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Status Epilepticus - Lessons and Challenges from Animal Models

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Seizures in Critical Care

Part of the book series: Current Clinical Neurology ((CCNEU))

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Abstract

Status epilepticus (SE) is not simply a prolonged seizure. Both the clinical course and the basic mechanisms are different from a single seizure. SE often fails to respond to sequential administration of antiepileptic drugs (AEDs), originally developed for treatment of chronic seizures. Pharmacoresistance to benzodiazepines and other AEDs, which is observed soon after onset of SE, leads to loss of the effectiveness of these medications and to poor clinical outcomes. Animal models have uncovered SE-induced changes in cellular and network pathophysiology, most of them maladaptive, leading to increased excitability. Whole-cell recordings from hippocampal slices obtained from animals in SE showed alteration in both inhibitory and excitatory postsynaptic physiology. These synaptic changes result at least in part from a decrease in functional synaptic GABAA receptors (through internalization/desensitization) accompanied by a simultaneous increase in the number of membrane NMDA receptors. These findings highlight the role played by receptor trafficking in transition to and maintenance of SE. They explain, at least in part, the development of pharmacoresistance to benzodiazepines and other GABAergic drugs. These SE-associated changes suggest that the current gold standard (benzodiazepine monotherapy) treats only half the problem and that consideration should be given to using a combination of GABAA agonists and NMDA antagonists in the initial treatment.

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Acknowledgments

We would like to extend special thank you to Roland McFarland, Dorota Kaminska, Ph.D., and Lyn Clarito, Pharm.D for their helpful comments on this manuscript. This work was supported by Merit Review Award # I01 BX000273-07 from the United States Department of Veterans Affairs, by NINDS (grant UO1 NS074926; CW), and by the James and Debbie Cho Foundation.

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Authors and Affiliations

  1. Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Inna Keselman & Jerome Niquet

  2. Department of Neurology, VA Greater Los Angeles Health Care System, 11301 Wilshire Blvd, Los Angeles, CA, 90073, USA

    Inna Keselman, Claude G. Wasterlain, Jerome Niquet & James W. Y. Chen

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  1. Inna Keselman
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  2. Claude G. Wasterlain
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Correspondence to James W. Y. Chen .

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  1. Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, Michigan, USA

    Panayiotis N. Varelas

  2. Neurocritical Care, Columbia University College of Physicians & Surgeons, New York, New York, USA

    Jan Claassen

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Keselman, I., Wasterlain, C.G., Niquet, J., Chen, J.W.Y. (2017). Status Epilepticus - Lessons and Challenges from Animal Models. In: Varelas, P., Claassen, J. (eds) Seizures in Critical Care. Current Clinical Neurology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-49557-6_1

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