Cytotoxic and Vasogenic Brain Edema

Introduction

Cerebral edema is a buildup of fluid in the brain. It occurs after brain ischemia and different types of cerebral hemorrhage, as well as other conditions such as traumatic brain injury and brain neoplasms. It is a major clinical issue. Because of the encasing skull, cerebral edema can cause increased intracranial pressure (ICP), reduced cerebral blood flow, brain herniation and death. Swelling of parenchymal cells can also disrupt the physical architecture of the brain and reduce the size of the brain extracellular space. This review examines normal fluid flow in the brain, mechanisms that cause brain edema (focusing on cerebral ischemia and hemorrhage), current methods of treatment and future potential directions.

Normal Fluid Movement in the Brain

An understanding of brain edema requires knowledge of normal fluid movement in the brain to elucidate how it becomes deranged in disease states. Broadly, fluid movement in the body follows hydrostatic or osmotic gradients. Thus, for example, in peripheral capillaries, a pressure gradient between the vasculature and tissue interstitial fluid drives fluid into the tissue; an osmotic (oncotic) pressure, due to plasma proteins, moves water from tissue to blood; and the difference in fluid movement between these two processes is drained by the lymphatic system. In other tissues involved in fluid handling, ion transport drive water fluxes (e.g., kidney) by creating an osmotic gradient. Tissues that are involved in fluid handling also express aquaporins (AQPs), water channels that facilitate water movement down such osmotic gradients.

In brain, the general consensus has been that most of the bulk flow of fluid occurs at the choroid plexuses in the cerebral ventricles [cerebrospinal fluid (CSF) production], as the result of vectoral ion transport . A portion of the fluid (∼30%) production is thought to occur across the blood–brain barrier (BBB), at the cerebral microvasculature, also linked to ion transport . Unlike peripheral capillaries, the cerebral endothelium forms a tight barrier as the cells are linked by tight junctions (TJs). This greatly limits hydrostatically driven water flow . Some water is also generated in the brain as a by-product of metabolism. Fluid from the BBB/brain is thought to drain into the CSF system. CSF is absorbed into blood or the systemic lymphatic system from the subarachnoid CSF space at sites including the arachnoid villi, the cribriform plate, and the spinal nerve roots space, with the brain lacking an intrinsic lymphatic system .

However, there are some current controversies . Questions have been raised over whether the choroid plexuses are the main site of CSF secretion, although the preponderance of data favors that they are . There have also been questions over whether the brain has a lymphatic system. It has been proposed that there are lymph vessels in the dura mater over the brain and that there is a brain glymphatic system . In the latter, fluid enters the brain in the periarterial spaces, moves into brain parenchyma through AQP4 channels on astrocyte end feet, and exits the brain via the perivascular space around the venous system . Such a glymphatic system would important implications (e.g., for the clearance of waste products from brain), but more work is needed to prove the hypothesis .

The glymphatic hypothesis places astrocytic end feet AQP4 with a central role in regulating brain fluid flow. In addition to being present on astrocyte end feet, AQP4 is highly expressed on the cells of the glia limitans and the ependyma, sites at the brain/CSF interface, and AQP4 may have a role in controlling fluid movements at those sites . It should be noted that the presence of an AQP in a cell may alter the rate at which it comes in osmotic equilibrium after ion shifts. It may, therefore, regulate cell and extracellular space volume and thus have important consequences for interstitial fluid flow. Apart from AQP4, AQP1 is also present in brain at the apical membrane of the choroid plexus epithelium where it is thought to participate in CSF secretion .

Under normal conditions there is no net movement of fluid into and out of brain, although rapid fluctuations occur related to the cardiac cycle and respiration. In contrast, with ischemic and hemorrhagic stroke, fluid influx exceeds efflux and edema results.

Cerebral Edema