Overview and Historical Background

Cerebral edema represents the accumulation of excess fluid in the intracellular or extracellular spaces of the brain. It can result from a variety of physiologic and pathologic processes and is frequently responsible for much of the morbidity and mortality associated with brain tumors and a variety of other disorders, including trauma, hemorrhage, and infection. A basic conception of the barriers that exist between and among blood, cerebrospinal fluid (CSF), and the brain is required to fully understand cerebral or brain edema. In this chapter we briefly outline the physiology of the blood-brain barrier (BBB) and describe and discuss the principal types and causes of cerebral edema. Several reviews that outline the history of research in this field and recent advances in this area and that provide more detailed summaries beyond the scope of this chapter are cited in the reference section.

Paul Ehrlich was the first to identify a potential barrier between the vasculature and the brain after he observed that intravenous albumin-bound dyes stained all tissues except the brain.¹ Goldmann carried Ehrlich’s studies further to demonstrate that dye injected into CSF did not circulate in the systemic circulation.² These barriers (Table 9-1), which are rate-limiting steps in the movement of water, ions, solutes, and macromolecules between compartments, help the brain regulate its own environment distinct from the rest of the body. The BBB is an essential component of brain homeostasis.

TABLE 9-1 Principal Features of the Blood-Brain Neurovascular Unit

ATP, adenosine triphosphate; ATPase, adenosine triphosphatase.

The Blood-Brain Barrier

The principal component of the BBB is the endothelial cells that line the cerebral microvasculature (Fig. 9-1).^3–10 The tight junctions between adjacent endothelial cells in the brain, which are nonpermissive in comparison to those in the systemic circulation, prevent the paracellular transport of most molecules. Although small substances, such as oxygen and carbon dioxide, and small lipophilic molecules, such as ethanol, may diffuse freely through the lipid membranes that constitute the BBB, larger, bulkier, more complex or hydrophilic molecules require active, transcellular transport mechanisms, potentially on both the luminal (endothelial) and abluminal (brain) membranes, to enter the brain.¹¹ The active transport mechanisms require energy in the form of adenosine triphosphate (ATP).¹¹

FIGURE 9-1 Microscopic representations of the blood-brain barrier (BBB) and the two most common forms of cerebral edema. A, The BBB is created by compact apposition of endothelial cells to create a barrier between the vascular system and the brain parenchyma. This is reinforced by numerous pericytes. A thin basement membrane surrounds the endothelial cells and provides both structural support and a dense physical barrier between the circulation and the microenvironment of the brain. Astrocytes extend cellular processes (astrocytic “foot processes”) that cover the basement membrane, which enhances the BBB by limiting the ability of macromolecules or circulating cells to gain access to the central nervous system. B, In vasogenic edema, increased permeability of the capillaries, through dehiscent or incompetent tight junctions, leads to exudation of a plasma ultrafiltrate and water into the extracellular space. Arrows demonstrate flow through the tight junctions and into the extracellular space. C, In cytotoxic edema, depletion of energy and metabolites leads to failure of the sodium-potassium adenosine triphosphatase (Na⁺,K⁺-ATPase) pump and accumulation of sodium within the cells (astrocytes and endothelial cells, as well as neurons); water follows the concentration gradient into the cells, which swell in response. Arrows demonstrate the path of water into cells from the vascular space. 1, Astrocytes and astrocytic foot processes; 2, endothelial cells; 3, neurons.

(A, Used with permission from the Cleveland Clinic.)

Several studies have identified a variety of molecular mechanisms and metabolic barriers that indicate that the BBB is an exceptionally active system.^11–13 For example, endothelial cells contain active peptides, peptidases that inactivate traversing proteins, and numerous intracellular enzymes, such as cytochrome P-450 (1A and 2B isoforms), that inactivate neuroactive and neurotoxic substances.^14,15 In general, to traverse the normal BBB, large or hydrophilic molecules require an active transport mechanism—either receptor-mediated or absorptive-mediated transcytosis. In the cerebral endothelium, these mechanisms are less efficient than in systemic (outside the central nervous system [CNS]) endothelial cells, which enhances the potential BBB. Thus, the BBB contains active and passive features that regulate the passage of substances from the systemic circulation into the brain. Similar versions of these tight junctions and permeability restrictions are found between CSF and the brain (except in the circumventricular organs [area postrema, tuber cinereum, and pineal gland], where the endothelium is penetrated more easily to permit secreted neuropeptides to act systemically; see Table 9-1).^11–16

The BBB has an extensive surface area—which some researchers have estimated to be approximately 20 m²/1.3 kg of brain. Consequently, no neuron is more than 20 to 25 µm away from a brain capillary, and thus the BBB plays several critical roles in regulation of the brain’s microenvironment.^17,18 It manages the entry of nutrients and controls elimination of wastes. The BBB limits distribution and thus contains within the brain generated neuroregulators and neurotransmitters that act centrally while excluding or regulating entry into the brain of similar molecules intended to act peripherally. This reduces or prevents debilitating biochemical crosstalk within the CNS. Finally, the BBB regulates movement of fluid and ions between the circulation and the brain, which permits maintenance of an ideal interstitial fluid that enhances neuronal function. The brain’s interstitial fluid has some similarities with plasma but has a lower protein content and lower concentration of calcium (Ca²⁺) and potassium (K⁺) ions and a higher concentration of magnesium (Mg²⁺), which generates a significant buffering capacity. This limits the effect of fluxes of systemic metabolism, such as occur with exercise, a meal, or starvation.^5,11,19 Continuous turnover of interstitial fluid and CSF, which is regulated by the cerebral endothelium and its barriers (see Table 9-1), is critical to homeostasis of the brain’s microenvironment.

Molecular Events in Cerebral Edema

Cerebral edema is a common end result of a variety of neurological and systemic disorders. Most classifications of cerebral edema describe four categories (summarized in Table 9-2): cytotoxic, or cellular swelling secondary to cell injury; vasogenic, which results from vascular leakage through a disrupted BBB and consequently increased fluid and altered concentrations of ions, peptides, and macromolecules in the extracellular space; interstitial, which occurs with transependymal flow of CSF in patients with hydrocephalus; and osmotic, when the brain is hyperosmolar relative to plasma and thus induces water to flow passively across an intact BBB along its concentration gradient. It may be difficult to separate edema into these distinct classes in every patient because more than one type may be present simultaneously as a result of the nature and timing of the underlying disorder (see Table 9-2). Because interstitial edema and osmotic edema have fewer causes or are uncommon in neurosurgical patients, our principal focus in this chapter is on vasogenic and cytotoxic edema.

Tissue swelling—edema—may be intracellular or extracellular. It has the potential to result in profound shifts in the relative volumes occupied by the cellular and interstitial elements. Continued redistribution of water, ions, peptides, and other neuroactive substances within and between the cells of the CNS (neurons, glia, microglia, and endothelial cells) may exacerbate the primary cause of the edema. These failures lead to a variety of molecular events and cascades that potentiate cerebral and BBB dysfunction, some of which are summarized later and are discussed in greater detail in several recent, specialized monographs.^4,5,20

Vasogenic Edema

Vasogenic edema may share some mechanisms with cytotoxic and other forms of brain edema. However, the principal source of edema formation is abnormal permeability of the BBB.²¹ The most common source is a primary or secondary brain tumor, in which case the nascent microvessels are deficient in tight junctions. This “brain-tumor barrier” is an incompetent obstacle that permits leakage of plasma ultrafiltrate into the brain’s extracellular space.^18,22,23

The edema associated with brain tumors results from this passive deficiency and from cellular invasion and migration.^10,24,25 In addition, many tumors have active mechanisms to promote vascular permeability and neovascularity. The most widely studied permeability and angiogenic agent secreted by tumor cells is vascular endothelial growth factor (VEGF), which induces capillary permeability, endothelial proliferation, and migration and organization of new capillaries that lack tight junctions.²⁶ Additional chemokines, cytokines, growth factors, and inflammatory mediators that play similar or complementary roles in blood-tumor permeability and angiogenesis have been identified. For example, angiopoietin-1, angiopoietin-2, fibroblast growth factor, hepatocyte growth factor/scatter factor, platelet-derived growth factor, interleukin-3 (IL-3), IL-4, IL-8, transforming growth factor-α (TGF-α), TGF-β, a variety of adhesion molecules and proteases such as urokinase plasminogen activator, multiple matrix metalloproteinases, integrins α_vβ₃ and α_vβ₅, and even oncogenes such as mutated Ras and tumor suppressor gene products such as Tp53 and vhl protein can affect BBB function. Many of these are discussed elsewhere in this volume.

The most thoroughly studied mechanism that produces cerebral edema is the vasogenic edema mediated by tumor production of a macromolecular protein initially identified as vascular permeability factor (VPF) and later, after its angiogenic activity had been identified, as VEGF. VPF/VEGF was initially identified by Senger and Dvorak in 1983.²⁷ Their landmark study demonstrated that the ascites caused by the intraperitoneal injection of hepatocarcinoma cells into guinea pigs was a product of excessive permeability of the small vessels that line the peritoneal cavity and, furthermore, that a protein secreted by the tumor and acting on the vessels was responsible for the enhanced vascular permeability. Hepatocarcinoma lines that did not produce the protein did not cause ascites. In addition, in an in vivo biologic assay of cutaneous vascular permeability, the enhanced vascular permeability produced by the protein was blocked by antibodies to the partially isolated protein. Secretion of the same protein was subsequently shown to occur in several systemic and CNS tumors.^28–30 Bruce and colleagues and Heiss and associates demonstrated that vascular permeability is increased by conditioned media from cultures of high-grade gliomas and meningiomas, the types of human brain tumors that most commonly produce clinically significant cerebral edema. In addition, they demonstrated that antibodies to VPF/VEGF block the permeability-enhancing effects of conditioned media from tumor types that produce cerebral edema and showed that glucocorticoids block the permeability-enhancing effects of VPF/VEGF on the vessel wall and inhibit tumor cell production of VPF/VEGF.^29,31 CNS tumors that are frequently associated with marked edema, such as glioblastomas, meningiomas, and metastases, are found to contain high levels of VPF/VEGF gene expression, whereas the types of CNS tumors that are not commonly associated with significant cerebral edema do not usually produce levels of VPF/VEGF mRNA higher than found in normal brain.³⁰ In clinical studies, the concept that VPF/VEGF is a principal mediator of peritumoral edema is confirmed by the reduction in contrast enhancement (vascular permeability) and surrounding cerebral edema on imaging studies by treatment of glioblastoma patients with bevacizumab, an anti-VEGF antibody (Fig. 9-2).^32,33

FIGURE 9-2

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