Treatment Of Super-refractory Status Epilepticus Research Articles

Successful Use of Inhalational Anesthesia and Electroconvulsive Therapy in a Child with New Onset Prolonged Super-Refractory Status Epilepticus

AbstractThe treatment of super-refractory status epilepticus (SRSE) and prolonged SRSE rests on urgent seizure control to minimize excitotoxic cerebral damage, other forms of neurologic damage, and multiple medical complications. To date no randomized controlled trials or clear-cut guidelines are available for the management of SRSE. We reported the case of a 10-year-old previously healthy male child patient who presented with a febrile illness and new onset prolonged SRSE that became refractory to multiple antiseizure medications (ASMs). Coma induction with anesthetic agents, 14 ASMs, ketogenic diet, immunotherapy failed to completely control the SRSE in our patient. On day 22, clinical and electroencephalographic seizure control was achieved with isoflurane inhalation anesthesia, which was continued for 3 weeks but was unable to be weaned. From day 57 onwards, electroconvulsive therapy was administered (total 14 sessions that resulted in complete control of seizures). He was discharged on the 80th day.

Pentobarbital coma therapy for super-refractory status epilepticus and in-hospital mortality: an observational study.

Treatment of super-refractory status epilepticus (SRSE) is associated with various complications of anaesthetic coma therapy. This study aimed to describe the factors affecting the prognosis, especially in-hospital mortality, of patients receiving pentobarbital coma therapy for the treatment of SRSE. This was a retrospective cohort study conducted in a single tertiary referral centre with patients who received pentobarbital coma therapy for the treatment of SRSE from 2006 to 2018. Exploratory analyses were performed for clinical, laboratory, electrographic, and radiological factors for the entire cohort and were compared between the mortality and survivor groups. In total, 19 patients were enrolled, and five (26.3%) patients died in the hospital. The maximal pentobarbital infusion dose was higher in the mortality group than in the survivor group (4.4±1.0mg/kg/h vs. 2.9±1.4mg/kg/h, respectively; p=0.025). The high-dose pentobarbital infusion group (>3.75mg/kg/h) underwent longer mechanical ventilation (24 [20-36.75] vs. 41 [28-70], p=0.025) and blood culture results were more frequently positive, suggestive of septicaemia (8.3% vs. 57.1%, p=0.038). The group of SRSE patients treated with pentobarbital coma therapy who died in the hospital received a higher pentobarbital infusion dose compared to survivors; a complication of high-dose pentobarbital infusion was septicaemia. Considering the high rate of septicaemia observed, systematic treatment strategies focusing on infectious complications should be established and implemented. The association between maximal pentobarbital infusion dose and in-hospital mortality needs to be further validated.

Ketogenic Diet in the Treatment of Super-Refractory Status Epilepticus at a Pediatric Intensive Care Unit: A Single-Center Experience.

Background: To evaluate the use of the ketogenic diet (KD) for treatment of super-refractory status epilepticus (SRSE) at a pediatric intensive care unit (PICU).Design: A retrospective analysis of all pediatric patients treated for SRSE with the KD at our center was performed using patient data from our prospective longitudinal KD database.Setting: SRSE is defined as refractory SE that continues or recurs 24 h or more after initiation of anesthetic drugs. We describe the clinical and electroencephalographic (EEG) findings of all children treated with KD at our PICU. The KD was administered as add-on after failure of standard treatment. Response was defined as EEG seizure resolution (absence of seizures and suppression–burst ratio ≥50%).Patients: Eight consecutive SRSE patients (four females) treated with KD were included. Median age at onset of SRSE was 13.6 months (IQR 0.9–105), and median age at KD initiation was 13.7 months (IQR 1.9 months to 8.9 years). Etiology was known in 6/8 (75%): genetic in 4 (50%), structural in 1 (12.5%), and autoimmune/inflammatory in 1 (12.5%).Main Results: Time from onset of SRSE to initiation of KD was median 6 days (IQR 1.3–9). Time until clinically relevant ketosis (beta-hydroxybutyrate (BHB) >2 mmol/L in serum) was median 68.0 h (IQR 27.3–220.5). Higher ketosis was achieved when a higher proportion of enteral feeds was possible. Four (50%) patients responded to KD treatment within 7 days. During follow-up (median 4.2 months, IQR 1.6–12.3), 5/8 patients—three of them responders—died within 3–12 months after SRSE.Conclusions: In eight patients with SRSE due to severe etiologies including Alpers syndrome, we report an initial 50% response to KD. KD was used early in SRSE and sufficient levels of ketosis were reached early in most patients. Higher ketosis was achieved with combined enteral and parenteral feedings.

A retrospective cohort study of super-refractory status epilepticus in a tertiary neuro-ICU setting

PurposeOver the last decade, the range of treatments available for the management of super-refractory status epilepticus (SRSE) has expanded. However, it is unclear whether this has had an impact on its high mortality and morbidity. The aim of this study was to investigate whether there has been a change in the outcome of SRSE over time in a neurological intensive care unit (ICU) within a tertiary centre. MethodsAnalysis of a retrospective cohort of 53 admissions from 45 patients to the neurological ICU at the National Hospital for Neurology and Neurosurgery, Queen Square, London, between January 2004 and September 2018. ResultsSignificant reductions were observed in both duration of SRSE over time and in the time spent in ICU, suggesting that treatment quality has improved over time. A median of four antiseizure drugs (ASDs) were given prior to seizure resolution. In 23 % resolution of SRSE occurred following optimisation of current treatment rather than introduction of a new ASD. The mortality rate was very low at 11 % by 6 months; however, there was no indication of improvement in outcome as all surviving patients had a modified Rankin scale score of 3−5 upon discharge from ICU, classified as moderate-to-severe disability. ConclusionNeither the survival rate nor the outcome score changed significantly over time, suggesting that changes in the treatment of SRSE have had no impact on patient outcome.

Different Attitudes in the Management of Different Types of Status Epilepticus

Purpose: The aim is to identify current diagnostic and therapeutic approach to different types of status epilepticus (SE) including convulsive SE (CSE), non-CSE (NCSE), and epilepsia partialis continua (EPC) to detect unmet needs and problems encountered during the management of these neurological emergencies in our country, Turkey. Methods: The specifically designed SE survey included 31 questions that were related to the incidence, the distribution of etiological causes, the diagnostic process, and the treatment approaches of the neurologists and individual electroencephalography (EEG) facilities of the institutions. Results: The total number of respondents was 152 with a median years of experience in professional practice of 10.8 years (1–39 years). The great majority of the neurologists preferred diazepam plus phenytoin as the first choice drug in the treatment of CSE. Of the respondents, only 55% accepted the SE as refractory after applying the second drug and they monitored these patients in the intensive care unit (ICU). Most of the participants (67.7%) did not provide any treatment except the standard medical approaches, while only 39 (30.7%) had used immunotherapy in the treatment of super-refractory SE. Forty-seven respondents (37%) indicated that they had difficulty identifying NCSE on EEG. While 37% of the participants treated EPC patients with preserved consciousness in ICU by general anesthesia, only 15% were previously applied immunotherapy. Strikingly, 41% of the participants stated that they did not feel themselves as sufficiently competent in terms of practical and theoretical knowledge about the management of SE. Conclusion: We demonstrated that there are no standardized attitudes for the management of different types of SE among neurologists. It is worth to emphasize that the neurologists did not feel themselves sufficiently competent in terms of practical and theoretical knowledge, especially with regard to the subtypes of SE.

Practical Considerations for Ketogenic Diet in Adults With Super-Refractory Status Epilepticus.

Ketogenic diet therapy can be used as an adjuvant treatment of super-refractory status epilepticus (SRSE). However, the drug and metabolic interactions with concomitant treatments present a challenge for clinicians. In this review, we focus on the practical considerations of implementing ketogenic dietary therapy in the acute setting, including the dietary composition, potential drug-diet interactions, and monitoring during ketogenic treatment. This report describes the ketogenic diet therapy protocol implemented for the treatment of SRSE and a review of the current evidence to support clinical practice. The control of SRSE is critical in reducing morbidity and mortality. There is emerging evidence that ketogenic diet may be a safe and effective treatment option for these patients.

Ketamine to treat super-refractory status epilepticus.

To 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). We 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. Mean 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. Ketamine 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. This study provides Class IV evidence that ketamine decreases seizures in patients with SRSE.

Super-Refractory Status Epilepticus Treated with High Dose Perampanel: Case Series and Review of the Literature

Introduction Acute symptomatic seizures are frequent in the critically ill patient and can be difficult to treat. The novel anticonvulsant perampanel may be effective in the treatment of status epilepticus considering its mechanism of action of being an AMPA antagonist. We present four cases of super refractory status epilepticus treated with high dose perampanel. Method Case report. Cases Four patients were treated with perampanel for their refractory status epilepticus. One patient had new onset refractory status epilepticus of unknown etiology. Three other patients had status epilepticus as a result of their cardiac arrest. Two of the cardiac arrest patients had myoclonus. In all patients, the additional of perampanel resulted in a reduction of seizure burden without affecting hemodynamics or hepatic or renal function. Conclusion Perampanel may be effective in the treatment of super-refractory status epilepticus of varying etiologies. A larger, prospective study is needed to further assess this therapy.

Xenon in the treatment of super-refractory status epilepticus. Case report

Tolerance to specific drug therapy may occur in the relief of epileptic status. One of the solutions this problem are use of volatile anesthetics, which have a number of negative properties in addition to positive effects. In the presented description of a clinical case of a super-refractory status epilepticus in a 5-year-old child, xenon, possessing the properties of a general anesthetic and having no negative side effects, was successfully used to relieve seizures. By inhalation of the xenon-oxygen mixture in the proportion of 60–70 % xenon and 30–40 % oxygen, it was possible to completely level the convulsive activity of the patient during the procedure, which was confirmed by electroencephalogram. The presented case gives grounds for further study of the possibility of using xenon in the treatment of super-refractory status epilepticus in children.

Consensus Protocol for the Treatment of Super-Refractory Status Epilepticus

Super-refractory status epilepticus is defined as status epilepticus that persists or recurs 24 hours after anaesthetictherapy onset or after its withdrawal. It is mostly found in intensive care units and carries high mortality but good long-term prognosisfor those who survive. In contrast with the initial phases of status epilepticus, treatment lacks strong scientific evidence and is mostlyderived from case reports or small case series. To propose a protocol for the treatment of super-refractory status epilepticus in level III intensive care units, focusing on thetreatment strategies to control clinical and/or electroencephalographic epileptic activity. Narrative review of the literature by PubMed search. Available evidence was discussed in consensus meetingsby intensive care and neurology experts' from a level III intensive care unit and one of the Portuguese reference centres for the treatmentof refractory epilepsy, respectively. Anaesthetics with the highest level of evidence are propofol, midazolam, thiopental and ketamine. These represent the basisof the treatment of super-refractory status epilepticus and should be used in combination with antiepileptic drugs. The level of evidencefor the latter is lower, however, levetiracetam, topiramate, pregabalin, lacosamide, valproic acid, phenytoin and perampanel may berecommended. Alternative therapeutic strategies with very low level of evidence are recommended in cases of total absence of clinicalresponse, such as magnesium sulphate, pyridoxine, ketogenic diet, therapeutic hypothermia and immunosupression. We propose a treatment protocol based on a sequential combination of anaesthetics, anti-epileptic drugs and alternativetherapies. Strategies to evaluate treatment response and to wean drugs based on clinical results are also proposed.

Stiripentol for the treatment of super-refractory status epilepticus with cross-sensitivity.

Cross-sensitivity of rash has been reported between various antiepileptic drugs (AEDs). However, few studies have determined the frequency and management of cross-sensitivity in patients with super-refractory status epilepticus (SRSE). To examine the optimal AED for treating SRSE with cross-sensitivity. We performed a retrospective review of adult patients with SRSE treated at Nagoya City University Hospital, in which we investigated the frequency of cross-sensitivity among patients with SRSE and their clinical and medical profiles. We identified 10 adult patients with SRSE, 5 of whom had cross-sensitivity. Stiripentol (STP) was administered when previously used AEDs had demonstrated cross-sensitivity and failed to control seizures. After initiation of STP, the dose of general anaesthetics was reduced, and status epilepticus (SE) eventually ceased with co-administered AEDs without additional adverse effects. The mean time to SE cessation after initiation of STP was 30.8days (range, 18-46days), mean duration of general anaesthesia was 101.2days (range, 74-128days), and mean number of AEDs was 9.0 (range, 6-11). This study suggests that cross-sensitivity between AEDs is common in adults with SRSE and that STP may be useful for treating SRSE with cross-sensitivity.

Stiripentol for the treatment of super-refractory status epilepticus with cross-sensitivity

Background: Cross-sensitivity of skin rashes has been reported between various antiepileptic drugs (AEDs). Clinicians who are confronted with cross-sensitivity must take this into account when asking, “Which AED should I choose next?”

First-in-man allopregnanolone use in super-refractory status epilepticus.

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.

Isoflurane Use in the Treatment of Super-Refractory Status Epilepticus is Associated with Hippocampal Changes on MRI.

Refractory status epilepticus (RSE) is associated with high morbidity and mortality. Experts recommend aggressive management with continuous intravenous infusions or inhaled anesthetics such as isoflurane. However, there is concern that MRI changes in RSE reflect isoflurane neurotoxicity. We performed a case-control study to determine whether isoflurane is neurotoxic, based on MRI signal changes. We performed a retrospective case-control study of the incidence of MRI changes in RSE treated with and without isoflurane. Charts were reviewed for demographic and treatment information. T1, T2, and FLAIR sequences of MRIs were reviewed independently by two neuroradiologists blinded to treatment group for presence or absence of signal change or atrophy in the meninges, cortex, white matter, basal ganglia, thalamus, hippocampus, brainstem, and cerebellum. Eight cases of RSE receiving treatment with isoflurane were identified and double-matched with 15 controls who received only intravenous anesthetics. Baseline characteristics were similar. Hippocampal signal change was observed more frequently in cases receiving isoflurane (p=0.026). Hippocampal signal changes were associated with isoflurane use in patients with RSE. They were also associated with number of seizure days prior to MRI and the use of multiple anesthetic agents. Similar changes have been seen as a result of RSE itself, and one cannot rule out the possibility these changes represent seizure-related effects. If isoflurane-related, these hippocampal signal changes may be the result of a direct neurotoxic effect of prolonged isoflurane use or failure of isoflurane to protect the hippocampus from seizure-induced injury despite achieving electrographic burst-suppression.

Is pentobarbital safe and efficacious in the treatment of super-refractory status epilepticus: a cohort study.

IntroductionSeizures refractory to third-line therapy are also labeled super-refractory status epilepticus (SRSE). These seizures are extremely difficult to control and associated with poor outcome. We aimed to characterize efficacy and side-effects of continuous infusions of pentobarbital (cIV-PTB) treating SRSE.MethodsWe retrospectively reviewed continuous electroencephalography (cEEG) reports for all adults with RSE treated with cIV-PTB between May 1997 and April 2010 at our institution. Patients with post-anoxic SE and those receiving cIV-PTB for reasons other than RSE were excluded. We collected baseline information, cEEG findings, side-effects and functional outcome at discharge and one year.ResultsThirty one SRSE patients treated with cIV-PTB for RSE were identified. Mean age was 48 years old (interquartile range (IQR) 28,63), 26% (N = 8) had a history of epilepsy. Median SE duration was 6.5 days (IQR 4,11) and the mean duration of cIV-PTB was 6 days (IQR 3,14). 74% (N = 23) presented with convulsive SE. Underlying etiology was acute symptomatic seizures in 52% (N = 16; 12/16 with encephalitis), remote 30% (N = 10), and unknown 16% (N = 5). cIV-PTB controlled seizures in 90% (N = 28) of patients but seizures recurred in 48% (N = 15) while weaning cIV-PTB, despite the fact that suppression-burst was attained in 90% (N = 28) of patients and persisted >72 hours in 56% (N = 17). Weaning was successful after adding phenobarbital in 80% (12/15 of the patients with withdrawal seizures). Complications during or after cIV-PTB included pneumonia (32%, N = 10), hypotension requiring pressors (29%, N = 9), urinary tract infection (13%, N = 4), and one patient each with propylene glycol toxicity and cardiac arrest. One-third (35%, N = 11) had no identified new complication after starting cIV-PTB. At one year after discharge, 74% (N = 23) were dead or in a state of unresponsive wakefulness, 16% (N = 5) severely disabled, and 10% (N = 3) had no or minimal disability. Death or unresponsive wakefulness was associated with catastrophic etiology (p = 0.03), but none of the other collected variables.ConclusionscIV-PTB effectively aborts SRSE and complications are infrequent; outcome in this highly refractory cohort of patients with devastating underlying etiologies remains poor. Phenobarbital may be particularly helpful when weaning cIV-PTB.

Treatment of super-refractory status epilepticus: the sooner the better with less adverse effects.

Treatment of super-refractory status epilepticus: the sooner the better with less adverse effects.

The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy

In a previous paper, we reviewed the range of therapies available for the treatment of super-refractory status epilepticus. Here we report a review of the outcome of therapies in refractory and super-refractory status epilepticus. Patients (n = 1168) are reported who had therapy with: thiopental, pentobarbital, midazolam, propofol, ketamine, inhalational anaesthetics (isoflurane, desflurane), antiepileptic drugs (topiramate, lacosamide, pregabalin, levetiracetam), hypothermia, magnesium, pyridoxine, immunotherapy, ketogenic diet, emergency neurosurgery, electroconvulsive therapy, cerebrospinal fluid drainage, vagal nerve stimulation and deep brain stimulation. The outcome parameters reported include control of status epilepticus, relapse on withdrawal, breakthrough seizures and mortality. Where reported (596 cases), the long-term outcome was found to be death (35%), severe neurological deficit (13%), mild neurological deficit (13%), undefined deficit (4%) and recovery to baseline (35%). The quality of reported outcome data is generally poor and the number of cases reported for all non-anaesthetic therapies is low. Outcome assessment is complicated by changes in co-medication, delay in response and publication bias. Given these deficits, only broad recommendations can be made regarding optimal therapy. An approach to therapy, divided into first-line, second-line and third-line therapy, is suggested on the basis of this outcome evaluation. The importance of treatments directed at the cause of the status epilepticus, and of supportive ITU care is also emphasized.

Neuroprotection and Hypothermia in Infants and Children

Brain injury is the leading cause of death in pediatric ICU. Current evidence supports the use of therapeutic hypothermia (TH) in unconscious patients after out-of-hospital cardiac arrest when the initial heart rhythm was ventricular fibrillation. TH has been proved to be also beneficial in term neonates after hypoxic-ischemic encephalopathy (HIE) and in children with traumatic brain injury (TBI). Recent reports have also investigated TH for the treatment of superrefractory status epilepticus. The clinical application of TH is based on the possibility to inhibit or lessen a myriad of destructive processes (including excitotoxicty, neuroinflammation, apoptosis, free radical production, seizure activity, blood- brain barrier disruption, blood vessel leakage) that take place in the injured tissue following ischemia-reperfusion. TH may also represent a useful tool when conventional therapy fails to achieve an effective control of elevated intracranial pressure. This review is aimed to provide an update of the available literature concerning this intriguing topic.

Treatment of Super-Refractory Status Epilepticus

Researchers at University College, Queen Square, London, UK have evaluated the world literature on the treatment of super-refractory status epilepticus (SRSE) and proposed a protocol and flowchart for management.

The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol

Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24 h or more after the onset of anaesthetic therapy, including those cases where status epilepticus recurs on the reduction or withdrawal of anaesthesia. It is an uncommon but important clinical problem with high mortality and morbidity rates. This article reviews the treatment approaches. There are no controlled or randomized studies, and so therapy has to be based on clinical reports and opinion. The published world literature on the following treatments was critically evaluated: anaesthetic agents, anti-epileptic drugs, magnesium infusion, pyridoxine, steroids and immunotherapy, ketogenic diet, hypothermia, emergency resective neurosurgery and multiple subpial transection, transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation, electroconvulsive therapy, drainage of the cerebrospinal fluid and other older drug therapies. The importance of treating the identifying cause is stressed. A protocol and flowchart for managing super-refractory status epilepticus is suggested. In view of the small number of published reports, there is an urgent need for the establishment of a database of outcomes of individual therapies.