Abstract
The development of epilepsy, a process known as epileptogenesis, often occurs later in life following a prenatal or early postnatal insult such as cerebral ischemia, stroke, brain trauma, or infection. These insults share common pathophysiological pathways involving innate immune activation including neuroinflammation, which is proposed to play a critical role in epileptogenesis. This review provides a comprehensive overview of the latest preclinical evidence demonstrating that early life immune challenges influence neuronal hyperexcitability and predispose an individual to later life epilepsy. Here, we consider the range of brain insults that may promote the onset of chronic recurrent spontaneous seizures at adulthood, spanning intrauterine insults (e.g. maternal immune activation), perinatal injuries (e.g. hypoxic–ischemic injury, perinatal stroke), and insults sustained during early postnatal life—such as fever-induced febrile seizures, traumatic brain injuries, infections, and environmental stressors. Importantly, all of these insults represent, to some extent, an immune challenge, triggering innate immune activation and implicating both central and systemic inflammation as drivers of epileptogenesis. Increasing evidence suggests that pro-inflammatory cytokines such as interleukin-1 and subsequent signaling pathways are important mediators of seizure onset and recurrence, as well as neuronal network plasticity changes in this context. Our current understanding of how early life immune challenges prime microglia and astrocytes will be explored, as well as how developmental age is a critical determinant of seizure susceptibility. Finally, we will consider the paradoxical phenomenon of preconditioning, whereby these same insults may conversely provide neuroprotection. Together, an improved appreciation of the neuroinflammatory mechanisms underlying the long-term epilepsy risk following early life insults may provide insight into opportunities to develop novel immunological anti-epileptogenic therapeutic strategies.
Highlights
Epilepsy may develop later in life following a prenatal or early postnatal insult such as cerebral ischemia, stroke, brain trauma, or infection
Early life insults that have been associated with the subsequent development of epilepsy share common pathophysiological pathways involving innate immune activation, including neuroinflammation, which is proposed to play a critical role in epileptogenesis (Vezzani et al, 2011a; Becker, 2018)
We will consider the most common early life insults linked to the development of epilepsy later in life— including prenatal immune activation, perinatal injuries, and immune challenges sustained during early postnatal life (Figure 1)
Summary
Epilepsy may develop later in life following a prenatal or early postnatal insult such as cerebral ischemia, stroke, brain trauma, or infection These so-called “acquired epilepsies” account for approximately one-third of all human epilepsies (Engel, 1996; Thomas and Berkovic, 2014), and present clinically after a latent period of variable length (months to years) following the precipitating insult. Early life insults that have been associated with the subsequent development of epilepsy share common pathophysiological pathways involving innate immune activation, including neuroinflammation, which is proposed to play a critical role in epileptogenesis (Vezzani et al, 2011a; Becker, 2018). We will consider the most common early life insults linked to the development of epilepsy later in life— including prenatal immune activation, perinatal injuries, and immune challenges sustained during early postnatal life (such as infections, neurotrauma, and even seizures themselves) (Figure 1). Such an understanding is necessary to inform the development and appropriate application of novel therapeutic agents targeting the relevant biological mechanisms, with the goal of disrupting and preventing the epileptogenic process from occurring
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