The long-standing concept that seizures result from an imbalance between reduced γ-aminobutyric acid (GABA)-ergic inhibition and enhanced glutamatergic excitation [67, 68], based upon the presence of large amplitude EEG discharges during the seizure event itself, is an over-simplified of a very complex network response. While excessive glutamatergic excitation has historically been considered of as the precipitating factor for a focal seizure, there is a lack of strong data to support this hypothesis. Instead, paradoxically, accumulating evidence indicates that increased synchronised GABAergic interneuronal activity is sufficient to disrupt neuronal networks and initiate the transition from interictal to ictal activity resulting in focal seizures [69]. The recruitment of neighboring neurons and subsequent seizure progression is then hypothesized to be mediated by an elevation in extracellular potassium [70]. Adding to the complexity of network-based activity, both excitatory and inhibitory roles of GABA and glutamatergic neurons have been reported, and a range of extrasynaptic as well as synaptic neurotransmitter receptors and ion channels have been implicated in seizures, in addition to those traditionally implicated, such as NMDA and GABA A receptors [71].

However, strong evidence also implicates a role for inflammation in seizure pathologies [45]. Seizure activity readily induces an inflammatory response, including the activation of microglia and production of pro-inflammatory cytokines [47, 63]. More importantly, experimental data has suggested that inflammatory mediators may initiate or trigger early seizures, preceding the onset of diagnosed epilepsy. For example, systemic inflammation by injection of bacterial lipopolysaccharide results in a lowered seizure threshold [72]. In the next sections, we will review clinical and experimental evidence suggesting an inherent link between inflammatory signaling, neuropathology, and seizure activity in the injured brain, as a likely mechanism of importance in the development and progression of PTE.

Seizures increase inflammation

Experimentally, induction of a seizure induces the rapid activation of glial cells in surrounding parenchyma, which respond by the production and release of inflammatory molecules [73]. Much of the research that has shown an increase in inflammation after seizures have used experimental models of status epilepticus. This involves the administration of a chemical or electrical pro-convulsant stimulus to create a sustained seizure event (the initial insult) followed by a latency period before the onset of spontaneous recurrent seizures to model epilepsy [74, 75]. In these experimental models, the inflammatory response displays a distinct temporal profile after induction, characterized by the early activation of astrocytes and microglia followed by BBB breakdown and neuronal activation [63, 76, 77]. In addition to the investigation of protein release, microarray analysis of gene transcripts have also demonstrated an upregulation of inflammatory genes [78]. Specific cell surface toll-like receptors (TLR’s), which respond to a range of inflammatory cytokines and other stress-related factors, are highly upregulated after pilocarpine-induced seizures on forebrain microglia of adult mice [77]. Simultaneously, a robust increase in cytokine levels has been observed in both chemically and electrically induced experimental models of epilepsy in adult rodents [77, 79, 80]. For example, IL-1β is expressed at low levels in a healthy brain, but is robustly upregulated for up to 60 days after the induction of self-sustaining limbic status epilepticus in rodents, a model using hippocampal electrical stimulation [76]. TNF-α and IL-6 are also rapidly upregulated after status epilepticus, peaking within 30 min of seizure onset and remaining elevated for up to 72 h in rats that progressed to spontaneous seizures [76].

These experimental findings that seizures result in inflammation are confirmed by evidence in the clinical setting. Analysis of cerebrospinal fluid (CSF) from newly diagnosed adult patients with tonic-clonic seizures detected an upregulation of IL-6 and IL-1 receptors (IL-1Rs) [81, 82]. Matched serum samples revealed a higher levels of IL-6 compared to in the CSF, suggesting that these cytokines likely originated in the brain [82]. High levels of cytokines including IL-1β and high-mobility group box protein-1 (HMGB1) have also been identified in neurons and glia of surgically resected epileptic tissue [83]. Together, these findings indicate that neuroinflammation is a common consequence of seizure activity.

Inflammation contributing to seizures

Accumulating evidence suggests that neuroinflammation is also a contributor to epileptogenic pathology after TBI [45, 63, 84]. In particular, experimental models have demonstrated that glial cell activation and recruitment and the synthesis of inflammatory factors, may precede and/or occur concurrently with epileptogenic events [85, 86]. For example, in a rodent model of experimental TBI, a reduced threshold to electroconvulsive shock-induced seizures was reversed when minocycline, a tetracycline antibiotic known to inhibit brain infiltration of monocytes and microglia, was applied [87, 88], implicating both microglial activity and pro-inflammatory cytokines in post-traumatic seizure activity.

Much of the evidence for a role of inflammation in epileptogenesis has focused on the effect of cytokines in seizure susceptibility. Cytokines can act as classical neurotransmitters through receptor modulation and phosphorylation at the neuronal membrane [89]. Models of chronic inflammation, such as transgenic mice systemically overexpressing IL-6 or TNF-α, can reduce seizure threshold and predispose the brain to seizure induced-neuronal loss [90, 91]. Indeed, inflammatory signaling may promote the loss of GABAergic neurons in the hippocampus, resulting in an increased propensity for seizures due to a reduction in synaptic inhibition [92].

N-methyl-D-aspartate (NMDA) receptors play a critical role in the glutamatergic system to contribute to neuronal excitability, and previous evidence suggests both direct and indirect interactions between these receptors and cyokines [93]. Cytokines have been found to inhibit the uptake of glutamate by astrocytes in culture [94] and modulate excitatory neurotransmission in the brain through NMDA and alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propoinate (AMPA) receptors [95, 96]. For example, IL-1β produced by microglia can enhance NMDA-mediated Ca2+ currents through cell surface type 1 IL-1R (IL-1R1) co-localized on pyramidal cell dendrites [89]. Pre-synaptic NMDA receptors are agonists for Ca2+-mediated glutamate release, and when activated by inflammatory factors such as IL-1β and HMGB1 can cause an excess of intracellular Ca2+ leading to an extracellular hyperexcitability and excitotoxicity [95]. Several other cytokines including TNF-α and IL-10 have also been associated with the regulation of seizure duration in experimental kindling models [97, 98]. Though these correlations have been seen in multiple studies with different models, the mechanisms underlying the relationship between the inflammatory environment and epileptogenesis, particularly in the context of brain injury, remain still poorly understood.

There is limited clinical data to confirm a cause-and-effect link between inflammation and the pathophysiology of epilepsy, however increasing evidence supports this hypothesis. Many studies have now demonstrated that early exposure of the brain to immune responses can have varied and persistent consequences on adult physiology [99–102]. Febrile seizures (FS) and febrile status epilepticus in children is a risk factor for developing epilepsy later in life [103], which may be induced by fever often associated with inflammation and infection [47]. Although the mechanisms underlying FS remains unclear, it is thought that cytokines play a key role in its development [104]. One study has reported specific polymorphisms in the promoter region of cytokine genes, including IL-1β, in children with FS compared to controls [105]. Such genetic variation may influence the production of IL-1β in both healthy tissue and after injury or stimulus [106], and similar polymorphisms have also been observed at a high frequency in patients with TLE [107].

Recently, the hypothesis of glial functions playing a pivotal role in biasing the neuronal network towards an epileptogenic environment has been gaining traction [108, 109]. In particular, interactions between neurons, glia, and the inflammatory mediators IL-1β, HMGB-1, and TGF-β, have been implicated in promoting seizure susceptibility, as described below. The main signaling pathways implicated in the proposed link between inflammation and epileptogenesis of these three mediators is summarized in Fig. 2.