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Victor et al. Neuroimmunol Neuroinflammation 2020;7:234-47 I http://dx.doi.org/10.20517/2347-8659.2020.02 Page 235

neurogenesis. Following seizures, microglia are activated, functioning as resident macrophages of the brain
[2]
and respond quickly to injury while trying to maintain the physiological processes under its control .
Changes in neuronal homeostasis are also observed, highlighting the diverse ways in which microglia could
be contributing to the development of epilepsy.

This review will discuss the roles of microglia in neuroinflammation and neurogenesis, and how these
contributions are altered post-seizure. We will examine microglia in the context of epileptogenesis, the
process by which “the previously normal brain is functionally altered and biased towards the generation
[3]
of abnormal electrical activity that subserves chronic seizures” . Additionally, we will explore studies of
pharmacological reagents and their effects on microglia as a therapeutic target to mitigate the epileptogenic
process that drives epilepsy.

EPILEPSY
Epilepsy is a chronic brain disorder characterized by abnormal brain activity that causes seizures. The
[4]
propensity to generate recurrent seizure events has neuropathological, cognitive, and social consequences .
Epileptic seizures are aberrant, excessive, or synchronous neuronal discharges and manifest in a variety
of ways. According to the International League Against Epilepsy (ILAE), seizures are classified into three
types based on their onset: generalized onset seizures do not have a determined area of origin and can
affect both sides of the brain; focal onset seizures originate from one area of the brain; and unknown onset
seizure when the onset is missed or obscured. Generalized onset seizures can present with a variety of
manifestations that include non-motor and motor presentations: they range from absence seizures (that
present with lapses in awareness, accompanied with staring into space, probably accompanied by rapid
blinking and/or orofacial automatisms) to generalized tonic-clonic seizures with tonic and/or clonic
spasms, and are always accompanied by loss of consciousness. Focal onset seizures may or may not be
accompanied by a loss of awareness and their origin can be attributed to a specific area of the brain that
causes motor or sensory changes, including taste or smell. Focal seizures may also result in a loss of
awareness, manifested by a person who appears to be dazed, confused, and unable to respond to questions
for several minutes. Focal seizures may become generalized if the original behavior, which was localized
[5]
to one brain hemisphere, expands to behaviors that involve both sides of the brain . The cause of epilepsy
in many patients is not known, though acquired causes include stroke, traumatic brain injury (TBI),
autoimmune disorders, infection, and tumors.

[6]
It is estimated that almost 10% of people will experience a seizure in their lifetime . Epilepsy affects
[7]
approximately 1.2% of the population in the United States alone . Higher incidence rates have been
reported in younger (early childhood and infancy) and older age groups (older than 55 years of age),
[8]
while a lower prevalence is seen in the period between early adulthood and midlife . The imbalance
between excitatory and inhibitory neurotransmission (E/I imbalance), with a propensity towards increased
excitation, is believed to be the underlying cause of seizures in epilepsy. Research demonstrates hyper-
excitability during ictogenesis, when excitatory glutamatergic activity is increased while inhibitory gamma
aminobutyric acid (GABA) ergic activity is dampened [9-11] . Currently, the treatment of epilepsy varies
from patient to patient. Anti-seizure medications are typically the first choice of therapy for subsequent
seizure prevention. When medication fails, surgery has been successful in significantly decreasing or
making patients seizure free, though only a small number of patients with focal onset seizures would
[12]
qualify for surgical options . When surgery is not an option, patients are treated with antiepileptic drugs
(AEDs). There have been > 30 medicines that have been approved by the United States Food and Drug
Administration (FDA) or the European Medicines Agency (EMA). Even though many seizure medication
options exist, nearly 33% of patients fail to respond to them . Some patients with pharmacologically
[13]
refractory epilepsy try to control seizures by exploring dietary changes, such as employing the ketogenic
diet, a high fat/low carbohydrate diet which can be successful in reducing seizures in about 50% of adult