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Author Notes:

Dr. W. Löscher, Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany; wolfgang.loescher@tiho-hannover.de.

We thank Dr. Rai D’Ambrosio for critical reading of a prefinal version of the manuscript and Nick Pirolli for help with the references.

See publication for full list of disclosures.

Subjects:

Research Funding:

A.V., A.P., W.L., E.A., and M.C.W. acknowledge support from the European Union’s Seventh Framework Programme (FP7) under grant agreement 602102 (EPITARGET).

W.L. acknowledges support from the German Research Foundation (DFG, Bonn, Germany; grant # LO 274/1 - LO 274/16), the National Institutes of Health (NIH; Bethesda, MD, USA: grant R21 NS049592), and the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony in Germany.

R.D. receives research support from the NIH (grants U01 NS058158, R01NS097776 and R21 NS03364).

A.B.K. acknowledges NIH grants R01 NS051710 and R21 NS083057 and DOD grant W81XWH-11-1-0501.

J.E.Jr. acknowledges NIH grants NS002808, NS033310, NS042372, NS065877, NS071048, NS080181, NS100064, and a grant from the Resnick Family Foundation.

P.L.P. receives research support from the NIH (R01NS082286) and the SSADH Foundation.

D.B. acknowledges NIH grants R01 NS065957, R01 NS084920, R21 NS088024, and R01 NS061844. M.A.R. acknowledges NIH Grant U54 NS079202.

A.V. acknowledges grants from Citizen United for Epilepsy Research (CURE) and Fondazione Italiana Ricerca Epilessia-Associazione Italiana Contro l’ Epilessia (FIRE-AICE).

I.B. receives research support from European Union’s Seventh Framework Programme (FP7) under grant agreement 602531 (DESIRE).

C.S. acknowledges support from the DFG (grant # STE 552/3), Network of European Funding for Neuroscience Research (ERA-NET NEURO project BrIE), and European Commission Horizon 2020 Programme (H2020-MSCA-ITN EU-GliaPhD).

A.P. received research support from The Academy of Finland (Grant #273909 and #272249). M.C.W. acknowledges grants from the MRC (G0400136, G0802158, MR/L01095X/1) and the Wellcome Trust (#083163).

P.A.F. acknowledges funding by the NIH (KL2TR001432 from NCATS, R01NS097762 from NINDS).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences & Neurology
  • acquired epilepsy
  • antiepileptogenesis
  • CNS infections
  • epileptogenesis
  • status epilepticus
  • stroke
  • traumatic brain injury

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

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Journal Title:

Epilepsia

Volume:

Volume 59, Number 1

Publisher:

, Pages 37-66

Type of Work:

Article | Post-print: After Peer Review

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/PLCγ1 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.

Copyright information:

Wiley Periodicals, Inc. © 2017 International League Against Epilepsy

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