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      Perampanel for treatment of status epilepticus in Austria, Finland, Germany, and Spain

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          Abstract

          Objective

          Novel treatments are needed to control treatment‐resistant status epilepticus (SE). We report a summary of clinical cases where perampanel was used in established SE, refractory SE (RSE), or super‐refractory SE (SRSE).

          Methods

          Medical records were retrospectively reviewed for perampanel administration in SE at five European hospitals between 2011 and 2015.

          Results

          Of 1319 patients identified as experiencing SE, 52 (3.9%) received perampanel. Median latency from SE onset to perampanel initiation was 10 days. Patients with SE had previously failed benzodiazepines (when received) and a median of five other antiepileptic drugs (AEDs). Median initial perampanel dose was 6 mg/d, up‐titrated to a median maximum dose of 10 mg/d. Perampanel was the last drug added in 32/52 (61.5%) patients, with response attributed to perampanel in 19/52 (36.5%) patients. A greater proportion of perampanel non‐responders had SRSE (51.5%; 17/33) vs perampanel responders (31.6%; 6/19), and had failed a higher mean number of AEDs before initiating perampanel (5.9 vs 5.1, respectively). Most commonly reported adverse effects during perampanel treatment were dizziness (n = 1 [1.9%]) and somnolence (n = 1 [1.9%]). No serious adverse effects were documented, and none led to discontinuation of perampanel.

          Conclusions

          Perampanel was administered to patients with established SE, RSE, or SRSE at greater initial doses than those administered in clinical practice to patients with epilepsy. The SE cases reported here represent a refractory and heterogeneous population, and rate of seizure cessation attributed to perampanel treatment (36.5%) represents a notable response. These data should be confirmed in a larger patient population.

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          Most cited references27

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          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.
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            Status epilepticus in adults.

            Status epilepticus is a common neurological emergency with considerable associated health-care costs, morbidity, and mortality. The definition of status epilepticus as a prolonged seizure or a series of seizures with incomplete return to baseline is under reconsideration in an effort to establish a more practical definition to guide management. Clinical research has focused on early seizure termination in the prehospital setting. The approach of early escalation to anaesthetic agents for refractory generalised convulsive status epilepticus, rather than additional trials of second-line anti-epileptic drugs, to avoid neuronal injury and pharmaco-resistance associated with prolonged seizures is gaining momentum. Status epilepticus is also increasingly identified in the inpatient setting as the use of extended electroencephalography monitoring becomes more commonplace. Substantial further research to enable early identification of status epilepticus and efficacy of anti-epileptic drugs will be important to improve outcomes.
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              Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus.

              During status epilepticus (SE), GABAergic mechanisms fail and seizures become self-sustaining and pharmacoresistant. During lithiumpilocarpine-induced SE, our studies of postsynaptic GABA(A) receptors in dentate gyrus granule cells show a reduction in the amplitude of miniature IPSCs (mIPSCs). Anatomical studies show a reduction in the colocalization of the beta2/beta3 and gamma2 subunits of GABA(A) receptors with the presynaptic marker synaptophysin and an increase in the proportion of those subunits in the interior of dentate granule cells and other hippocampal neurons with SE. Unlike synaptic mIPSCs, the amplitude of extrasynaptic GABA(A) tonic currents is augmented during SE. Mathematical modeling suggests that the change of mIPSCs with SE reflects a decrease in the number of functional postsynaptic GABA(A) receptors. It also suggests that increases in extracellular [GABA] during SE can account for the tonic current changes and can affect postsynaptic receptor kinetics with a loss of paired-pulse inhibition. GABA exposure mimics the effects of SE on mIPSC and tonic GABA(A) current amplitudes in granule cells, consistent with the model predictions. These results provide a potential mechanism for the inhibitory loss that characterizes initiation of SE and for the pharmacoresistance to benzodiazepines, as a reduction of available functional GABA(A) postsynaptic receptors. Novel therapies for SE might be directed toward prevention or reversal of these losses.
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                Author and article information

                Contributors
                strzelczyk@med.uni-frankfurt.de
                Journal
                Acta Neurol Scand
                Acta Neurol. Scand
                10.1111/(ISSN)1600-0404
                ANE
                Acta Neurologica Scandinavica
                John Wiley and Sons Inc. (Hoboken )
                0001-6314
                1600-0404
                20 January 2019
                April 2019
                : 139
                : 4 ( doiID: 10.1111/ane.2019.139.issue-4 )
                : 369-376
                Affiliations
                [ 1 ] Department of Neurology, Epilepsy Center Frankfurt Rhine‐Main Goethe University Frankfurt am Main Germany
                [ 2 ] Department of Neurology, Epilepsy Center Hessen Philipps University Marburg Germany
                [ 3 ] LOEWE Center for Personalized Translational Epilepsy Research (CePTER) Goethe University Frankfurt am Main Germany
                [ 4 ] School of Medicine University of Eastern Finland Kuopio Finland
                [ 5 ] Epilepsy Center/Neuro Center Kuopio University Hospital Kuopio Finland
                [ 6 ] Epilepsy Unit Hospital Vall d’Hebron Barcelona Spain
                [ 7 ] Department of Neurology, Christian Doppler Klinik Paracelsus Medical University Salzburg Austria
                [ 8 ] Centre for Cognitive Neuroscience University of Salzburg Salzburg Austria
                [ 9 ] Department of Public Health, Health Services Research and Health Technology Assessment UMIT – University for Health Sciences, Medical Informatics and Technology Hall in Tirol Austria
                Author notes
                [*] [* ] Correspondence

                Adam Strzelczyk, Department of Neurology, Epilepsy Center Frankfurt Rhine‐Main, Goethe University, Frankfurt am Main, Germany.

                Email: strzelczyk@ 123456med.uni-frankfurt.de

                Author information
                https://orcid.org/0000-0001-6288-9915
                Article
                ANE13061
                10.1111/ane.13061
                6590284
                30613951
                d76803bc-7dff-4b8a-985d-6b4d2c57c9da
                © 2019 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 30 October 2018
                : 10 December 2018
                : 30 December 2018
                Page count
                Figures: 1, Tables: 2, Pages: 8, Words: 11304
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                ane13061
                April 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:24.06.2019

                ampa,perampanel,refractory status epilepticus,summary of cases,super‐refractory status epilepticus

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