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Why won’t it stop? The dynamics of benzodiazepine resistance in status epilepticus

Nature Reviews Neurology volume 18, pages 428–441 (2022)Cite this article

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An Author Correction to this article was published on 18 May 2022

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Abstract

Status epilepticus is a life-threatening neurological emergency that affects both adults and children. Approximately 36% of episodes of status epilepticus do not respond to the current preferred first-line treatment, benzodiazepines. The proportion of episodes that are refractory to benzodiazepines is higher in low-income and middle-income countries (LMICs) than in high-income countries (HICs). Evidence suggests that longer episodes of status epilepticus alter brain physiology, thereby contributing to the emergence of benzodiazepine resistance. Such changes include alterations in GABAA receptor function and in the transmembrane gradient for chloride, both of which erode the ability of benzodiazepines to enhance inhibitory synaptic signalling. Often, current management guidelines for status epilepticus do not account for these duration-related changes in pathophysiology, which might differentially impact individuals in LMICs, where the average time taken to reach medical attention is longer than in HICs. In this Perspective article, we aim to combine clinical insights and the latest evidence from basic science to inspire a new, context-specific approach to efficiently managing status epilepticus.

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Fig. 1: Socioeconomic and temporal differences in benzodiazepine-resistant convulsive status epilepticus.
Fig. 2: Benzodiazepines bind to Cl−-permeable GABAARs and enhance channel conductance.
Fig. 3: Changes in intracellular Cl− concentration set the properties of GABAAR-mediated signalling.
Fig. 4: Status epilepticus causes disruptions to GABAAR composition and function.
Fig. 5: Proposed timeline of changes affecting benzodiazepine efficacy during status epilepticus.
Fig. 6: Spatial dynamics of activity-dependent shifts in [Cl−]i and [K+]e might explain different responses to benzodiazepines.

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Code availability

All code used to generate Fig. 1 and Supplementary Fig. 1 can be accessed at https://github.com/richardjburman/bzp_review.

Data availability

All data used to generate Fig. 1 and Supplementary Fig. 1. can be accessed at https://github.com/richardjburman/bzp_review.

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Acknowledgements

The authors thank A. J. Trevelyan (Institute of Neurosciences, Newcastle, UK) for his helpful comments on this manuscript. R.J.B. is supported by a Shaun Johnson Memorial Scholarship through the Leverhulme Trust. R.J.B., R.E.R. and G.R. are supported by project grants from the Theodor and Ida Herzog-Egli Foundation and the Anna Mueller Grocholski Foundation. R.E.R. is supported by a Sir Henry Wellcome Fellowship (209164/Z/17/Z). A.S. is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). C.J.A. received funding from the European Research Council under the European Community’s Seventh Framework Programme FP7/2007-2013, ERC Grant Agreement 617670. J.V.R. is supported by the National Research Foundation of South Africa, a Wellcome Trust Seed Award (214042/Z/18/Z), the South African Medical Research Council and by the FLAIR Fellowship Programme (FLR\R1\190829): a partnership between the African Academy of Sciences and the Royal Society funded by the UK Government’s Global Challenges Research Fund.

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Authors and Affiliations

  1. Department of Pharmacology, University of Oxford, Oxford, UK

    Richard J. Burman & Colin J. Akerman

  2. Oxford Epilepsy Research Group, NIHR Biomedical Research Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    Richard J. Burman & Arjune Sen

  3. Department of Neuropediatrics, University Children’s Hospital Zürich, Zürich, Switzerland

    Richard J. Burman, Richard E. Rosch & Georgia Ramantani

  4. MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Richard E. Rosch

  5. Department of Paediatric Neurology, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa

    Jo M. Wilmshurst

  6. Neuroscience Institute, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Jo M. Wilmshurst & Joseph V. Raimondo

  7. Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Joseph V. Raimondo

  8. Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Joseph V. Raimondo

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Contributions

R.J.B and J.V.R. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission. All other authors made a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission.

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Review criteria

The studies mentioned in Table 1 were found using medical search headings (MeSH) on the PubMed and Embase database search platforms. We searched within the main heading of ‘convulsive status epilepticus’ and included ‘drug therapy’ and ‘prevention and control’ as subheadings. We added ‘benzodiazepines’ with the subheadings ‘administration and dosage’ and ‘therapeutic use’ to our search requirements. We limited our search to studies published from 1 January 1990 to 1 July 2021 and to peer-reviewed studies that were published in English and had the full text available. Studies were included if they were performed in patients, both adult and/or paediatric, presenting in convulsive status epilepticus and where monotherapy with a benzodiazepine (consisting of one or two doses), of any kind or formulation, was assessed in terms of its efficacy in terminating status epilepticus. In addition to this search, we also assessed the studies mentioned in two systematic reviews7,188 and added additional studies that met our inclusion criteria.

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Glossary

Co-transporters

Transmembrane proteins that allow the coupled, simultaneous transport of multiple substances across the membrane.

Equilibrium potential

The electrical potential difference at which the flow of ions down their transmembrane concentration gradient is exactly balanced by the opposing potential difference across the membrane; at the equilibrium potential there is no net flux of ions.

Ionotropic receptor

A ligand-gated ion channel in which ligand binding results in transmembrane ion flux through the receptor’s pore.

Phasic inhibition

The fast activation of synaptic GABAA receptors following pre-synaptic release of GABA.

Resting membrane potential

The electrical potential difference across the cell membrane at rest (that is, when the cell is not receiving synaptic input or engaged in action potential firing).

Secondary active transport

The transport of chemical substances across a membrane (also known as co-transport), where the energy to move one substance against its concentration gradient is provided by the movement of another substance down its concentration gradient.

Shunting

A type of inhibition whereby activated GABAA receptors lower the local membrane resistance, which reduces (or ‘shunts’) the impact of concurrent excitatory synaptic inputs.

Tonic inhibition

The continuous activation of perisynaptic and extrasynaptic GABAA receptors owing to the presence of ambient GABA in the extracellular space, or spontaneous GABAA receptor openings.

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Burman, R.J., Rosch, R.E., Wilmshurst, J.M. et al. Why won’t it stop? The dynamics of benzodiazepine resistance in status epilepticus. Nat Rev Neurol 18, 428–441 (2022). https://doi.org/10.1038/s41582-022-00664-3

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