Why do steroids reduce cerebral edema?
Steroids are used a lot in medicine. They are prescribed to treat exacerbations of chronic obstructive pulmonary disease and asthma, as part of initiation and maintenance therapy of autoimmune diseases, and to treat airway swelling, gout, and many others. We also use steroids to treat cerebral edema related to brain tumors. But why do they work? Is it via their anti-inflammatory activity? As is often the case, the answer is “yes and no.”
The potential role of steroids in the treatment of cerebral edema emerged in 1955 when three neurosurgeons from the University of Michigan published a case series in the Journal of Neurosurgery. They reviewed 21 patients who had undergone resection of craniopharyngiomas. One of the known complications of this surgery is damage to the sella turcica and pituitary gland. Given this concern, the patients had received perioperative cortisone as a means of replacing endogenous corticosteroids. The neurosurgeons noticed that the patients who had received cortisone demonstrated improved post-operative outcomes, particularly the prevention of circulatory collapse. But there was one line in the paper that mentioned the possibility that cortisone improved outcomes by reducing postoperative cerebral edema. A seed was planted, though many questions remained.
A 1961 case series provided some clarity. The series reported on the outcomes of 14 patients with various types of brain tumors who were treated with dexamethasone. Prior to dexamethasone, the patients had severe symptoms including confusion, stupor, and coma as well as papilledema and other signs of elevated intracranial pressure. Within 48 hours of receiving dexamethasone, these patients saw a reversal of these ominous neurological signs. The most dramatic response occurred in a patient with glioblastoma who had been completely obtunded for six weeks. Twenty-four hours after receiving dexamethasone they woke up and started to speak and eat. This presumably resulted from a rapid decrease in edema and swelling around the tumor. What led to this remarkable response?
To understand why steroids were able to produce such a dramatic anti-edema effect it is important to delineate two distinct types of cerebral edema:
Vasogenic edema begins with the disruption of the brain-brain barrier, the layer of tightly bound endothelial cells that prevent stuff in the blood from accessing the brain. As long as the blood-brain barrier is intact, it protects the brain from an influx of excess fluid that would otherwise cause cerebral edema.
This barrier is created by tight junctions between endothelial cells. These tight junctions are known as zonulae occludentes and appear like staple points between cells when viewed three-dimensionally.
Brain tumors elicit an inflammatory response, which breaks up the tight junctions and causes gaps between endothelial cells. As a result, the typically impermeable blood-brain barrier becomes leaky. One way that steroids like dexamethasone reduce edema and vascular leakiness around tumors in the brain is through their anti-inflammatory effects. But that isn’t all that steroids do.
A 2003 study suggested another mechanism. Researchers took an immortalized rat endothelial cell line and created a monolayer in cell culture. They then exposed the endothelial cells to dexamethasone and tested the permeability of the monolayers. Surprisingly, the endothelial cells exposed to dexamethasone were significantly less permeable than at baseline. They were less leaky. And because a tissue culture plate is unlikely to be an inflammatory environment, the response to dexamethasone was felt to be something other than anti-inflammatory.
It appears that dexamethasone up-regulates tight junction proteins. That same 2003 rat endothelial study found that when the endothelial cells were exposed to dexamethasone they increased the expression of tight junction proteins, including ZO-1 and occludin. This implies that steroids reduce vasogenic edema by reinforcing the blood-brain barrier via tightening endothelial tight junctions – essentially making the tight junctions even tighter.
The other form of cerebral edema accompanies the death of cells and is called cytotoxic edema. While it is true that cell injury and death lead to an inflammatory response, there is a specific perturbation that occurs in the interstitium of the brain that leads to cytotoxic edema. Injury to cells including astrocytes leads to mitochondrial dysfunction. This metabolic disturbance depletes ATP, and without ATP cells cannot maintain intra and extracellular ion balance. In particular, the Na-K ATP pump cannot function. This causes Na and fluid to rush into cells. The influx of sodium and fluid into cells creates ionic gradients between the extracellular space and intravascular compartment. Sodium and fluid follow this gradient out of blood vessels and into the interstitium. This second step leads to extracellular cerebral edema, or so-called cytotoxic cerebral edema.
An intriguing study in rats found that treatment with dexamethasone decreased sodium flow into brain tissue after an ischemic injury, thereby decreasing cytotoxic edema. Despite this animal data, steroids are not used clinically for cytotoxic edema, such as with post-cardiac arrest cerebral edema, as they have failed to show positive effects on outcomes. We are left using dexamethasone for vasogenic edema. Fortunately, it works well in that context.
Take Home Points
- Dexamethasone has anti-edema effects for brain tumors.
- Dexamethasone leads to a decrease in vasogenic edema by decreasing capillary leak from the blood-brain barrier.
- The reduced capillary leak is accomplished by two main mechanisms: (a) anti-inflammatory effects; (b) upregulation of endothelial tight junction proteins.
- The impact of steroids on cytotoxic edema is less clear but do not appear to have clinical effects.
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Credits & Citation
◾️Episode written by Avi Cooper
◾️Show notes written by Avi Cooper and Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com
Cooper AZ, Abrams HR, Breu AC. Crossing a Barrier. The Curious Clinicians Podcast. March 22, 2023.
This episode is sponsored by BetterHelp! You can give online therapy a try at betterhelp.com/CLINICIANS.
Image credit: https://pubmed.ncbi.nlm.nih.gov/2554636/