Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage

Abstract

A growing body of clinical literature emphasizes the impact of cerebral edema in early brain injury following aneurysmal subarachnoid hemorrhage (aSAH). Aneurysm rupture itself initiates global cerebral edema in up to two thirds of cases. Although cerebral edema is not a universal feature of aSAH, it portends a poor clinical course, with quantitative analysis revealing a direct correlation between cerebral edema and poor outcome, including mortality and cognitive deficits. Mechanistically, global cerebral edema has been linked to global ischemia at the time of aneurysm rupture, dysfunction of autoregulation, blood breakdown products, neuroinflammation, and hyponatremia/endocrine abnormalities. At a molecular level, several culprits have been identified, including aquaporin-4, matrix metalloproteinase-9, SUR1-TRPM4 cation channels, vascular endothelial growth factor, bradykinin, and others. Here, we review these cellular and molecular mechanisms of global cerebral edema formation in aSAH. Given the importance of edema to the outcome of patients with aSAH and its status as a highly modifiable pathological process, a better understanding of cerebral edema in aSAH promises to hasten the development of medical therapies to improve outcomes in this frequently devastating disease.

Keywords: Edema; Keywords; Subarachnoid hemorrhage.

Figure 1

Starling’s equation. Net fluid movement (Jv) results from differences in both hydrostatic (ΔP) and osmotic (Δπ) pressures. Although the differences in pressures drive fluid movement, the rate of flow is limited by the permeability of the capillary to each pressure type, K_H and K_O, for hydrostatic and osmotic pressure respectively. Starling’s original equation considered the K_H and the K_O terms to be identical, but modern studies of the blood-brain barrier suggest that these terms differ from each other and thus should be considered separately.^, In the healthy brain, the K_H term is very small, essentially allowing flow to be governed by the osmotic term. In the injured brain, values for both K_H and K_O are increased above baseline.

Figure 2

Schema of edema formation following aSAH. Transient ischemia due an abrupt rise in intracranial pressure caused by aSAH may lead to homeostatic failure of CNS cells, including neurons and astrocytes, resulting in cellular (cytotoxic) edema. The resulting depletion of ions and water from the interstitial space leads to secondary transcapillary flow of ions and water from the vascular compartment, resulting in interstitial ionic edema despite an intact blood brain barrier. A variety of post-hemorrhagic environmental factors can lead to failure of the blood-brain barrier with late formation of vasogenic edema, including inflammation-mediated endothelial cell apoptosis, as well as destruction of membrane components of the blood-brain barrier secondary to proteolytic activity of MMP-9.