out in these cases.
Does inflammation cause cell loss?
Available studies suggest that seizure-related or injury-related inflammation might contribute to cell loss and synaptic reorganization, which are important mediators of the development of hyperexcitable circuits that lead to epilepsy after insults such as status epilepticus or TBI in the adult rodent brain (Bartfai and Schultzberg, 1993; Buckmaster and Dudek, 1997; Pitkanen and Sutula, 2002). Inflammation is induced rapidly following such insults, preceding neurodegeneration in lesional models of seizures (Rizzi et al., 2003; Ravizza and Vezzani, 2006). This finding is consistent with the idea that inflammation augments cell death, which is further supported by data from studies involving injection of inflammatory mediators together with excitotoxic stimuli (Allan et al., 2005). Activation of microglia and astrocytes and production of cytokines and PGE2 can occur in seizure models where cell loss is not detected in immature or adult rodents (Vezzani et al., 1999, 2000a; Rizzi et al., 2003; Kovacs et al., 2006; Dube et al., 2010). Such observations suggest that rather than being a consequence of cell loss, seizure-induced brain inflammation can contribute to cell death (Vezzani and Baram, 2007). Additional interactions between inflammation and cell death in the context of epilepsy have been observed. Brain injury, such as TBI, causes tissue inflammation that seems to contribute to both cell death and long-term hyperexcitability (Clausen et al., 2009; Longhi et al., 2009). In the context of CNS injury (for example, in chronic neurodegenerative diseases or acute stroke), inflammation can have a neuroprotective role (Liesz et al., 2009; Schwartz and Shechter, 2010). Indeed, whether micro-glia, macrophages and/or T cells are destructive or neuroprotective seems to depend on their activation status, which is orchestrated by the specific inflammatory environment (Rothwell, 1989; Schwartz and Shechter, 2010). This balance, together with the specific brain regions in which inflammation develops, might account for the relatively low incidence of seizures in other neurological disorders associated with brain inflammation (Vezzani et al., 2013).
Mechanistic insights
Several established and novel mechanisms could mediate the effects of inflammatory mediators on neuronal excitability and epilepsy. Some of these mechanisms could be involved in the precipitation and recurrence of seizures, while others are implicated in the development of epileptogenesis (Vezzani and Baram, 2007). These mechanisms constitute potential molecular targets for drug design, and are briefly summarized here. As discussed above, IL-1β and HMGB1 activate convergent signalling cascade through binding to IL-1R1 and TLR4, respectively (Akira et al., 2001; Perkins, 2007; Hoebe and Beutler, 2008). The downstream pathways activated by these ligands converge with the TNF pathways at the transcription factor NFκB, which regulates the synthesis of chemokines, cytokines, enzymes (for example, COX-2) and receptors (for example, TLRs, IL-1R1, and TNF p55 and p75 receptors) (Gilmore, 2006). This transcriptional pathway modulates the expression of genes involved in neurogenesis, cell death and survival, and in synaptic molecular reorganization and plasticity (processes that occur concomitantly with epileptogenesis in experimental models) (Buckmaster and Dudek, 1997; Pitkanen and Lukasiuk, 2009).
Immune and anti-inflammatory therapies
If immune mechanisms and inflammation do indeed have a role in the generation of seizures, immune-modulating and anti-inflammatory therapies might be effective treatments for some or all forms of epilepsy. Therapies such as ACTH, corticosteroids, plasmapheresis and intravenous immunoglobulin (IVIg) have been employed to treat seizures and/or epilepsy, with varying success. These therapies have all been employed in human patients with presumed autoimmune limbic encephalitis, where early and aggressive treatment often seems to be useful (Vincent et al., 2010).
The presumed mechanism of action of the therapeutic agents listed above is suppression of inflammation; however, other modes of action might also be involved, including direct effects on brain excitability, and suppression of endogenous proconvulsant brain agents (Baram and Hatalski, 1998; Joels and Baram, 2009).
The use of steroids in various forms is common for more severe, treatment-resistant forms of childhood epilepsy. ACTH, steroids and IVIg have all been employed to treat AEM-unresponsive paediatric epilepsies, difficult focal (partial) epilepsies and myoclonic epilepsies (You et al., 2008). Unfortunately, determination of whether patients received benefit from these treatments is problematic, since most of these epilepsies are extremely heterogeneous in aetiology and severity, and exhibit notoriously variable courses. In addition, most of the clinical studies are retrospective case series, with occasional prospective case series that lack controls (Mikati et al., 2002; Verhelst et al., 2005).
Follow-up duration in these case series was also often variable. A recent review of investigations of IVIg in intractable childhood epilepsy found no randomized or controlled studies and, in fact, only two case series employed statistics in assessing outcome (Mikati et al., 2010). One series showed a statistically significant reduction in seizures with IVIg treatments, while the other revealed an insignificant trend with such therapy (Mikati et al., 2010). However, a Cochrane Collaboration review on the use of ACTH for other childhood epilepsies, published in 2007, found only a single randomized controlled trial, which only included five patients (Gayatri et al., 2007). The authors of this review concluded that, at present, no evidence exists to support either the safety or the efficacy of ACTH for general paediatric epilepsies (Gayatri et al., 2007).
Disorders of Neuronal Migration and Seizures
The major developmental disorders noted in humans giving rise to epilepsy are disorders of neuronal migration that may have genetic or intrauterine causes (Engelborghs et al., 2000). Abnormal patterns of neuronal migration lead to various forms of agyria or pachygyria whereas lesser degrees of failure of neuronal migration induce neuronal heterotopia in the subcortical white matter. Experimental data suggest that cortical malformations can both form epileptogenic foci and alter brain development such that diffuse hyperexcitability of the cortical network occurs (Chevassusau-Louis et al., 1999). Other studies revealed increases in postsynaptic glutamate receptors and decreases in GABAA receptors in micro-gyric cortex, which could promote epileptogenesis (Jacobs et al., 1999).
Periventricular heterotopia is a human X-linked dominant disorder of cerebral cortical development. Mutations in the filamin 1 gene prevent migration of cerebral cortical neurons causing periventricular heterotopia (Fox et al., 1998). Affected females present with epilepsy whereas affected males die embryonically.
Lissencephaly is a brain malformation characterized by a paucity of gyral formation and a thickening of the cerebral cortex. It is presumed to occur secondary to incomplete migration of immature neurons to the cortical plate during fetal development (Saito et al., 2002). Lissencephaly is considered to be the most severe type of neuronal migration disorder compatible with survival. In humans, it is presumed to result from an arrest of neuronal migration at approximately 3 to 4 months (Dobyns et al., 1993). Once they exit the cell cycle in the periventricular proliferative zone, immature neurons must migrate to the cortical plate along radial glial fibres (Rakic, 1988). The six layers of the cerebral cortex are formed in an ‘inside out’ pattern, with early migrating neurons forming the deep layer and later migrating neurons passing their migratory predecessors to form the superficial layers. Interruption at any stage of the process of neuronal migration may result in the arrest of neurons in an intermediate position between the periventricular zone and the cortex (Saito et al., 2002). Such an interruption may be due to a genetic lack of appropriate molecular cues, or secondary to non-genetic influences such as in utero infection or ischaemia. Secondary influences are a more common mechanism for the related cortical malformation, polymicrogyria.
In
