Neuroelectric Mechanisms of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage

Abstract

Delayed cerebral ischemia (DCI) remains a challenging but very important condition, because DCI is preventable and treatable for improving functional outcomes after aneurysmal subarachnoid hemorrhage (SAH). The pathologies underlying DCI are multifactorial. Classical approaches to DCI focus exclusively on preventing and treating the reduction of blood flow supply. However, recently, glutamate-mediated neuroelectric disruptions, such as excitotoxicity, cortical spreading depolarization and seizures, and epileptiform discharges, have been reported to occur in high frequencies in association with DCI development after SAH. Each of the neuroelectric disruptions can trigger the other, which augments metabolic demand. If increased metabolic demand exceeds the impaired blood supply, the mismatch leads to relative ischemia, resulting in DCI. The neuroelectric disruption also induces inverted vasoconstrictive neurovascular coupling in compromised brain tissues after SAH, causing DCI. Although glutamates and the receptors may play central roles in the development of excitotoxicity, cortical spreading ischemia and epileptic activity-related events, more studies are needed to clarify the pathophysiology and to develop novel therapeutic strategies for preventing or treating neuroelectric disruption-related DCI after SAH. This article reviews the recent advancement in research on neuroelectric disruption after SAH.

Keywords: cortical spreading depolarization; delayed cerebral ischemia; early brain injury; excitotoxicity; glutamate; inflammation; microcirculation; receptor; seizure; subarachnoid hemorrhage.

Figure 1

Glutamate release at the rupture of intracranial aneurysm. Released glutamate causes secondary brain injury.

Figure 2

Glutamate action via the receptors. In normal conditions, glutamate is a major excitatory neurotransmitter via the receptor. In pathological conditions, excessive glutamates activate the receptors excessively and cause epileptiform discharges, cortical spreading depolarization, and excitotoxicity, depending on the extent of the cell membrane depolarization. Each of the neuroelectric disruptions triggers the other. Surviving cells irrespective of these events achieve epileptogenicity.

Figure 3

Metabolic supply-demand mismatch hypothesis for delayed cerebral ischemia. When metabolic demand is increased due to depolarizing events such as cortical spreading depolarizations or epileptiform activities and exceeds the impaired blood supply (decreased blood supply or not sufficiently increased blood supply) due to large-vessel vasospasm or microcirculatory disturbance after subarachnoid hemorrhage, a mismatch in neuronal metabolism occurs, resulting in relative cerebral ischemia, that is, delayed cerebral ischemia.

Figure 4

A mechanism for cortical spreading depolarization or epileptiform discharges to cause delayed cerebral ischemia. In the compromised brain after subarachnoid hemorrhage, the neuroelectric disruption increases metabolic demand but decreases cerebral blood flow through inverse vasoconstrictive neurovascular coupling, leading to DCI.