The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol
TL;DR: There is an urgent need for the establishment of a database of outcomes of individual therapies for super-refractory status epilepticus, which is an uncommon but important clinical problem with high mortality and morbidity rates.
Abstract: 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.
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Virginia Commonwealth University1, Thomas Jefferson University2, Columbia University3, University of California, San Francisco4, Rush University Medical Center5, Cincinnati Children's Hospital Medical Center6, Emory University7, New York University8, University of Cincinnati9, Arizona State University10, University of California, Los Angeles11
TL;DR: Recommendations were developed based on the literature using standardized assessment methods from the American Heart Association and Grading of Recommendations Assessment, Development, and Evaluation systems, as well as expert opinion when sufficient data were lacking.
Abstract: Status epilepticus (SE) treatment strategies vary substantially from one institution to another due to the lack of data to support one treatment over another. To provide guidance for the acute treatment of SE in critically ill patients, the Neurocritical Care Society organized a writing committee to evaluate the literature and develop an evidence-based and expert consensus practice guideline. Literature searches were conducted using PubMed and studies meeting the criteria established by the writing committee were evaluated. Recommendations were developed based on the literature using standardized assessment methods from the American Heart Association and Grading of Recommendations Assessment, Develop- ment, and Evaluation systems, as well as expert opinion when sufficient data were lacking.
1,215 citations
TL;DR: An extensive and comprehensive overview of Mg(2+) research over the last few decades is provided, focusing on the regulation of M g(2+) homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.
Abstract: Magnesium (Mg(2+)) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg(2+) availability has been proven to be disturbed during several clinical situations, serum Mg(2+) values are not generally determined in patients. This review aims to provide an overview of the function of Mg(2+) in human health and disease. In short, Mg(2+) plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg(2+) supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg(2+) transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg(2+) in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg(2+) research over the last few decades, focusing on the regulation of Mg(2+) homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.
996 citations
TL;DR: An approach to therapy, divided into first-line, second-line and third-line therapy, is suggested on the basis of this outcome evaluation, noting the importance of treatments directed at the cause of the status epilepticus, and of supportive ITU care.
Abstract: 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.
362 citations
Cites background or methods from "The treatment of super-refractory s..."
...viewed elsewhere (Shorvon and Ferlisi, 2011), and these findings...
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...categorizing outcome Details of the literature used as the basis of this review are published elsewhere (Shorvon and Ferlisi, 2011, including the associated Supplementary material)....
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...Their advantages and disadvantages have been reviewed elsewhere (Shorvon and Ferlisi, 2011), and these findings are summarized in Table 4....
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...A number of therapies are in current usage and the literature reporting these therapies has been reviewed in detail elsewhere (Shorvon and Ferlisi, 2011)....
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...A treatment protocol has been suggested elsewhere (Shorvon and Ferlisi, 2011)....
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TL;DR: Achieving control of the SE without requiring prolonged drug-induced coma or severe electroencephalographic suppression portends better prognosis, and three-quarters of patients with RSE have a poor outcome.
Abstract: Objective To further characterize the demographics, outcomes, and prognostic factors for refractory status epilepticus (RSE). Design Retrospective analysis of all the episodes of RSE treated between January 1, 1999, and August 30, 2011. Setting Neurointensive care unit within a tertiary referral center, Mayo Clinic, Rochester, Minnesota. Patients Refractory status epilepticus was defined as generalized convulsive or nonconvulsive status epilepticus (SE) that continued despite initial first- and second-line therapies. Exclusion criteria were aged younger than 18 years, anoxic/myoclonic SE, psychogenic SE, simple partial SE, and absence SE. Main Outcome Measures Functional outcome was defined by modified Rankin scale (mRS) dichotomized into good (mRS, 0-3) and poor (mRS, 4-6). Functional decline was defined as a change in mRS greater than 1 from hospital admission to discharge. Results We identified 63 consecutive episodes of non–anoxic RSE in 54 patients. Anesthetic agents were used in 55 episodes (87.30%), and duration of drug-induced coma was (mean [SD]) 11.0 (17.9) days. In-hospital mortality was 31.75% (20 of 63 episodes). Poor functional outcome at discharge occurred in 48 of 63 episodes (76.19%). Hospital length of stay was (mean [SD]) 27.7 (37.3) days. Duration of drug-induced coma (P = .03), arrhythmias requiring intervention (P = .01), and pneumonia (P = .01) were associated with poor functional outcome. Prolonged mechanical ventilation was associated with mortality (P = .04). Seizure control without suppression-burst or isoelectric electroencephalogram predicted good functional recovery (P = .01). Age, history of epilepsy, previous SE, type of SE, and anesthetic drug used were not associated with functional outcome. Conclusions Three-quarters of patients with RSE have a poor outcome. Achieving control of the SE without requiring prolonged drug-induced coma or severe electroencephalographic suppression portends better prognosis.
213 citations
TL;DR: A BBB‐centric view of seizure disorders is offered, linking several aspects of seizures and epilepsy physiopathology to BBB dysfunction, and the therapeutic, antiseizure effect of drugs that promote BBB repair is reviewed.
Abstract: The blood-brain barrier (BBB) is located within a unique anatomic interface and has functional ramifications to most of the brain and blood cells. In the past, the BBB was considered a pharmacokinetic impediment to antiepileptic drug penetration into the brain; nowadays it is becoming increasingly evident that targeting of the damaged or dysfunctional BBB may represent a therapeutic approach to reduce seizure burden. Several studies have investigated the mechanisms linking the onset and sustainment of seizures to BBB dysfunction. These studies have shown that the BBB is at the crossroad of a multifactorial pathophysiologic process that involves changes in brain milieu, altered neuroglial physiology, development of brain inflammation, leukocyte-endothelial interactions, faulty angiogenesis, and hemodynamic changes leading to energy mismatch. A number of knowledge gaps, conflicting points of view, and discordance between clinical and experimental data currently characterize this field of neuroscience. As more pieces are added to this puzzle, it is apparent that each mechanism needs to be validated in an appropriate clinical context. We now offer a BBB-centric view of seizure disorders, linking several aspects of seizures and epilepsy physiopathology to BBB dysfunction. We have reviewed the therapeutic, antiseizure effect of drugs that promote BBB repair. We also present BBB neuroimaging as a tool to correlate BBB restoration to seizure mitigation. Add-on cerebrovascular drug could be of efficacy in reducing seizure burden when used in association with neuronal antiepileptic drugs.
191 citations
Cites background or methods from "The treatment of super-refractory s..."
...Of interest, the clinical protocol for the treatment of SRSE includes the use of intravenous steroids and IgG ‘‘for all patients in whom there is no cause identified for the super-refractory status epilepticus’’ (Shorvon & Ferlisi, 2011)....
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...Recently, a role for BBB dysfunction in super refractory status epilepticus (SRSE) was proposed (Shorvon & Ferlisi, 2011)....
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...A role for BBB dysfunction was also proposed for super refractory status epilepticus (Shorvon & Ferlisi, 2011)....
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References
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TL;DR: The voltage dependence of the NMDA receptor-linked conductance appears to be a consequence of the voltage dependenceof the Mg2+ block and its interpretation does not require the implication of an intramembrane voltage-dependent ‘gate’.
Abstract: The responses of vertebrate neurones to glutamate involve at least three receptor types. One of these, the NMDA receptor (so called because of its specific activation by N-methyl-D-aspartate), induces responses presenting a peculiar voltage sensitivity. Above resting potential, the current induced by a given dose of glutamate (or NMDA) increases when the cell is depolarized. This is contrary to what is observed at classical excitatory synapses, and recalls the properties of 'regenerative' systems like the Na+ conductance of the action potential. Indeed, recent studies of L-glutamate, L-aspartate and NMDA-induced currents have indicated that the current-voltage (I-V) relationship can show a region of 'negative conductance' and that the application of these agonists can lead to a regenerative depolarization. Furthermore, the NMDA response is greatly potentiated by reducing the extracellular Mg2+ concentration [( Mg2+]o) below the physiological level (approximately 1 mM). By analysing the responses of mouse central neurones to glutamate using the patch-clamp technique, we have now found a link between voltage sensitivity and Mg2+ sensitivity. In Mg2+-free solutions, L-glutamate, L-aspartate and NMDA open cation channels, the properties of which are voltage independent. In the presence of Mg2+, the single-channel currents measured at resting potential are chopped in bursts and the probability of opening of the channels is reduced. Both effects increase steeply with hyperpolarization, thereby accounting for the negative slope of the I-V relationship of the glutamate response. Thus, the voltage dependence of the NMDA receptor-linked conductance appears to be a consequence of the voltage dependence of the Mg2+ block and its interpretation does not require the implication of an intramembrane voltage-dependent 'gate'.
3,977 citations
"The treatment of super-refractory s..." refers background in this paper
...There is a body of experimental evidence demonstrating its anti-epileptic action (Nowak et al., 1984), and its effect in blockading the N-methyl-D-aspartate receptor may be the basis of this action....
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TL;DR: HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs.
Abstract: Brain inflammation is a major factor in epilepsy, but the impact of specific inflammatory mediators on neuronal excitability is incompletely understood. Using models of acute and chronic seizures in C57BL/6 mice, we discovered a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. Antagonists of HMGB1 and TLR4 retard seizure precipitation and decrease acute and chronic seizure recurrence. TLR4-defective C3H/HeJ mice are resistant to kainate-induced seizures. The proconvulsant effects of HMGB1, like those of interleukin-1beta (IL-1beta), are partly mediated by ifenprodil-sensitive N-methyl-d-aspartate (NMDA) receptors. Increased expression of HMGB1 and TLR4 in human epileptogenic tissue, like that observed in the mouse model of chronic seizures, suggests a role for the HMGB1-TLR4 axis in human epilepsy. Thus, HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs.
786 citations
"The treatment of super-refractory s..." refers background in this paper
...…epileptogenesis, and especially the activation of specific inflammatory signalling pathways such as the interleukin-1 receptor/toll-like receptor (IL-1R/ TLR) pathway, both experimentally and in human tissue (Vezzani et al., 2009; Maroso et al., 2010; Vezzani and Ruegg, 2011; Zurolo et al., 2011)....
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Journal Article•
732 citations
TL;DR: Refractory status epilepticus occurs in approximately 30% of patients with SE and is associated with increased hospital length of stay and functional disability, and nonconvulsive SE and focal motor seizures at onset are risk factors for RSE.
Abstract: Background Refractory status epilepticus (RSE) is a life-threatening condition in which seizures do not respond to first- and second-line anticonvulsant drug therapy. How often RSE occurs, risk factors that predispose to this condition, and the effect of failure to control seizures on clinical outcome are poorly defined. Objective To determine the frequency, risk factors, and impact on outcome of RSE. Design Retrospective cohort study. Setting Large academic teaching hospital. Patients Consecutive sample of 83 episodes of status epilepticus in 74 patients (mean age, 63 years). Main Outcome Measures Refractory status epilepticus was defined as seizures lasting longer than 60 minutes despite treatment with a benzodiazepine and an adequate loading dose of a standard intravenous anticonvulsant drug. Factors associated with RSE were identified using univariate and backward stepwiselogistic regression analyses. Results In 57 episodes (69%), seizures occurred after treatment with a benzodiazepine, and in 26 (31%), seizures occurred after treatment with a second-line anticonvulsant drug (usually phenytoin), fulfilling our criteria for RSE. Nonconvulsive SE (P= .03) and focal motor seizures at onset (P= .04) were identified as independent risk factors for RSE. Eleven (42%) of 26 patients with RSE had seizures after receiving a third-line agent (usually phenobarbital). Although mortality was not increased (17% overall), RSE was associated with prolonged hospital length of stay (P Conclusions Refractory status epilepticus occurs in approximately 30% of patients with SE and is associated with increased hospital length of stay and functional disability. Nonconvulsive SE and focal motor seizures at onset are risk factors for RSE. Randomized controlled trials are needed to define the optimal treatment of RSE.
605 citations
"The treatment of super-refractory s..." refers background in this paper
...Other retrospective studies have shown that 12–43% of the cases with status epilepticus become refractory (Lowenstein and Aldredge, 1993; Mayer et al., 2002; Holtkamp et al., 2005; Rosetti et al., 2005)....
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...BRAIN A JOURNAL OF NEUROLOGY...
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01 Jan 1993
TL;DR: Common to all patients is the need for a clear plan, prompt administration of appropriate drugs in adequate doses, and attention to the possibility of apnea, hypoventilation, or other metabolic abnormalities.
Abstract: Convulsive status epilepticus is an emergency that is associated with high morbidity and mortality. The outcome largely depends on etiology, but prompt and appropriate pharmacological therapy can reduce morbidity and mortality. Etiology varies in children and adults and reflects the distribution of disease in these age groups. Antiepileptic drug administration should be initiated whenever a seizure has lasted 10 minutes. Immediate concerns include supporting respiration, maintaining blood pressure, gaining intravenous access, and identifying and treating the underlying cause. Initial therapeutic and diagnostic measures are conducted simultaneously. The goal of therapy is rapid termination of clinical and electrical seizure activity; the longer a seizure continues, the greater the likelihood of an adverse outcome. Several drug protocols now in use will terminate status epilepticus. Common to all patients is the need for a clear plan, prompt administration of appropriate drugs in adequate doses, and attention to the possibility of apnea, hypoventilation, or other metabolic abnormalities.
509 citations