The cumulative impact of seizures: the science underlying how seizures beget seizures

Seizures are symptoms of epilepsy but spontaneous seizure recurrence can also be considered a biomarker of disease progression. The temporary imbalance between excitatory and inhibitory drive that culminates in a hyperexcitable, hypersynchronous state clinically observed as seizure, initiates an insidious cascade of neurochemical, structural, genetic, epigenetic, and neuroinflammatory processes that increases seizure frequency, duration, and severity. As seizure activity increases, the hyperexcitable and hypersynchronous states entrain neuronal networks, leading to a further reduction in seizure threshold and further increases in seizure frequency, duration, and severity over time. The pathological circuitry generated and sustained by epileptic events not only drive hyperexcitable states within the seizure circuit but also can affect wider network connections. These effects lead to altered network physiology, which is associated with neuropsychiatric comorbidities, such as cognitive decline and psychiatric disorders, and can impact the operation of other organ systems. Here, we review the current understanding of how seizures can hijack normal brain function and set off a cascade of pathobiological events that support continued seizure activity and epilepsy progression. Understanding the neurobiology of seizure progression is fundamental to building comprehensive treatment strategies and developing new pharmacotherapies that aim to retrain seizure circuitry, with the goal of reducing overall seizure burden, improving quality of life, and limiting disease progression.