Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

Klein P, Dingledine R, Aronica E, Bernard C, Blümcke I, Boison D, Brodie MJ, Brooks-Kayal AR, Engel J, Forcelli PA, Hirsch LJ, Kaminski RM, Klitgaard H, Kobow K, Lowenstein DH, Pearl PL, Pitkanen A, Puhakka N, Rogawski MA, Schmidt D, Sillanpaa M, Sloviter RS, Steinhaeuser C, Vezzani A, Walker MC, Loescher W (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 59

Pages Range: 37-66

Journal Issue: 1

DOI: 10.1111/epi.13965

Abstract

The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post-status epilepticus models of focal epilepsy by transient treatment with a trkB/PLC?1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.

Authors with CRIS profile

Involved external institutions

Stiftung Tierärztliche Hochschule Hannover (TiHo) Germany (DE) Morehouse School of Medicine United States (USA) (US) University of Turku / Turun yliopisto Finland (FI) Epilepsie-Zentrum Berlin-Brandenburg / Institut für Diagnostik der Epilepsien gGmbH (IDE) Germany (DE) University of California Davis (UCDAVIS) United States (USA) (US) University of Eastern Finland Finland (FI) Harvard University United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US) UCB Pharma Ltd United Kingdom (GB) Yale University United States (USA) (US) Georgetown University United States (USA) (US) University of California Los Angeles (UCLA) United States (USA) (US) University of Colorado System United States (USA) (US) NHS Greater Glasgow and Clyde United Kingdom (GB) Robert S. Dow Neurobiology Laboratories United States (USA) (US) Aix-Marseille University / Aix-Marseille Université France (FR) University of Amsterdam Netherlands (NL) Emory University United States (USA) (US) Mid-Atlantic Epilepsy and Sleep Center United States (USA) (US) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) University College London (UCL) United Kingdom (GB) Mario Negri Institute for Pharmacological Research (IRCCS) / Istituto di Ricerche Farmacologiche Mario Negri Italy (IT)

How to cite

APA:

Klein, P., Dingledine, R., Aronica, E., Bernard, C., Blümcke, I., Boison, D.,... Loescher, W. (2018). Commonalities in epileptogenic processes from different acute brain insults: Do they translate? Epilepsia, 59(1), 37-66. https://dx.doi.org/10.1111/epi.13965

MLA:

Klein, Pavel, et al. "Commonalities in epileptogenic processes from different acute brain insults: Do they translate?" Epilepsia 59.1 (2018): 37-66.

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