Neurocrit Care DOI 10.1007/s12028-013-9939-6
REVIEW ARTICLE
NMDA Antagonists for Refractory Seizures F. A. Zeiler • J. Teitelbaum • L. M. Gillman M. West
•
Ó Springer Science+Business Media New York 2014
Abstract Refractory status epilepticus (RSE) poses significant challenge, with a variety of novel therapeutics employed. Our goal was to evaluate the effectiveness of N-methyl Daspartate (NMDA) receptor antagonists in the control of RSE. We performed a systematic review of all the literature, with all articles pulled from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to September 2013), reference lists of relevant articles, and gray literature. Two reviewers independently identified all manuscripts pertaining to the administration of NMDA receptor antagonists in humans for the purpose of controlling refractory seizures. Secondary outcome of adverse NMDA antagonist effects and patient outcome was assessed. Two reviewers
Electronic supplementary material The online version of this article (doi:10.1007/s12028-013-9939-6) contains supplementary material, which is available to authorized users.
independently extracted data including population characteristics, treatment characteristics, and outcomes. The strength of evidence was adjudicated using both the Oxford and GRADE methodology. Our search strategy produced a total of 759 citations. Twenty-three articles, 16 manuscripts, and seven meeting proceedings, were considered for the review with all utilizing ketamine for seizure control. Only three studies were prospective studies. Fifteen and nine studies pertained to adults and pediatrics, respectively. Across all studies, of the 110 adult patients described, ketamine was attributed to electroencephalogram seizure response in 56.5 %, with a 63.5 % response in the 52 pediatric patients described. Adverse events related to ketamine were rare. Outcomes were poorly documented in the majority of the studies. There currently exists Oxford level 4, GRADE C evidence to support the use of ketamine for refractory seizures in the adult and pediatric populations. Further prospective study of early ketamine administration is warranted.
F. A. Zeiler (&) M. West Section of Neurosurgery, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada e-mail: [email protected]
Keywords Status epilepticus Refractory status Ketamine NMDA antagonists
F. A. Zeiler J. Teitelbaum Section of Neurocritical Care, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Introduction
J. Teitelbaum Section of Neurology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada L. M. Gillman Section of Critical Care Medicine, Department of Medicine, University of Manitoba, Winnipeg, MB, Canada L. M. Gillman Section of General Surgery, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada
The protocoled management of status epilepticus (SE) is quite variable throughout the literature [1–3]. Standard initial medication options for SE are derived from the literature on general seizure management, and can vary depending on a variety of etiologies [4]. To date the level of evidence supporting the majority of medication choices for seizure control is based on level II or worse recommendations [1], with the only level I evidence stemming from the use of short acting benzodiazepines to abort early seizure activity.
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Neurocrit Care
Medically refractory status epilepticus (RSE) poses significant challenges pharmacologically. For those patients that fail initial medical management of their SE and continue on toward the half-hour mark of uncontrolled either clinical or electrographic seizure activity, the cessation of seizures utilizing standard pharmacological means decreases steadily with time. Based on a few very important neurochemical changes within the brain (as documented in animal models), it can be predicted that a large number of standard antiepileptics will have impaired function with prolonged seizure duration. First, GABAA receptor number decreases with prolonged seizure activity, followed by a return in number of non-functioning GABAA receptors (likely related to receptor sub-type changes) [5, 6]. These GABAA receptor changes lead to impaired responsiveness to GABA mediated antieplieptics. Second, SE has been known to induce P-glycoprotein expression leading to increased export of phenytoin and phenobarbital across the blood brain barrier, potentially leading to reduced brain concentration of these medications and pharmacoresistant seizures [7–9]. Finally, SE can lead to up-regulation of N-methyl D-aspartate (NMDA) receptors, causing glutamate induced intra-cellular calcium influx and excitoxicity that may further potentiate seizure activity [7, 10]. Thus, based on the mentioned mechanisms of pharmacoresistance, novel approaches to anti-epileptic choices need to be made to achieve adequate and rapid seizure control. Given the literature on excitotoxicity and the NMDA mediated potentiation of SE, numerous studies have emerged in the last 15 years focusing on the use of NMDA receptor antagonists in the setting of refractory seizures [11– 33]. The goal of our study is to perform a systematic review of the current literature on the use of ketamine or any other NMDA receptor antagonist for the control of RSE.
Methods A systematic review using the methodology outlined in the Cochrane Handbook for Systematic Reviewers [34] was conducted. The data was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [35]. The review questions and search strategy were decided upon by the primary author and supervisor. Search Question, Population, Inclusion and Exclusion Criteria The question posed for systematic review was: What is the effectiveness of ketamine, or NMDA antagonists, for control of RSE in humans? All studies, prospective and retrospective of any size based on human subjects were included. The reason for an all-inclusive search was based
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on the small number of studies of any type identified by the primary author during a preliminary search of MEDLINE. The primary outcome measure was electrographic seizure control, defined as: complete (100 % of patients response), moderate (>50 % of patients response), mild (50 % patients in the study responded) was documented in two studies with a total of 16 patients. Mild electrographic seizure response (
REVIEW ARTICLE
NMDA Antagonists for Refractory Seizures F. A. Zeiler • J. Teitelbaum • L. M. Gillman M. West
•
Ó Springer Science+Business Media New York 2014
Abstract Refractory status epilepticus (RSE) poses significant challenge, with a variety of novel therapeutics employed. Our goal was to evaluate the effectiveness of N-methyl Daspartate (NMDA) receptor antagonists in the control of RSE. We performed a systematic review of all the literature, with all articles pulled from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to September 2013), reference lists of relevant articles, and gray literature. Two reviewers independently identified all manuscripts pertaining to the administration of NMDA receptor antagonists in humans for the purpose of controlling refractory seizures. Secondary outcome of adverse NMDA antagonist effects and patient outcome was assessed. Two reviewers
Electronic supplementary material The online version of this article (doi:10.1007/s12028-013-9939-6) contains supplementary material, which is available to authorized users.
independently extracted data including population characteristics, treatment characteristics, and outcomes. The strength of evidence was adjudicated using both the Oxford and GRADE methodology. Our search strategy produced a total of 759 citations. Twenty-three articles, 16 manuscripts, and seven meeting proceedings, were considered for the review with all utilizing ketamine for seizure control. Only three studies were prospective studies. Fifteen and nine studies pertained to adults and pediatrics, respectively. Across all studies, of the 110 adult patients described, ketamine was attributed to electroencephalogram seizure response in 56.5 %, with a 63.5 % response in the 52 pediatric patients described. Adverse events related to ketamine were rare. Outcomes were poorly documented in the majority of the studies. There currently exists Oxford level 4, GRADE C evidence to support the use of ketamine for refractory seizures in the adult and pediatric populations. Further prospective study of early ketamine administration is warranted.
F. A. Zeiler (&) M. West Section of Neurosurgery, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada e-mail: [email protected]
Keywords Status epilepticus Refractory status Ketamine NMDA antagonists
F. A. Zeiler J. Teitelbaum Section of Neurocritical Care, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Introduction
J. Teitelbaum Section of Neurology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada L. M. Gillman Section of Critical Care Medicine, Department of Medicine, University of Manitoba, Winnipeg, MB, Canada L. M. Gillman Section of General Surgery, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada
The protocoled management of status epilepticus (SE) is quite variable throughout the literature [1–3]. Standard initial medication options for SE are derived from the literature on general seizure management, and can vary depending on a variety of etiologies [4]. To date the level of evidence supporting the majority of medication choices for seizure control is based on level II or worse recommendations [1], with the only level I evidence stemming from the use of short acting benzodiazepines to abort early seizure activity.
123
Neurocrit Care
Medically refractory status epilepticus (RSE) poses significant challenges pharmacologically. For those patients that fail initial medical management of their SE and continue on toward the half-hour mark of uncontrolled either clinical or electrographic seizure activity, the cessation of seizures utilizing standard pharmacological means decreases steadily with time. Based on a few very important neurochemical changes within the brain (as documented in animal models), it can be predicted that a large number of standard antiepileptics will have impaired function with prolonged seizure duration. First, GABAA receptor number decreases with prolonged seizure activity, followed by a return in number of non-functioning GABAA receptors (likely related to receptor sub-type changes) [5, 6]. These GABAA receptor changes lead to impaired responsiveness to GABA mediated antieplieptics. Second, SE has been known to induce P-glycoprotein expression leading to increased export of phenytoin and phenobarbital across the blood brain barrier, potentially leading to reduced brain concentration of these medications and pharmacoresistant seizures [7–9]. Finally, SE can lead to up-regulation of N-methyl D-aspartate (NMDA) receptors, causing glutamate induced intra-cellular calcium influx and excitoxicity that may further potentiate seizure activity [7, 10]. Thus, based on the mentioned mechanisms of pharmacoresistance, novel approaches to anti-epileptic choices need to be made to achieve adequate and rapid seizure control. Given the literature on excitotoxicity and the NMDA mediated potentiation of SE, numerous studies have emerged in the last 15 years focusing on the use of NMDA receptor antagonists in the setting of refractory seizures [11– 33]. The goal of our study is to perform a systematic review of the current literature on the use of ketamine or any other NMDA receptor antagonist for the control of RSE.
Methods A systematic review using the methodology outlined in the Cochrane Handbook for Systematic Reviewers [34] was conducted. The data was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [35]. The review questions and search strategy were decided upon by the primary author and supervisor. Search Question, Population, Inclusion and Exclusion Criteria The question posed for systematic review was: What is the effectiveness of ketamine, or NMDA antagonists, for control of RSE in humans? All studies, prospective and retrospective of any size based on human subjects were included. The reason for an all-inclusive search was based
123
on the small number of studies of any type identified by the primary author during a preliminary search of MEDLINE. The primary outcome measure was electrographic seizure control, defined as: complete (100 % of patients response), moderate (>50 % of patients response), mild (50 % patients in the study responded) was documented in two studies with a total of 16 patients. Mild electrographic seizure response (
