Commonalities in epileptogenic processes from different acute brain insults

Do they translate?

Pavel Klein, Raymond Dingledine, Eleonora Aronica, Christophe Bernard, Ingmar Blümcke, Detlev Boison, Martin J. Brodie, Amy R. Brooks-Kayal, Jerome Engel, Patrick A. Forcelli, Lawrence J. Hirsch, Rafal M. Kaminski, Henrik Klitgaard, Katja Kobow, Daniel H. Lowenstein, Phillip L. Pearl, Asla Pitkänen, Noora Puhakka, Michael A Rogawski, Dieter Schmidt & 6 others Matti Sillanpää, Robert S. Sloviter, Christian Steinhäuser, Annamaria Vezzani, Matthew C. Walker, Wolfgang Löscher

Research output: Contribution to journalReview article

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)37-66
Number of pages30
JournalEpilepsia
Volume59
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Epilepsy
Brain
Animal Models
Multiple Trauma
Neurons
Wounds and Injuries
Seizures
HMGB1 Protein
Percussion
Topical Administration
Central Nervous System Infections
Losartan
Partial Epilepsy
Temporal Lobe Epilepsy
Gap Junctions
Isoflurane
Therapeutics
Blood-Brain Barrier
Astrocytes
Adenosine

Keywords

  • acquired epilepsy
  • antiepileptogenesis
  • CNS infections
  • epileptogenesis
  • status epilepticus
  • stroke
  • traumatic brain injury

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

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

Commonalities in epileptogenic processes from different acute brain insults : Do they translate? / Klein, Pavel; Dingledine, Raymond; Aronica, Eleonora; Bernard, Christophe; Blümcke, Ingmar; Boison, Detlev; Brodie, Martin J.; Brooks-Kayal, Amy R.; Engel, Jerome; Forcelli, Patrick A.; Hirsch, Lawrence J.; Kaminski, Rafal M.; Klitgaard, Henrik; Kobow, Katja; Lowenstein, Daniel H.; Pearl, Phillip L.; Pitkänen, Asla; Puhakka, Noora; Rogawski, Michael A; Schmidt, Dieter; Sillanpää, Matti; Sloviter, Robert S.; Steinhäuser, Christian; Vezzani, Annamaria; Walker, Matthew C.; Löscher, Wolfgang.

In: Epilepsia, Vol. 59, No. 1, 01.01.2018, p. 37-66.

Research output: Contribution to journalReview article

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, Pitkänen, A, Puhakka, N, Rogawski, MA, Schmidt, D, Sillanpää, M, Sloviter, RS, Steinhäuser, C, Vezzani, A, Walker, MC & Löscher, W 2018, 'Commonalities in epileptogenic processes from different acute brain insults: Do they translate?', Epilepsia, vol. 59, no. 1, pp. 37-66. https://doi.org/10.1111/epi.13965
Klein P, Dingledine R, Aronica E, Bernard C, Blümcke I, Boison D et al. Commonalities in epileptogenic processes from different acute brain insults: Do they translate? Epilepsia. 2018 Jan 1;59(1):37-66. https://doi.org/10.1111/epi.13965
Klein, Pavel ; Dingledine, Raymond ; Aronica, Eleonora ; Bernard, Christophe ; Blümcke, Ingmar ; Boison, Detlev ; Brodie, Martin J. ; Brooks-Kayal, Amy R. ; Engel, Jerome ; Forcelli, Patrick A. ; Hirsch, Lawrence J. ; Kaminski, Rafal M. ; Klitgaard, Henrik ; Kobow, Katja ; Lowenstein, Daniel H. ; Pearl, Phillip L. ; Pitkänen, Asla ; Puhakka, Noora ; Rogawski, Michael A ; Schmidt, Dieter ; Sillanpää, Matti ; Sloviter, Robert S. ; Steinhäuser, Christian ; Vezzani, Annamaria ; Walker, Matthew C. ; Löscher, Wolfgang. / Commonalities in epileptogenic processes from different acute brain insults : Do they translate?. In: Epilepsia. 2018 ; Vol. 59, No. 1. pp. 37-66.
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