Post Stroke Seizures and Epilepsy: From Proteases to Maladaptive Plasticity

Abstract

Post stroke epilepsy (PSE) is the most common cause of seizures in the elderly, yet its underlying mechanism is poorly understood. The classification of PSE is confusing, and there is neither a clear agreement on its incidence and prognosis nor a consensus about specific treatments. The diagnosis of PSE requires the occurrence of late seizures: epileptic events occurring 1 week or more after an ischemic stroke. Late seizures differ from early seizures by the presence of permanent structural changes in the brain. Those structural changes cause a shift in the regulation of neuronal firing and lead to circuit dysfunctions, and thus to a long-term epileptic condition. The coagulation cascade and some of its major components, serine proteases such as thrombin, are known to participate in the acute phase of a stroke. Recent discoveries found that thrombin and its protease-activated receptor 1 (PAR1), are involved in the development of maladaptive plasticity. Therefore, we suggest that thrombin and PAR1 may have a role in the development of PSE by inducing permanent structural changes after the ischemic events toward the development of epileptic focuses. We are confident that future studies will lead to a better understanding of the pathophysiology of PSE, as well as development of more directed therapies for its treatment.

Predictors of Pharmaco-Resistance in Patients with Post-Stroke Epilepsy

“…Sprouting of the synaptic connections between surviving deafferented neurons and the substantial remodeling of spared areas and pathways are crucial for recovery from brain damage. Nonetheless, post-stroke plasticity can also result in aberrant synaptogenesis [ 24 ]. The maladaptive organization of neuronal networks may suppress the endogenous seizure control system, generate synchronized neuronal circuits, and restrict ASMs from accessing neuronal targets, therefore leading to pharmaco-resistance [ 15 ].…”

Early Post-Stroke Seizures in Acute Ischemic Stroke

“…[ 29 ] Recent studies have revealed thrombin to be the major driving force not only for ES but also for LS by predisposing to maladaptive plasticity. [ 31 ]…”

Role of Thrombin in Central Nervous System Injury and Disease

“…Conversely, injured brain cells release neurotoxic thrombin [ 111 ]. Moreover, thrombin promotes maladaptive synaptic plasticity that may result in seizures [ 89 , 112 ]. Furthermore, thrombin is involved in intracerebral coagulation, as in the remainder of the body [ 113 ].…”

“…These factors trigger a positive feedback loop that promotes epilpetogenesis [ 217 ]. Stroke may also precipitate the development of post-stroke epilepsy by generating permanent structural changes from which an epileptic focus arises [ 112 ]. Additionally, thrombin has direct epileptogenic effects.…”