Journal
EPILEPSIA
Volume 59, Issue 1, Pages 37-66Publisher
WILEY
DOI: 10.1111/epi.13965
Keywords
acquired epilepsy; antiepileptogenesis; CNS infections; epileptogenesis; status epilepticus; stroke; traumatic brain injury
Categories
Funding
- European Union's Seventh Framework Program (FP7) [602531]
- German Research Foundation [LO 274/1-LO 274/16]
- National Institutes of Health [R21 NS049592, U01 NS058158, U54 NS083932, R01NS097776, R21 NS03364, R01 NS051710, R21 NS083057, W81XWH-11-1-0501, NS002808, NS033310, NS042372, NS065877, NS071048, NS080181, NS100064, R01NS082286, R01 NS065957, R01 NS084920, R21 NS088024, R01 NS061844, U54 NS079202]
- Niedersachsen-Research Network on Neuroinfectiology of the Ministry of Science and Culture of Lower Saxony in Germany
- Resnick Family Foundation
- Citizen United for Epilepsy Research (CURE)
- Fondazione Italiana Ricerca Epilessia-Associazione Italiana Contro l' Epilessia
- DFG [STE 552/3]
- Network of European Funding for Neuroscience Research
- European Commission Horizon Program
- Academy of Finland [273909, 272249]
- Medical Research Council [G0400136, G0802158, MR/L01095X/1]
- Wellcome Trust [083163]
- National Center for Advancing Translation Sciences [KL2TR001432, R01NS097762]
- Medical Research Council [MR/P025641/1, G116/147] Funding Source: researchfish
- Epilepsy Research UK [P1702] Funding Source: researchfish
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD090255] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [KL2TR001432, UL1TR001409] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS084920, R01NS051710, R01NS082286, R01NS097762, U54NS083932, R01NS033310, R01NS065877, R01NS061844, R01NS065957, U54NS079202, U01NS058158, R21NS088024, R01NS097776, U54NS100064] Funding Source: NIH RePORTER
- MRC [G0802158, MR/P025641/1, G0400136, G116/147, MR/L01095X/1] Funding Source: UKRI
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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/PLC1 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.
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