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

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.

Keywords: CNS infections; acquired epilepsy; antiepileptogenesis; epileptogenesis; status epilepticus; stroke; traumatic brain injury.

Fig. 1. Epileptogenic processes and risk factors involved in development of epilepsy after acute brain insults: a conceptual view

Possibly depending on crucial modifiers or risk factors, the same brain injury can be epileptogenic or not. In the majority of patients, brain insults do not cause epilepsy as discussed in the text. Furthermore, as illustrated in the figure, not all epileptogenic processes, once initiated, result in epilepsy, i.e. complete their course to clinically obvious disease. The term epileptogenesis includes processes that render the brain susceptible to spontaneous recurrent seizures and processes that intensify seizures and make them more refractory to therapy (progression). During epileptogenesis, multiple brain alterations occur, including altered excitability of neurons and/or neuronal circuits, activation of microglia, astrocyte dysfunction, alterations in expression and function of receptors and ion channels (in part recapitulating ontogenesis), loss of neurons, neurogenesis, axonal and dendritic sprouting, gliosis, inflammatory processes, and more. It is important to note that some of these alterations may be related to post-injury repair or recovery and not suited as targets to halt the epileptogenic process. The figure has been modified from previous versions.^,,

Fig. 2. Common patterns of astrogliosis in epileptic human brain tissue

A: Reactive astrogliosis in the neocortex of human epilepsy surgery brain specimens is commonly seen along cortical capillaries (arrow). B: In white matter, there is another common pattern of astrogliosis built by a dense glial fibrillary meshwork. The arrow points towards an enlarged venous vessel. Scale bar in A = 100 μm, in B = 200 μm. GFAP immunohistochemistry (brownish color) with bluish hematoxylin counterstaining.

Fig. 3. Common patterns of heterotopic neurons in the white matter of epileptic human brain tissue

A: The white matter of human temporal lobe usually contains only single heterotopic neurons. B: In many epilepsy specimens of human temporal lobe, there is a vast excess of heterotopic neurons with ramifying neuronal processes in white matter. Scale bar in A and B = 200 μm. MAP2 immunohistochemistry (brownish color) with bluish hematoxylin counterstaining.

Fig. 4. Schematic illustrating components of the limbic (A) and thalamocortical (B) seizure circuits

Areas impacted by particular epileptogenic insults (both classic and newer models of acquired epilepsy) are noted near particular network nodes. Arrows indicate interconnections between the nodes. Due to the distributed nature of these circuits, many sites may trigger, lead, or participate in seizure activity.^,

Fig. 5. Word clouds summarizing altered biological processes in the hippocampus in experimental models of structural epilepsies and in human drug-refractory temporal lobe epilepsy (TLE)

The analysis included (A) genome-wide (GW) changes in gene expression and (B) predicted targets of regulated miRNAs. Studies included in the analysis are listed in Supplementary Tables 2 and 3. Biological functions/processes were collected from the gene ontology (GO) or pathway analyses performed in each study. The data was organized to align with different phases of epileptogenic process (acute post-injury time point, latency phase, and epilepsy phase). Word clouds were generated using Wordcloud for R Package. For the sake of clarity, the words: ‘regulation’, ‘cell’, ‘cells’, ‘process’ and stop words (‘English’) were removed from the figures. All other words presented in original articles were included (minimum frequency=1). Larger the word font size in the cloud, more often the word appeared e.g. in the DAVID or IPA^® analyses. Note that there were differences in the original analyses, for example, in the terminology used to name different classes of biological functions and use of cut-off p-values (e.g., analyses performed by DAVID or IPA^®). Also, the word cloud generated from the human data in panel B is not unbiased (asterisk) as it was extracted from the text (no pathway or GO analysis was presented by authors). Major differences between models were observed, especially when predicted miRNA-target regulated processes were compared (B). SE models appeared more similar with each other than with TBI.

Fig. 6. Pathophysiological immune/inflammatory sequelae triggered by various acute brain injuries

Rapid activation of brain resident innate immunity cells at the site of injury and BBB functional and structural alterations result in the generation of the inflammatory cascade in seizure-prone brain areas. Leukocytes may contribute to perpetuate the inflammatory cascade following interactions with the brain vasculature. The time-locked sequence of these events likely depends on the type of injury. Inflammatory mediators can promote brain damage and dysfunction or contribute to tissue repair depending on their levels and persistence. If the inflammatory milieu exceeds the homeostatic threshold it may lead to hyperexcitability, decrease seizure threshold and promote neuropathology thereby contributing to disease progression. These pathologic events depend on the ability of inflammatory molecules such as cytokines, DAMPs and prostaglandins to alter expression and function of gap junctions, voltage-gated or receptor-coupled ion channels thus contributing to acquired channelopathies, to modify GABA and glutamate release and re-uptake^,, and to alter BBB permeability. BBB dysfunction results in albumin extravasation which compromises homeostatic astrocytic functions and induces excitatory synaptogenesis by activating the TGF-β/ALK5 signaling.^,,

Fig. 7. Signaling pathway commonalities

Epileptogenic brain injuries, including TBI, stroke, and SE, increase levels of growth factors, cytokines and hormones that activate the (A) JAK/STAT, IL-1R1/TLR4 and mTORC1 signaling and (B) BDNF/trkB/PLCγ signaling pathways resulting in altered expression of genes and proteins involved in cell growth, cell survival, cell proliferation, neurotransmission, learning and memory, potentially contributing to epileptogenesis and cognitive co-morbidities.