasgow Outcome Scale (GOS) score. We applied TH using the Artic Sun® temperature management system (target temperature, 34-35 °C; duration, 48-72 h). Of the 11 patients who received TH, 7 had febrile infection-related epilepsy syndrome (FIRSE), one had Dravet syndrome, and three had traumatic brain injury. The TH group had significantly shortern seizure durations than did the control group (hrs; median (IQR) 24(40) vs. 96(90), p < 0.05). Two patients in the TH group died of pulmonary embolism and extreme brain edema. The length of PICU stay was similar between the groups (days; median (IQR) 30(42) v.s 30.5(30.25)). The TH group had significantly better long-term outcomes than did the control group (GOS score, median (IQR) 4(2) v.s 3 (0.75), p = 0.01∗). The TH group had a significantly lower incidence of later chronic refractory epilepsy than did the control group (TH v.s non-TH, 5/11 (45%) v.s. 12/12(100%), p < 0.01).ConclusionsTH effectively reduced the seizure burden in patients with RSE/SRSE. Our findings support that for patients with RSE/SRSE, TH shortens the seizure duration, ultimately reducing the occurrence of post-status epilepticus epilepsy and improving patients' long-term survival.
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Project description: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 GABAA receptors, has been proposed as a novel treatment. We describe the first two patients with SRSE who were each successfully treated with a 120-h continuous infusion of allopregnanolone. Both patients recovered from prolonged SRSE with good cognitive outcomes.
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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.
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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