Cerebral Blood Vessels and the Neurovascular Unit

The total surface of the capillary endothelial cells forms the major interface between the blood and brain. Other, less extensive, interface surfaces include choroid plexuses and arachnoid granulations (Table 59.2). At each of the BBB interfaces, high-resistance junctions between cells, which make the surface into an epithelial-like structure, restrict bulk transport. The epithelial sheets impede non–lipid-soluble substances, charged substances, or large molecules, whereas lipid-soluble substances, such as anesthetic gases, pass easily through the cells. Water has an anomalous structure that allows it to pass rapidly through endothelial cells but with slight restrictions.

Table 59.2 Characteristic Features of the Blood-Brain Interfaces

ATPase, Adenosine triphosphatase; CSF, cerebrospinal fluid; ISF, interstitial fluid.

In 1925, Cushing and Weed described the pathways involved in the movement of CSF and ISF through the ventricles and around the brain, recognizing that the CSF/ISF acted as a lymph-like fluid in brain. They compared that circulation to those of the blood and lymph. The importance of this circulation has grown with the discovery that ISF is formed by cerebral blood vessels, which have electrolyte pumps that make fluid in a fashion similar to that of the epithelial cells. Flowing around cells, ISF brings nutrients such as glucose and oxygen to neurons and astrocytes and removes the products of metabolism. ISF is absorbed either into the blood via terminal capillaries and venules or into CSF for eventual absorption through the arachnoid granulations (Fig. 59.1).

Fig. 59.1 Illustration of the third circulation. Cerebrospinal fluid (CSF) is formed by the choroid plexuses in the ventricles, and interstitial fluid (ISF) is formed by cerebral capillaries. At both sites, the action of the Na⁺/K⁺-ATPase pump creates the osmotic gradient that pulls water from the blood. Tight junctions (TJ) are found at each site of blood/brain interface. This includes the apical surface of the choroid plexus epithelial cells, the cerebral endothelial cells, and the arachnoid. Substances move between the brain and CSF across the gap junctions (GJ) on ependymal and pial surfaces.

Brain extracellular space comprises 15% to 20% of the total brain volume. Complex carbohydrates are found in the extracellular space, including hyaluronic acid, chondroitin sulfate, and heparan sulfate. Hyaluronic acid forms large water domains. These large extracellular matrix glycoproteins impede cell movement. After an injury, astrocytes secrete an extracellular molecule, hyaluron, which impedes movement of fluids in the extracellular space, slowing tissue repair. Treatment with hyaluronidase reduces hyaluron and improves regrowth of injured fibers (Back et al., 2005).

Proteases are secreted during development, angiogenesis, and neurogenesis to clear a path for the growing cells, similar to the secretion of proteases by spreading cancer cells (Candelario-Jalil et al., 2009; Yong, 2005). An important concept that has emerged over the past few years is that of the neurovascular (or gliovascular) unit. Neurons, astrocytes, and pericytes comprise the neurovascular unit (Neuwelt et al., 2008). On the abluminal surface of the endothelial cells is a thin layer of basal lamina composed of type IV collagen, fibronectin, heparan sulfate, laminin, and entactin. Entactin connects type IV collagen and laminin to add a structural element to the capillary. Fibronectin from the cells joins the basal lamina to the endothelium. Basal lamina provides structure through type IV collagen, charge barriers by heparan sulfate, and binding sites on the laminin and fibronectin molecules. Within the basal lamina reside the pericytes, which are a combination of smooth muscle and macrophage. Astrocyte foot processes surround the basal lamina. Glia limitans is found at the pial surface and at the interface between astrocytes and blood vessels (Owens et al., 2008). Neurons complete the group of cells that comprise the neurovascular unit (Girouard and Iadecola, 2006) (Fig. 59.2).

Fig. 59.2 The cerebral capillary is a fluid-secreting, epithelial-like cell with a high metabolic rate. The Na⁺/K⁺-ATPase pump on the apical surface forms cerebrospinal fluid. Tight junctions (TJ) between the endothelial cells maintain the electrical resistance. A large number of mitochondria are seen in the capillary. Amino acid and glucose transporters are present. Around the cell is a basal lamina composed of type IV collagen, laminin, fibronectin, and heparan sulfate. Astrocytic end-feet surround cells. Pericytes, which are embedded in the basal lamina, are macrophage-like cells that have macrophage and smooth-muscle functions in the perivascular space.

Cerebral blood vessels have very low permeability and high electrical resistance, making them more similar to epithelial cells than systemic capillaries, which are passive structures with low electrical resistance and fenestrations that permit passage of large protein molecules. In addition, cerebral blood vessels have highly selective molecular transport properties. During development, cerebral blood vessels acquire the characteristics that distinguish them from systemic capillaries. Astrocytes are critical in this differentiation process, which involves interactions between blood vessels and astrocytes. The critical nature of the astrocytes in this process was shown in transplantation studies involving chicken and quail cells, which can be separated histologically. Quail brain grafts from 3-day-old quails transplanted into the coelomic cavity of chick embryos become vascularized by chick endothelial cells and form a competent BBB. On the other hand, when avascular embryonic quail coelomic grafts are transplanted into embryonic chick brain, chick endothelial cells form leaky capillaries and venules (Stewart and Wiley, 1981). Subsequent studies showed that astrocytes induced BBB properties in non-neural endothelial cells in vivo (Janzer and Raff, 1987).

Electron microscopic studies with electron-dense tracers identified a major site of the BBB as the endothelial tight junctions (Reese and Karnovsky, 1967). Isolation of tight-junction proteins and cloning of the molecules permitted production of antibodies that identified their location. Zona occludins tether the tight-junction proteins to actin within the endothelial cells (Hawkins and Davis, 2005). Occludin and claudin form the actual tight junctions within the endothelial clefts (Furuse et al., 1993). Occludin attaches to the zona occludins, while claudins attach to occludin and protrude into the clefts between cells. The extracellular tails of claudins from adjacent cells self-assemble to form the tight junctions that are “zip-locked” together (Nitta et al., 2003).

Tight junctions between the endothelial cells create the unique membrane properties of the cerebral capillaries by greatly increasing the electrical resistance, which blocks transport of non–lipid-soluble substances (Box 59.1). Brain tissue has a very high demand for glucose and essential amino acids, which can be met by specialized molecules that transport glucose and amino acids across the BBB. Glucose transporters are densely distributed in the capillaries. At low levels of blood glucose, the carriers function at full capacity to meet metabolic needs, but at higher levels of blood glucose, the carriers are saturated and transport is dominated by diffusion rather than active transport. Several isoforms of the glucose transporter molecule have been isolated and cloned (Vannucci et al., 1997). High concentrations of one isoform, GLUT1, are found on cerebral blood vessels. GLUT3 is found on neurons and GLUT5 in microglia. GLUT2 is found predominantly in the liver, intestine, kidney, and pancreas. Impairment of glucose transport due to lack of transporters has been described in patients with Alzheimer disease and in other neurological disorders (Kalaria and Harik, 1989). Amino acid transporters carry essential amino acids into the brain. Competition for the amino acid transporters can lead to a deficiency state; serotonin uptake is decreased in patients with phenylketonuria, which competes for the transporter.

Steady-state levels of brain electrolytes are preserved by transport mechanisms at the BBB. Potassium is maintained at a constant level in the CSF and brain by the BBB (Katzman and Pappius, 1973). This prevents fluctuations of electrolyte levels in the blood from influencing brain levels. Calcium is similarly regulated. Glutamate, which is an excitotoxin, is excluded from the brain. Highly lipid-soluble gases such as carbon dioxide and oxygen are rapidly exchanged across the capillary. Anesthetic gases are effective because they readily cross the BBB and enter the brain.

The presence of the BBB creates a major impediment for the transport of drugs into the brain. For example, penicillin is restricted from entry into the brain, so high doses are needed to achieve therapeutic brain levels. Newer generations of antibiotics such as the cephalosporins penetrate more readily, making them better agents for treatment of brain infections. Chemotherapy of brain tumors has been hampered by the poor lipid solubility of most agents; to overcome this impediment, chemotherapeutic agents can be injected intrathecally or into permanent CSF catheters implanted into the ventricles, with injection bulbs buried beneath the scalp. Drugs of addiction are often modified to allow them to more readily cross the BBB. For example, heroin, which is derived from morphine, is modified to increase its lipid solubility to make it more easily transported into the brain. Similarly, other addictive substances such as nicotine and alcohol are highly lipid soluble and easily transported into brain.

Different rates for equilibration of various substances between blood and brain can cause paradoxical clinical situations. For example, to compensate for a metabolic acidosis, bicarbonate levels fall in both the blood and the brain. Metabolic acidosis is balanced by a respiratory alkalosis due to lowering of carbon dioxide by hyperventilation, which compensates for the acidosis. Carbon dioxide is reduced in both the blood and CSF compartments, since it readily crosses the BBB, while bicarbonate is much more slowly exchanged between the two compartments. This adjustment results in a stable, albeit pathological, situation. However, when the metabolic acidosis is corrected by intravenous infusion of bicarbonate, there is a rapid adjustment of Pco₂ as the hyperventilation stops and CO₂ builds up. Bicarbonate adjusts very slowly because of the limited transport across the BBB, and the CO₂ entering the brain causes a further fall in brain pH. This dangerous situation continues until the bicarbonate levels in the brain rise. Although treatment is necessary to correct the metabolic acidosis, patients may become worse due to brain acidosis if treatment is too rapid (Posner and Plum, 1967).

Production of Cerebrospinal Fluid and Interstitial Fluid

Production of brain fluids comes from multiple sources including the choroid plexuses within the ventricles, the electrolyte pumps on the abluminal surface of the cerebral capillaries, and metabolism. The main source is the choroid plexuses that form an important interface between CSF and blood. Choroid plexuses protrude into the cerebral ventricles; they are covered with a specialized type of ependymal cell that has tight junctions on the apical surface.

Choroid plexus capillaries are fenestrated. Substances from the blood can cross into the stroma next to the ependymal cells. They are blocked from entering the CSF by tight junctions that form at the apical surface of the ependymal cells. Choroid plexus ependymal cells are enriched with mitochondria, Golgi complexes, and endoplasmic reticulum—suggesting a high rate of metabolic activity—and are covered with microvilli that increase their surface area.

While choroid plexuses are the major source of CSF, capillaries contribute ISF to varying degrees, depending on the species. Production of CSF is constant across species when the volume of fluid formed is divided by the weight of the choroid plexus (Cserr, 1971). In humans, the volume of CSF in the ventricles is 140 mL, with a rate of CSF production of 0.35 mL/min or about 500 mL/day. Obstructive hydrocephalus can rapidly cause life-threatening symptoms when the rate of production remains constant but there is no absorption. On the other hand, removal of 20 mL of CSF at the time of LP for the treatment of idiopathic intracranial hypertension does not make physiological sense (although it seems to help at times, which may be due to the hole placed in the dura, with a slow leak of CSF).

CSF production occurs at both choroidal and extrachoroidal sites, and estimates of the proportion of CSF from each site vary, depending on the species and the method of measurement. Extrachoroidal production accounts for 30% of total CSF production in the cat (Rosenberg et al., 1980) and approximately 60% in the nonhuman primate (Milhorat, 1969). No measurements of the relative proportion of CSF produced at each source have been made in humans.

Higher levels of sodium, chloride, and magnesium and lower levels of potassium, calcium, bicarbonate, and glucose are found in CSF than are expected from a plasma ultrafiltrate, which suggests that the CSF is actively secreted. An ATPase pump on the apical surface of the choroidal cells secretes three sodium ions in exchange for two potassium ions; osmotic water follows the increased sodium gradient. Carbonic anhydrase converts carbon dioxide and water into bicarbonate, which is removed along with chloride to balance the sodium charge.

Production of CSF continues even when the ICP is high. Only acetazolamide, which inhibits carbonic anhydrase, can be used for the long-term reduction in CSF production. Experimentally, hypothermia, hypocarbia, hypoxia, and hyperosmolality have been shown to reduce production, but these are not practical to use for other than short periods. Osmotic agents such as mannitol and glycerol increase serum osmolality, lowering CSF production temporarily by about 50%. Agents that interfere with Na⁺/K⁺-ATPase reduce CSF production. Digitalis has an effect on the rate of CSF production, but ouabain, which is a more effective agent experimentally, is too toxic for use in patients. Recently, hypertonic saline has been shown to reduce CSF pressure; some of this effect may be due to a reduction in CSF production, but the mechanism of action remains to be clarified.

Capillaries, which have Na⁺/K⁺-ATPase on the abluminal surface, are a source of extrachoroidal ISF production. Gray matter has a dense neuropil that impedes the flow of water, whereas white matter, being more regularly arranged, is a conduit for normal flow of ISF as well as a route for movement of edema in pathological conditions. Normally the flow of ISF in the white matter is toward the ventricle, where it mixes with the CSF from the choroid plexus to be eventually drained across the arachnoid granulations that protrude into the sagittal sinus.

Water Molecules: Basis for Magnetic Resonance Imaging

Resonance signals detected by MRI are from water molecule protons. Since water is the most abundant source of protons in the brain, water protons dominate the signals. New rapid-acquisition pulse sequences are fast enough to show diffusion of water. Cytotoxic edema shrinks the extracellular space and restricts the diffusion of water (Moseley et al., 1990). The ability to monitor water diffusion by MRI has greatly improved our ability to diagnose an acute ischemic event. Water diffusion between cells in the extracellular space occurs normally. When there is cellular swelling and the extracellular space shrinks, the diffusion of water slows, and the apparent diffusion coefficient (ADC) shows a loss of signal, which appears black on the image. The diffusion-weighted image (DWI) has a bright signal. Because the DWI may show T2 shine-through that will be misinterpreted as reduced diffusion, both a darkened ADC and a bright DWI should be seen in the region of the infarct. In cerebral ischemia, the DWI is abnormal within minutes after the onset of the ischemia, making this an excellent diagnostic test for the presence of cerebral ischemia (Adami et al., 2002).

Diffusion tensor imaging (DTI) reveals the patterns of white matter tracts in three dimensions. Taking advantage of the directional flow of water protons along white matter, diffusion is measured in three planes, and the separate pathways for water movement between the fibers are traced. In patients with white-matter pathology, such as in vascular cognitive impairment and MS, injury patterns in the white matter can be revealed by DTI (Nitkunan et al., 2008).

Contrast agents are important in determining injury to the BBB. Iodine-containing contrast agents are used in CT scanning because they are radiopaque. When injected intravenously, contrast agents show the site of injury to the blood vessels by the appearance of the contrast agent on the scan. Iodine-containing contrast agents can cause anaphylactic reactions, however, particularly in individuals with allergy to shellfish. Contrast agents used in MRI studies are safer and more sensitive, making them the agents of choice. Gadolinium-containing compounds are used in MRI because they produce a paramagnetic effect. When they leak from the vessels into tissue, they cause a rapid relaxation of the protons that can be seen on T1-weighted images as a hyperintensity, compared to the precontrast scan.

Anatomical Sites of Central Nervous System Infection

The terminology used to describe various types of central nervous system (CNS) infections is anatomically based (Table 59.3). An infection limited to the subarachnoid space, with inflammation of the meninges, is called meningitis. Meningeal signs of headache, stiff neck, and photophobia are present without focal findings that would indicate spread into the parenchyma. When the infection spreads contiguously from the subarachnoid space through the pial surface or along Virchow-Robin spaces, crossing the gap-junctioned linings, the brain parenchyma is infected, and the term meningoencephalitis is used. In addition to meningeal signs, there are focal findings and possibly impaired consciousness and seizures. An infection in the brain tissue that is most likely spread via blood begins as a loose collection of invading cells referred to as a cerebritis; walling off of the infected brain tissue leads to an abscess. Finally, the term encephalitis is used to describe a more diffuse brain infection in both the gray and white matter, which is usually indicative of a viral infection. Occasionally the infection spreads in a potential space beneath the dura but outside the arachnoid; subdural empyema describes a life-threatening collection of pus over the brain surface that has often spread from an infected sinus through the venous plexus of the ethmoid or sphenoid sinuses into the subdural space. The presence of a subdural empyema should be suspected in a patient with sinus infection, fever, seizures, focal findings, and altered consciousness. Diagnosis of meningitis can be done by examination of CSF for signs of infection such as increased white blood cells or protein. Infections that invade the brain are best diagnosed with MRI, which can readily demonstrate a meningoencephalitis, cerebritis, abscess, or encephalitis. Use of contrast agents increases the potential of reaching a correct diagnosis based on site of infection. Subdural empyema is the most difficult condition to diagnose because it may only be a thin layer of pus on the surface of the brain and be obscured by the skull. Diagnosis can be missed on LP or CT.

Gap Junctions on Ependymal and Pial Surfaces

Lining the cerebral ventricles (other than over the choroid plexus) is a layer of ciliated ependymal cells connected by gap junctions. Pial cells lining the surface of the brain, which form the limiting glial membrane, the glial limitans, also have gap junctions. Fluid, electrolytes, and large protein molecules move through the gap junctions, allowing exchange between the CSF and ISF. Intrathecal administration of antibiotics and chemotherapeutic agents has been used to bypass the BBB.

Blood vessels penetrate the brain from the surface. As they enter the brain, they are invested with pia mater. The space between the penetrating blood vessels and the brain, prior to the point where only brain tissue surrounds the vessels, is called the Virchow-Robin space. After injection of substances intrathecally, the large proteins in the CSF space penetrate into the brain from the surface via the Virchow-Robin spaces. These perivascular routes may be involved in the spread of infection into the brain from the subarachnoid space in meningitis.

Arachnoid Granulations and Absorption of Cerebrospinal Fluid

Arachnoid granulations (pacchionian granulations) are the major sites for the drainage of CSF into the blood. They protrude through the dura into the superior sagittal sinus and act as one-way valves. As CSF pressure increases, more fluid is absorbed. When CSF pressure falls below a threshold value, the absorption of CSF ceases (Fig. 59.3). In this way, CSF pressure is maintained at a constant level, with the rate of CSF production as one determining factor.

Fig. 59.3 Schematic drawing of the relationship of cerebrospinal fluid (CSF) formation and absorption to pressure. CSF is formed at a constant rate of 0.35 mL/min. Absorption begins above a threshold value that varies from person to person. Once CSF absorption begins, it is linear, as seen in a one-way valve. When formation rate equals absorption rate, the steady-state CSF pressure is determined.

(Modified with permission from Cutler, R.W., Page, L., Galicich, J., et al., 1968. Formation and absorption of cerebrospinal fluid in man. Brain 91, 707-720.)

Although channels are seen in the arachnoid granulations, actual valves are absent. Tissue appears to collapse around the channel as the pressure falls, and the channels enlarge as pressure rises. Resistance to outflow across the arachnoid granulations leads to CSF pressure elevation. Substances can clog outflow channels and increase resistance to CSF absorption. Blood cells are trapped in the arachnoid villi, and subarachnoid hemorrhage causes a transient increase in CSF pressure and can occasionally lead to hydrocephalus. Similarly, white blood cells and increased protein from meningitis can block the arachnoid granulations and increase CSF pressure.

Cerebrospinal Fluid Pressure

Measurement of CSF pressure is a critical part of the LP. Pressures should be measured with the patient in the lateral recumbent position, and a narrow-bore spinal needle should be used to minimize CSF leakage. Performing the LP with the patient in the sitting position, although easier for the physician, eliminates the possibility of obtaining an accurate CSF pressure. Whenever CSF pressure is a critical piece of information, such as in the diagnosis of idiopathic intracranial hypertension, the sitting position should not be used.

The opening CSF pressure is measured with a manometer attached to the needle. Normal CSF pressure ranges from 80 to 180 mm H₂O but may go as high as 200 mm H₂O in obese patients or those who are not relaxed. Three components contribute to the measured pressure: volume of blood within the cranial cavity, amount of CSF, and the brain tissue. The CSF pressure recorded by the manometer represents the venous pressure transmitted from the right side of the heart through the venous sinuses. Small fluctuations from the cardiac systolic pulse and larger fluctuations from respirations can be seen in the column of fluid in the manometer. Pulsations in the manometer represent the fluctuations in the thin-walled veins (Davson, 1967). Arteries have thick elastic walls that dampen the pulsations from arteries. Deep respirations cause wide fluctuations in the CSF pressure, whereas changes in arterial pressure are barely visible. As ICP rises, tissue compliance falls and reserve capacity of the intracranial contents is lost. When tissue compliance is lost, small changes in fluid volume may lead to large increases in ICP.

Patients with increased ICP can be continuously monitored with indwelling catheters in the ventricles or with a sensor on the dura. Both procedures are invasive and only used in critically ill patients. Pathological elevations in ICP cause plateau waves that increase in steps to 50 mm Hg, where they persist for up to 20 minutes before returning to baseline. Treatment of patients with raised ICP can be monitored at the bedside with pressure monitors. Monitoring is used to gauge response to osmotic agents and to determine the severity of head injury. Treatment decisions can be made on the basis of the ICP.

In addition to complications of elevated CSF pressure, there are circumstances that lead to low pressure. Some patients have low pressure after LP owing to a persistent tear in the dura. Headaches occur with standing up and are often relieved with bedrest. Low-pressure headaches after LP generally resolve spontaneously. However, rarely they persist and require placement of a epidural blood-patch, which is accomplished by injecting the patient’s own blood to close the hole in the dura. Postsurgical and posttraumatic leakage of CSF can cause low-pressure headaches, and occasionally a spontaneous tear occurs. Diagnosis of a spontaneous leak can at times be difficult and may require injection of radiolabelled substances or contrast agents into the CSF (Schievink et al., 2008). Enhancement of the meninges can be seen on MRI in patients with low CSF pressure, but the cause of this abnormality is uncertain.

Composition of the Cerebrospinal Fluid

Normal CSF resembles water; it contains much less protein than blood and very few cells. The protein content is generally less than 40 mg/dL, compared to approximately 4 g/dL in the blood. CSF protein is primarily albumin produced in the liver. Three to five lymphocytes are considered normal in CSF, but any neutrophils are abnormal. Glucose values are two-thirds of those in blood. Some IgG is produced in the brain, but in the absence of an inflammatory disease (e.g., MS), amounts should be very small. The IgG index can be used to determine the source of CSF IgG.

Diagnosis of MS is aided by obtaining CSF for a demyelinating test profile. Acute MS attacks cause an increase in myelin basic protein, which represents breakdown of myelin; oligoclonal bands suggest a longer disease course (Noseworthy et al., 2000). The ratio of IgG to albumin in both the blood and brain is calculated according to the formula: (CSF IgG × serum albumin) / (serum IgG × CSF albumin). Dividing the ratio in the brain by that in the blood indicates whether the IgG comes from the blood across a leaky BBB, in which case the ratio is low, or whether the source of IgG is the brain, in which case the IgG index is elevated. An IgG index above 0.7 indicates intrathecal IgG synthesis.

Cells in the CSF provide an important indication of the underlying pathology. Bacterial infection typically leads to an increase in polymorphonuclear leukocytes; viruses cause a lymphocytosis. Large numbers of red blood cells in the CSF suggests a subarachnoid hemorrhage, which is confirmed by the presence of xanthochromia due to break down of blood products. In some forms of encephalitis, such as herpes encephalitis, there may be red blood cells in the CSF. Vasculitis can increase white blood cell numbers, as can an acute attack of MS. Presence of more than 50 cells increases the likelihood of vasculitis over MS. Parameningeal infections may not cause an increase in white blood cells but will increase CSF protein.

Molecular Cascade in Injury

Cerebral edema is the end result of many neurological diseases. Excess fluid can accumulate in the intracellular or extracellular spaces. A convenient (though simplified) classification separates brain edema into cytotoxic or cellular swelling, and vasogenic or vascular leakage (Klatzo, 1967). Another proposed category is interstitial edema, which represents the accumulation of fluid in interstitial spaces in hydrocephalus (Fishman, 1975). Separation into distinct categories, while useful, is often difficult because of the overlap between the various types of edema.

Disruption of the BBB leads to vasogenic edema, which expands the extracellular space. Vasogenic edema moves more readily in between the linearly arranged fibers that form the white matter. The gray matter restricts water movement because of the dense nature of the neuropil, while the more loosely connected fiber tracts can be separated to allow edema fluid to flow. Cytotoxic edema, which results from pathological processes that damage cell membranes, constricts the extracellular spaces, constraining movement of fluid between the cells. Because of the lack of cell damage in vasogenic edema, once the damage to the blood vessel resolves, there may be a return to normal in the edematous tissue. This is generally not the case in cytotoxic edema, which is due to direct injury to cells. The resolution of interstitial edema from hydrocephalus is variable; some resolution may occur once the pressure in the expanded cerebral ventricle is reduced by insertion of a ventriculoperitoneal shunt.

Cellular and blood vessel damage follows activation of an injury cascade (Dirnagl et al., 1999). The cascade begins with depletion of energy and glutamate release into the extracellular space (Fig. 59.4). This occurs during a hypoxic, ischemic, or traumatic injury and causes cytotoxic damage. Release into the extracellular space of excessive amounts of the excitatory neurotransmitter, glutamate, opens calcium channels on cell membranes, allowing extracellular calcium to enter the brain. Because one calcium ion is exchanged for three sodium ions, the removal of excess calcium from the cell, which requires an intact cellular membrane, causes a buildup of sodium within the cell, creating an osmotic gradient that pulls water into the cell. While the cell membrane is intact, the increase in water causes dysfunction but not necessarily permanent damage.

Fig. 59.4 Mechanisms of ischemic-hypoxic injury leading to cell swelling and death. Chart shows the time course of early events involving glutamate release, immediate early gene production, and energy failure. This leads to changes in electrolytes and initiation of the inflammatory response. Cytokines continue the damage, which results in opening of the blood-brain barrier. Chemokines attract white blood cells to the injury site, where they release free radicals and proteases and enhance the injury. Finally, the proteases attack structural components, leading to membrane damage and cell death.

Accumulation of calcium ions within the cell activates intracellular cytotoxic processes, leading to cell death. An inflammatory response is initiated by the formation of immediate early genes (e.g., c-fos and c-jun) and cytokines, chemokines, and other intermediary substances. Microglial cells are activated and release free radicals and proteases, which contribute to the attack on cell membranes and capillaries. Irreversible damage to the cell occurs when the integrity of the membrane is lost. Free radicals are pluripotential substances produced in the ischemic brain and after traumatic injury. The arachidonic acid cascade produces reactive oxygen species such as superoxide ion, hydrogen peroxide, and hydroxyl ion. Release of fatty acids (e.g., arachidonic acid) provides a supply of damaging molecules. Superoxide dismutase-1 and catalase are the major enzymes that catalyze the breakdown of reactive oxygen species. Other defenses include glutathione, ascorbic acid, vitamin E, and iron chelators such as the 21-amino steroids. The role of oxygen radicals has been extensively studied. Transgenic mice that overexpress the superoxide dismutase-1 gene have smaller ischemic lesions than controls (Jung et al., 2009).

Nitric oxide (NO) is another source of free radicals, which have both positive and negative effects. NO synthetase (NOS) has three forms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible or immunological NOS (iNOS). Macrophages and activated microglial cells form NO through the action of iNOS in response to ischemia, injury, and inflammatory stimuli. NO acts both as a normal vasodilator of blood vessels, by release of cyclic guanosine monophosphate in smooth muscle, and as a toxic compound in pathological conditions through the action of peroxynitrite anions (ONOO−), which are formed from the reaction of NO with superoxide anions (Beckman et al., 1990; Endres et al., 2004).

Manipulation of the NOS gene has helped reveal the action of the enzyme. Neuronal NOS produces toxic free radicals early in ischemic injury. Deletion of the nNOS gene in transgenic mice results in smaller infarcts from middle cerebral artery occlusion (Huang et al., 1994; Iadecola et al., 1994). On the other hand, eNOS causes vasodilatation and increases cerebral blood flow. Removing the eNOS genes leads to increased infarct size. Inflammation induces iNOS, which enhances injury and reaches a maximum at 24 hours (Huang and Lo, 1998).

Neuroinflammation and Vasogenic Edema

Vasogenic edema occurs when there is damage to the capillary and subsequent disruption of the BBB. Protein and blood products enter brain tissue, increasing the oncotic pressure in the brain and exposing brain cells to toxic products from the blood. Opening of the BBB could occur by loosening of tight junctions, development of pinocytotic vesicles in the endothelial cell, or an alteration in the basal lamina surrounding the capillaries. Tight junctions in the endothelial cells are the first line of protection. Proteases and free radicals are the major substances that attack the capillaries. The layer of basal lamina around the capillary, containing type IV collagen, fibronectin, and laminin, is degraded by proteases. The proteases involved include the serine proteases, plasminogen activators/plasmin system, and matrix metalloproteinases (MMPs) (Cunningham et al., 2005). Free radicals activate the proteases and attack the membranes directly (Jian and Rosenberg, 2005). Brain cells and infiltrating leukocytes are the sources of proteases and free radicals. Neutrophils contain prepackaged gelatinase B (MMP-9), which is released at the injury site and activated.

Extracellular matrix undergoes remodeling by the action of MMPs during development and repair (Yong, 2005). The MMPs are a gene family of over 24 enzymes that are expressed constitutively during normal remodeling but are induced in an injury. MMPs are expressed in a latent form that requires activation. Constitutively expressed MMP-2 is normally expressed by astrocytic foot processes around cerebral blood vessels, where it modulates the permeability of the BBB. Membrane-type MMP (MT-MMP) is membrane bound and forms a trimolecular complex with tissue inhibitor to metalloproteinases 2 (TIMP-2) to activate MMP-2. This configuration keeps the action of MMP-2 close to the membrane where it can gradually remodel the extracellular matrix around the blood vessel (Candelario-Jalil et al., 2009).

Bacterial meningitis initiates an inflammatory response in the meninges caused by the invading organisms and by the secondary release of cytokines and chemokines. The secondary inflammatory response may aggravate the infection. Cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, are elevated in the CSF of patients with bacterial meningitis and contribute to the secondary tissue damage. MMPs are increased in bacterial meningitis, and MMP inhibitors (e.g., doxycycline) block the damage secondary to infection (Leib et al., 2001). Steroids suppress the expression of MMPs and other inflammatory mediators. In children, treatment of bacterial meningitis with steroids along with the antibiotic reduces secondary injury. Use of steroids in adults with bacterial meningitis is more controversial. Doxycycline, a tetracycline derivative, suppresses MMP-9 expression and has a beneficial effect in reducing inflammation in meningitis when combined with another antibiotic (Meli et al., 2006).

Cytotoxic Brain Edema

Stroke, trauma, and toxins induce cytotoxic edema. After a stroke, brain water increases rapidly owing to energy failure and loss of ATP. Cytotoxic edema is seen between 24 and 72 hours after the stroke, when the danger of brain herniation is greatest (Fig. 59.5). Damage to the blood vessels, resulting in vasogenic edema, occurs at multiple times after the insult. In brain trauma, there is an early opening of the BBB along with extensive damage to the brain tissue, and a mixture of cytotoxic and vasogenic edema leads to severe brain edema in the early stages after injury. Permanent occlusion of a blood vessel decreases blood flow to the vessel territory, and unless collateral vessels take over, there is infarction of the ischemic tissue. Greater damage occurs in transient ischemia, because the restoration of blood flow returns oxygen and white blood cells to the region, enhancing the damage. Reperfusion injury particularly damages the capillary, with disruption of the BBB seen in two phases: an early opening after several hours and a more disruptive secondary opening after several days. Emboli are more likely to lead to reperfusion injury than thrombosis because the breaking up of the clot can restore blood flow to a previously ischemic region. When that occurs, the risk of hemorrhage is increased (Fig. 59.6). In animal studies of reperfusion injury after stroke, there is a biphasic opening of the BBB, with the first opening within several hours after reperfusion (Rosenberg et al., 1998). The initial opening, which is transient, is related to the activation of MMP-2, which is constitutively expressed and normally found in the latent form. Opening of the tight junctions is seen transiently after the onset of reperfusion, where disruption of tight junction proteins is observed (Yang et al., 2007). A second, more disruptive, phase of injury to the capillary begins around 24 to 48 hours after the onset of reperfusion. This is related to activation of MMP-3 and MMP-9, along with cycloxygenase-2, which are induced from several cell types including microglia/macrophages during the amplification phase of the secondary inflammatory response.

Fig. 59.5 Patient with cytotoxic edema secondary to a large middle cerebral artery infarction. A, Computed tomography (CT) shows early stages of infarction, with loss of definition of the insular stripe, an early sign of infarction. B, Diffusion-weighted image (DWI) later that day shows restricted diffusion in region of infarct. C, One week after admission, CT shows mass effect and herniation, with hydrocephalus on contralateral side (arrow) due to obstruction of foramen of Monro.

Fig. 59.6 Hemorrhagic transformation and enhancement of an infarct. Patient presented with left-sided weakness of uncertain duration but probably less than 12 hours. Computed tomography (CT) without intravenous (IV) contrast (A) shows a posterior right temporo-occipital, cortically based area of low attenuation with smaller areas of higher attenuation. Magnetic resonance imaging (MRI) was performed the following day. The greater sensitivity of MRI for hemorrhage is illustrated by the areas of low T2 signal intensity on an axial spin-echo image (B) and even more prominently on a gradient-echo image (C). Follow-up CT showed very little change; difference is due primarily to differences in imaging technique and sensitivity, not further hemorrhage. Minimal foci of T1 hyperintensity are present before IV contrast administration (D). After gadolinium administration (E), extensive enhancement within the area of infarct indicates breakdown of the blood-brain barrier.

Cerebrovascular diseases are the major cause of brain edema in the adult because of the high incidence of cerebral ischemia in the elderly, but other causes include acute hepatic failure, osmotic changes, exposure to toxins, and high altitude. In acute hepatic failure, cerebral edema may cause death. Patients with hepatic failure are often young and have an acute cause for liver failure. They may have overdosed on a drug that is toxic to the liver, such as acetaminophen, or they may have infectious hepatitis. Long-standing liver disease with cirrhosis and hepatic encephalopathy shows changes of astrocytes in the brain, but it is generally not complicated by cerebral edema. Reye syndrome, which is seen primarily in children after an influenza infection (particularly when they are treated with aspirin), has a high incidence of brain swelling. Parents are warned not to use aspirin for childhood fevers, and since warnings appeared and use of aspirin declined, the number of patients with Reye syndrome has decreased.

Effect of Blood Pressure and Osmolality Changes on Brain Edema

Cerebral blood pressure is tightly regulated in the waking state to ensure adequate flow to the brain. Loss of autoregulation occurs at both the lower and upper extremes of blood pressure, with resulting syncope and hypertensive encephalitis, respectively. The normal level of autoregulation varies greatly between patients, depending on age, prior diseases such as hypertension and diabetes, and years of treatment for hypertension. When a young patient with average blood pressures in the 100/60 range has an increase to 160/110, there may be hypertensive encephalopathy, whereas in an older individual with long-standing hypertension, a blood pressure of 160/110 would have no adverse effects. When such an individual has a stroke, the blood pressure may increase to 200/120 without producing a hypertensive crisis. In fact, lowering the blood pressure too rapidly may worsen the ischemia; a gradual reduction in blood pressure is safer. Therefore, it is critical to understand the normal range for the individual before making a decision to treat.

Rapid elevation of blood pressure causes hypertensive encephalopathy. In experimental animals, hyperemia is present, suggesting that the blood vessels are dilated and have increased permeability. Confusion, focal findings, seizures with papilledema, and increased CSF protein are present in some patients with hypertensive encephalopathy. MRI shows vasogenic edema, primarily in the posterior white matter of the brain (Fig. 59.7), a condition referred to by some as reversible posterior leukoencephalopathy syndrome (Hinchey et al., 1996).

Fig. 59.7 Patient with hypertensive encephalopathy secondary to eclampsia, with the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. A, T2-weighted magnetic resonance imaging shows extensive cerebral edema in posterior white matter regions, with less involvement of the gray matter. B, A higher level of the same scan sequence as in A, showing some frontal lobe involvement. C-D, Diffusion-weighted images (DWI), with only one small area of involvement. The lack of DWI changes is consistent with this being a vasogenic type of edema, and the patient had a good recovery without residual.

Common causes of rapid elevations of blood pressure are kidney disease, particularly in children with lupus erythematosus or pyelonephritis, and in the pregnancy-induced syndrome of eclampsia. Changes may be transient, and complete recovery is possible if treatment is instituted before hemorrhage or infarction occurs. A characteristic pattern of vasogenic edema without cytotoxic edema is present on MRI: there is extensive edema seen in the white matter, generally in the posterior regions, but spread in frontal regions can be seen, and an absence of DWI lesions indicating this is only vasogenic edema. Absence of signs of ischemia, such as a normal DWI in the face of marked white matter edema, supports a good prognosis for recovery (Covarrubias et al., 2002). Rapid reduction in blood pressure is necessary. The reason for involvement of the posterior circulation is uncertain. Eclamptic patients have visual disturbances due to involvement of the occipital lobes; on postmortem examination, petechial hemorrhages may be seen in the occipital lobes, explaining the visual symptoms.

Another cause of cerebral edema is a rapid change in serum osmolality. For example, rapid reduction of plasma glucose and sodium puts patients treated for diabetic ketoacidosis at risk for edema secondary to water shifts into the brain (Bohn and Daneman, 2002). Long-standing hyperosmolality leads to solute accumulation in the brain to compensate for hyperosmolar plasma levels. These idiogenic osmoles are thought to include taurine and other amino acids. During treatment of the diabetic ketoacidosis, blood osmolality is reduced, and water moves into brain along the osmotic gradient, resulting in cerebral edema. Rapid reduction of serum hyperosmolality, as in diabetic ketoacidosis, should be avoided to prevent brain edema due to the residual idiogenic osmoles (Edge et al., 2001). Dialysis disequilibrium may also be due to an osmotic imbalance that results from urea buildup in brain tissue.

Rapid correction of chronic serum hyponatremia can cause central pontine myelinolysis (Murase et al., 2006). In this syndrome, patients have very low sodium, usually less than 120 mEq/L, secondary to a variety of causes including inappropriate secretion of antidiuretic hormone (ADH), excessive water drinking, anorexia nervosa, alcohol withdrawal, meningitis, and subarachnoid hemorrhage. When there is inappropriate secretion of ADH, serum osmolality is low in the face of high urine osmolality. Treatment involves water restriction. In other patients, there is a salt-wasting syndrome that is treated by careful salt replacement. Low serum sodium can develop over an extended time period and be remarkably well tolerated. Shifts of water during treatment can result in central pontine myelinolysis due to damage to the myelinated tracts, particularly in the brainstem, but extrapontine myelinolysis may also be present.

Cerebral edema is a complication of acute mountain sickness, which in rare circumstances may be life threatening (Wilson et al., 2009). Cerebral symptoms are prominent, and there is an increase in cerebral blood volume related to the hypoxia. Raised ICP causes headaches, ataxia, and confusion. Papilledema has been seen in people with high-altitude cerebral edema. MRI shows changes in the white matter, particularly the corpus callosum, with involvement of the splenium, which may accompany high-altitude pulmonary edema (Yarnell et al., 2000). At high altitude, hypoxia occurs along with extreme exertion; hyperventilation may lead to a drastic reduction in carbon dioxide, resulting in vasoconstriction and cerebral ischemia (Hackett and Roach, 2001). Climbers develop headaches and impaired thinking. Paradoxically, re-breathing carbon dioxide was shown to improve symptoms by reducing vasoconstriction and restoring cerebral blood flow (Harvey et al., 1988).

Edema in Venous Occlusion and Intracerebral Hemorrhage

Occlusion of the venous sinuses draining the brain can cause increased ICP and venous hemorrhagic infarction. When the superior sagittal sinus is involved, there may be hemorrhagic infarction in both hemispheres (Fig. 59.8). Dehydration and hypercoagulable states are often found in such patients. Early symptoms may be subtle, with headache due to vessel occlusion or increased ICP. As infarction develops, however, other symptoms such as seizures develop, leading to hemorrhagic conversion of the infarction, herniation, and death. CT scan is usually unhelpful, and MRI may have subtle findings. Definitive diagnosis can be made with an MR venogram showing the occluded veins. Partial occlusions resulting in increased ICP are underdiagnosed. Patients may recanalize the thrombosed superior sagittal sinus and have an excellent outcome (Fig. 59.9). Although still controversial, most studies suggest that anticoagulation of the patient with sagittal sinus thrombosis is indicated even when there is hemorrhage into the brain.

Fig. 59.8 Sagittal sinus occlusion in 17-year-old with severe dehydration. A, Magnetic resonance venogram shows absence of sagittal sinus on coronal view (arrowhead). B, T2-weighted image shows extensive venous hemorrhagic infarction.

Fig. 59.9 Patient with sagittal sinus occlusion that developed after pregnancy. Images shown were obtained several months after the event and demonstrate ability to recover. At illness onset, there was papilledema and increased intracranial pressure. A, Sagittal sinus is intact in this coronal view from a magnetic resonance (MR) venogram. B, Lateral view from venogram, showing flow in sagittal sinus (arrow) and straight sinus (arrowhead). C, Region of prior venous infarction is shown on axial T2-weighted MR image. D, Same region as in C on the coronal T1-weighted image.

Intracerebral hemorrhage (ICH) causes brain edema around the hemorrhagic mass (Qureshi et al., 2001). This edema is both cytotoxic (direct damage to cells) and vasogenic (inflammatory response induced by toxic blood products). Growth of hematoma was observed after 24 hours in 38% of patients who were imaged within 3 hours of hemorrhage onset and again within 24 hours (Brott et al., 1997). The origin of the intracranial bleeding is obscured by the tissue destruction following the bleed and cellular necrosis. In primary ICH, a vessel ruptures, releasing blood into the brain. Secondary hemorrhage occurs in an area of infarction, particularly when the ischemic region is large. Generally, the hemorrhagic transformation is found 24 to 72 hours after the insult, but occasionally it can be seen relatively soon after the infarct and appear as a primary intracerebral hemorrhage. Since the tissue is massively destroyed, the origin of the blood is difficult to determine.

Primary ICH most commonly occurs in the region of the basal ganglia, where the lenticulostriate arteries are subjected to hypertensive changes. The pons and cerebellum are less common sites (Fig. 59.10). Accumulation of blood causes both mass effect on the surrounding tissues and release of toxic blood products into adjacent tissues. Mass effect can lead to herniation. Several blood products have been shown to cause a secondary inflammatory response that leads to BBB damage and cytotoxic edema. Blood contains coagulation cascade enzymes such as thrombin and plasmin which are pluripotential molecules that can damage cells both directly by their toxic effects and indirectly by activation of other proteases. In experimental animals, injection of thrombin into the brain produces a focal increase in brain water content (Lee et al., 1996). Thrombin stimulates production of hypoxia-inducing factor (HIF)-1α and induces the tumor suppressor gene, which promotes apoptosis (Xi et al., 2006). In addition to proteases, free radicals are thought to be involved in hemorrhagic injury, but evidence of free radical involvement is indirect and comes from studies showing that free radical scavengers and spin trap agents reduce bleeding and improve function in experimental models of ICH (Peeling et al., 1998).

Fig. 59.10 Computed tomography scan shows intracerebral hemorrhage with rupture into the ventricle. Contralateral ventricle is dilated as the result of compression of cerebrospinal fluid outflow.

Another cause of intracerebral bleeding is the breakdown of tissue and blood vessels after ischemia. Emboli from extracranial sources produce a region of ischemic injury. When the clot dissolves and blood returns to the damaged areas, there is a high risk of bleeding. This results in a hemorrhagic transformation. If the process is rapid, it can produce a large tissue mass similar to a primary ICH. A recent study in humans showed that treatment with recombinant factor VII reduced the growth of the hemorrhage (Mayer et al., 2005), but initial enthusiasm was dampened when a second study could not confirm the positive results of the first, owing to thrombotic side effects (Diringer et al., 2008). Treatment of ICH is conservative, with control of cerebral edema being most important. In spite of many well-controlled studies of surgical treatment of ICH, no benefit can be found (Qureshi et al., 2009).

Treatment of Brain Edema

Treatment of brain edema has lagged behind the advances in understanding the mechanisms producing the edema (Rabinstein, 2006). Reduction of volume in one of the three compartments may be helpful. Blood volume can be reduced with hyperventilation, which lowers carbon dioxide. However, excessive hyperventilation can cause vasoconstriction and ischemia. Reduction of CSF volume can be done mechanically by placing a drainage catheter into one of the ventricles. This can be difficult when cerebral edema has compressed the ventricular system. Intraventricular drainage is mainly used in patients with head injuries or acute hydrocephalus, or is done postsurgically. Agents that reduce the production of CSF (e.g., acetazolamide, diuretics) may be used but are of marginal benefit.

For many years, osmotic therapy has been the treatment of choice to temporarily lower ICP. Initially, urea was used, but the small molecule entered the brain, causing rebound edema. Current osmotic treatment is done primarily with mannitol, which reduces brain volume, lowers CSF production, and improves cerebral blood flow. Osmotherapy with low-dose mannitol infused over several days lowers ICP. Earlier studies employed 3 g/kg of mannitol, which had a drastic effect on the serum electrolytes and permitted only one or two doses to be given. More recently, it was found that low doses of mannitol (0.25-1 g/kg) are as effective as higher doses, without affecting electrolytes. Lower doses raised serum osmolality only slightly, suggesting that mannitol has several mechanisms of action. The effect of the small change in osmolality is to reduce brain tissue volume; this effect is more prominent in the noninfarcted than in the infarcted hemisphere. Other effects are that mannitol reduces CSF and ISF secretion by 50%, which may contribute to its action. Some investigators have proposed that mannitol hyperosmolality alters the rheological properties of blood, whereas others have noted an antioxidant effect. Prolonged administration of mannitol results in an electrolyte imbalance that may override its benefit and that must be carefully monitored. Although mannitol is often used to treat edema in acute stroke, its efficacy has not been proven. More recently, hypertonic saline has been advocated for use in treatment of cerebral edema. Studies in animals have shown that it lowers ICP, and studies in humans are underway.

Corticosteroids lower ICP primarily in vasogenic edema because of their beneficial effect on blood vessel permeability. They have been less effective in cytotoxic edema, however, and are contraindicated in the treatment of edema secondary to stroke or hemorrhage. In fact, systemic complications of corticosteroids can worsen the patient’s condition when used to treat ICH. Edema surrounding brain tumors, particularly metastatic brain tumors, responds dramatically to treatment with high doses of dexamethasone; this corticosteroid rapidly closes the BBB. Hence, it is important to obtain contrast-enhanced MRI or CT scans before treatment with corticosteroids. Otherwise, enhancement of the lesion may be missed. High doses of corticosteroids have been shown to be effective in brain edema secondary to inflammation in MS; the steroids act by closing the BBB, which can be seen on contrast-enhanced MRI. Inflammatory lesions such as those that occur in acute attacks of MS respond well to high-dose methylprednisolone. Treatment with 1 g/day of methylprednisolone for 3 to 5 days reduces the inflammatory changes in the blood vessels during an acute exacerbation. Dramatic reduction in enhancement on MRI may be seen after treatment. However, the effect is lost after several months.

Clinical Features

Patients with IIH have a constellation of symptoms that includes headaches, transient visual obscurations, pulsatile tinnitus, diplopia, and sustained visual loss. Headache is the most frequent symptom; it is the presenting symptom in most patients and is an important reason for searching for papilledema in all headache patients. The pain characteristically wakes the patient from sleep in the early morning hours. Sudden movements such as coughing aggravate the headache. Headaches may be present for months before a diagnosis is made. Some patients complain of dizziness. Transient obscuration of vision occurs when changing position from sitting to standing. Visual fields show an enlarged blind spot due to the encroachment of the swollen optic nerve head. Prolonged papilledema may lead to sector scotomas and, rarely, vision loss when the swollen disc encroaches on the region of the macula. It is important to differentiate papillitis due to inflammation from papilledema due to increased CSF pressure. In the former, vision loss is prominent early in the course and the papillary response is abnormal, whereas with papilledema, the vision is preserved until the late stages when the swollen disc encroaches on the macula. Dysfunction of one or both sixth cranial nerves may occur as an effect of shifts of cerebral tissue. Because the sixth cranial nerve is remote from the site of the process producing intracranial hypertension, the cranial neuropathy is a false localizing sign. The sixth nerve has a long course as it travels to the eye. Before entering the eye socket, it makes a ninety degree turn and goes through the canal of Dorello at the tip of the temporal bone. It is possibly at this site where compression of the abducens nerve could occur (Nathan et al., 1974).

Diagnosis requires ruling out other causes of increased ICP. All patients require a CT or MRI scan to look for hydrocephalus and mass lesions. After a mass lesion is ruled out, LP is needed, with careful attention to accurately measuring the CSF pressure, which must be elevated by definition. Characteristic CSF findings include normal or low protein, normal glucose, no cells, and elevated CSF pressure. The upper limit for normal CSF pressure is 180 mm H₂O. Most IIH patients will have readings above 200 mm H₂O, with pressures at times exceeding 500 mm H₂O. Measurement of CSF pressure should be done with the patient’s legs extended and neck straight. As noted earlier, pressures taken with the patient in the sitting position are inaccurate. Movements of the fluid column with respiration should be seen to confirm proper placement of the needle. It is important to obtain an accurate pressure reading at the time of the initial LP, since measurements of pressure in subsequent LPs may be falsely reduced by damage to the dura and the loss of fluid during the initial puncture. Occasionally, CSF leaks into the epidural space and forms a false pocket; subsequent attempts at LP may sample this space rather than the actual CSF space.

IIH occurs more frequently in women than in men. Obesity and menstrual irregularities, with excessive premenstrual weight gain, are often present. Because many illnesses may be associated with increased ICP, a search for an underlying cause is essential before the diagnosis of IIH is made by exclusion of other causes.

MRI has rekindled interest in conditions that cause occlusions of the venous sinuses. When the sinuses draining blood from the brain are obstructed, absorption of CSF is reduced, causing the pressure of the CSF to increase. MR venography (MRV) is better for showing thrombosis of the sinuses than conventional MRI. The role of venous sinus obstruction in raising ICP, although important to rule out, is uncommon. When venous sinus obstruction is found as the cause, a hypercoagulable workup is important.

Obesity is often found in women with IIH. Endocrine abnormalities have been extensively investigated in both obese and nonobese subjects, but none has been identified. Drugs associated with the syndrome include tetracycline-type antibiotics, nalidixic acid, nitrofurantoin, sulfonamides, and trimethoprim-sulfamethoxazole (Box 59.2). Paradoxically, the withdrawal of corticosteroids used to treat increased ICP can cause an increase in ICP. Large doses of vitamin A, which are used in the treatment of various skin conditions, may cause the syndrome. Hypercapnia leads to retention of carbon dioxide and increase in blood volume. Sleep apnea and lung diseases may cause headaches and papilledema due to this mechanism. Less frequent causes include Guillain-Barré syndrome, in which increased CSF protein clogs the arachnoid villa, leading to an increase in ICP. Similarly, a cellular response in meningitis may increase CSF pressure by blocking outflow pathways. Uremic patients have an increased incidence of papilledema with IIH. Renal failure patients have increased levels of vitamin A, use corticosteroids, and take cyclosporine, which have all been linked to IIH.

Table 59.3 Terms Used to Describe Different Sites of Inflammation in the CNS

Other less well-substantiated causes of elevated CSF pressure include obstruction to venous outflow. Venous pressure measurement has shown high pressure in the superior sagittal sinus and proximal transverse sinuses, with a drop in venous pressure distal to the transverse sinus (King et al., 1995). Angiography does not show this well. In patients without a documented structural defect in the venous sinuses, increased right atrial filling pressure that was transmitted to the venous sinuses has been shown (Karahalios et al., 1996). Whether the high venous pressure and imaging evidence of venous narrowing is the cause or the result of the increased ICP is controversial. Several patients with venous sinus occlusion as the cause of increased ICP have had intravascular stents placed to improve flow. In a series of 12 patients with refractory IIH who had venous pressure gradients, after stenting 7 were improved, with 5 of these becoming asymptomatic and 5 patients being unimproved (Higgins et al., 2002). There are no controlled studies of the efficacy and long-term consequences of placing venous stents in this population of younger patients, and since the normal course is resolution with time, this invasive procedure should be considered experimental until such studies are done.

Treatment

Treatment involves reducing ICP. Acetazolamide is an inhibitor of carbonic anhydrase that lowers CSF production and pressure. It is given in a dose of 1 to 2 g/day. Electrolytes must be monitored to look for metabolic acidosis. Distal paresthesias are reported to occur in up to 25% of patients. The hyperosmolar agent, glycerol (0.25-1 g/kg, 2 or 3 times daily), was advocated at one time but is no longer indicated; the increased blood sugar caused weight gain in a group of patients that are often obese. Corticosteroids reduce increased ICP, but the pressure may increase when they are tapered. In patients with rapidly progressive visual loss, corticosteroids can be given in high doses for several days before a more definitive treatment is started.

Drug effects are often transient, and when the syndrome does not resolve spontaneously, other treatments are needed. Although the relationship of obesity to IIH is uncertain, loss of weight can lead to resolution of the syndrome, and some patients have undergone bariatric surgery to control the obesity, but controlled studies of this procedure are lacking.

Visual fields should be measured and the size of the blind spot plotted. Swelling of the optic disc causes the enlarged blind spot. When papilledema spreads into the region of the macula, visual acuity falls, and in extreme cases, blindness may occur. Although most patients with IIH retain normal vision, a small percentage of patients develop impairment of vision. When vision is threatened and drugs and LPs fail to lower CSF pressure, surgical intervention is necessary.

Lumboperitoneal shunting has a reportedly high initial success rate, but subsequent shunt malfunction is common. Fenestration of the optic nerve sheath to drain CSF into the orbital region reduces the ICP, and some consider it the treatment method of choice in medically refractory patients. Stereotactic insertion of ventriculoperitoneal shunts is now possible and provides better long-term patency than lumboperitoneal shunts. In obese patients with IIH, weight loss is an important adjunct treatment, and some authors argue that it is as important as acetazolamide.

Patients with fulminant IIH are rare but require urgent treatment with acetazolamide, high-dose steroids, and optic nerve fenestration or ventriculoperitoneal shunting. In one study from two institutions, a total of 16 patients were studied, all of whom were women between the ages of 14 and 39 years. All were obese with mean CSF pressures of 541 mm H₂O. All had surgical treatment, which reduced headaches and vomiting, but 50% remained legally blind, showing the serious nature of this form of the illness (Thambisetty et al., 2007).

Brain Edema in Idiopathic Intracranial Hypertension

Several studies have suggested the presence of brain edema in patients with IIH. A biopsy showed brain edema in one patient who was subjected to a temporal decompression, a procedure that is no longer done (Sahs and Joynt, 1956). Two recent MRI studies showed edema in the white matter in patients with IIH; there was an increase in white-matter water signal of a heavily T2-weighted imaging sequence obtained at 1.5 T (Gideon et al., 1995). Another study compared diffusion maps of the apparent diffusion coefficient (ADC) in 12 patients fulfilling conventional diagnostic criteria for IIH and in 12 healthy volunteers. They reported a significantly larger ADC within subcortical white matter in the patient group than in the control group, without significant differences within cortical gray matter, the basal nuclei, the internal capsule, or the corpus callosum. In addition, 4 of 7 patients with increased ADC in subcortical white matter also had increased ADC within gray matter (Moser et al., 1988). Another group measured mean diffusivity of water and the proton longitudinal relaxation time in 10 patients with IIH and 10 age-, sex-, and weight-matched controls. They failed to find significant differences in DWI and T1 values between patient and control groups in any of the brain regions investigated, concluding that IIH is not associated with abnormalities of convective transependymal water flow leading to diffuse brain edema (Bastin et al., 2003). Thus, based on the results of MRI studies, there is no consensus as to the presence of brain edema.

Hydrocephalus in Children

In children younger than 2 years of age, enlargement of the ventricles produces an increase in head circumference because the skull sutures are still open. Children with head growth that is more rapid than expected for age are suspected of having hydrocephalus and imaged early in the course, preventing the large heads and lower-extremity spasticity that once occured as part of the childhood form of hydrocephalus.

The cause of hydrocephalus in newborns is often an infection in utero that causes scarring and closure of the cerebral aqueduct, with subsequent obstruction to the outflow of CSF. Infection in the meninges can cause scarring over the channels connecting the CSF in the ventricles with that in the subarachnoid space. Closure of the foramina of Luschka and Magendie leads to noncommunicating hydrocephalus. Obstruction of CSF circulation may result in increased CSF pressure as the cerebral ventricles enlarge, but once that has occurred compensatory drainage mechanisms may lower the CSF pressure, as is often the case in the adult with idiopathic normal-pressure hydrocephalus.

Acute noncommunicating hydrocephalus develops rapidly, reaching 80% of maximal ventricular enlargement within 6 hours owing to the continued production of CSF in spite of the increased pressure. A slower phase of enlargement follows the initial rapid expansion, and ventricular enlargement plus continual production of CSF causes fluid accumulation in the periventricular white matter interstitial space, producing interstitial brain edema. When the hydrocephalus stabilizes and enters a chronic phase, CSF pressure may decrease, resulting in normal pressure recordings on random measurements, although long-term monitoring reveals intermittent increases in ICP.

Long-standing hydrocephalus may cause atrophy in the white matter surrounding the ventricles but rarely affects the gray matter. When the rate of ventricular enlargement stabilizes in patients with incomplete ventricular obstruction, CSF production is balanced by transependymal absorption (Fig. 59.11). Occasionally a patient escapes detection of hydrocephalus in early life, and an enlarged head is the only sign of an underlying problem. Many years may elapse before the hydrocephalus manifests symptoms, and they may decompensate after many years of stability.

Fig. 59.11 Transependymal flow. Computed tomography scan performed several hours after a small amount of contrast material was infused through a ventricular shunt catheter to evaluate communication shows that dependent contrast in the lateral ventricles has diffused into the surrounding brain through the ependyma.

Hydrocephalus in children is often due to a structural abnormality such as a Chiari I or II malformation, aqueductal stenosis due to intrauterine infection, or other congenital causes such as anoxic injury, intraventricular hemorrhage, and bacterial meningitis. When the sutures are open and some expansion of the skull may be possible, the only sign of increased ICP may be bulging of the anterior fontanel along with thinning of the skull and separation of the sutures. If the diagnosis is delayed, abnormal eye movements and optic atrophy may develop. Spasticity of the lower limbs may be observed at any stage. Acute enlargement of the ventricles is associated with nausea and vomiting.

During the neonatal and early childhood period, irritability is a common symptom of hydrocephalus. The child feeds poorly, appears fretful, and may be lethargic. In the older child, headache may be a complaint. Vomiting due to increased ICP may be present in the morning. Remote effects of the increased pressure may affect the sixth cranial nerves on one or both sides, leading to the complaint of diplopia in the older child. The enlarged ventricles affect gait. A wide-based ataxic gait due to the stretching of the white matter tracts from the frontal leg regions around the ventricles may be present.

Premature infants weighing less than 1500 g at birth have a high risk of intraventricular hemorrhage, and approximately 25% of these infants develop progressive ventricular enlargement, as shown by CT or ultrasound (Papile et al., 1978). Ventricular size in the neonate may be followed at the bedside with B-mode ultrasound through the open fontanelle. Long-term follow-up studies of children with intraventricular hemorrhage due to prematurity show that 5% require shunting for hydrocephalus. The survivors of a large germinal plate hemorrhage often have multiple disabilities. Angiogenic factors play a role in the development of the hemorrhages (Ballabh et al., 2007).

Once the sutures are closed, which generally occurs by the age of 3, hydrocephalus causes signs of increased ICP rather than head enlargement. Meningitis, aqueductal stenosis, Chiari malformations, and mass lesions may be the cause of hydrocephalus in these young children. Tumors originating from the cerebellum and brainstem produce acute symptomatology including headaches, vomiting, diplopia, visual blurring, and ataxia. Symptoms are due to the acute hydrocephalus secondary to obstruction of the cerebral aqueduct and to pressure on brainstem structures.

Examination shows papilledema, possible sixth cranial nerve palsy, and spasticity of the lower limbs. When the hydrocephalus is more long-standing, endocrine dysfunction may occur, involving short stature, menstrual irregularities, and diabetes insipidus. Excessively rapid growth of the head is the hallmark of hydrocephalus in the child before closure of the sutures. Charts are available to plot head growth and compare it with standardized curves for normal children. Bulging of the anterior fontanelle is found even with the child relaxed and upright. After 1 year, the firmness of the fontanelle cannot be used, because the sutures have closed. Other findings include the “cracked-pot” sound on percussion of the skull (McEwen sign), engorged scalp veins, and abnormalities of eye movements. As spasticity develops, the deep tendon reflexes are increased.

Treatment involves shunting CSF from the ventricles to drain fluid into another body cavity. The shunted CSF is generally drained into the peritoneal cavity. Complications of shunt placement include malfunction and shunt infection. Revisions of the shunt as the child grows are frequently necessary.

Adult-Onset Hydrocephalus

In the adult, symptoms of acute hydrocephalus include headaches, papilledema, diplopia, and mental status changes. Sudden death may occur with severe increases in pressure. Although rare, hydrocephalus can cause an akinetic mutism due to pressure on the structures around the third ventricle. Other symptoms include temporal lobe seizures, CSF rhinorrhea, endocrine dysfunction (e.g., amenorrhea, polydipsia, polyuria), and obesity, which suggest third ventricle dysfunction. Gait disturbances are reported in patients with aqueductal stenosis, but hyperreflexia with Babinski sign is infrequent.

The causes of adult-onset hydrocephalus are similar to those in children, but the frequencies differ. As in children, acute obstruction of the ventricles in adults results in rapidly progressive hydrocephalus with symptoms of raised ICP. Adults are more likely than children to present with an acute blockage of CSF flow by intraventricular masses, such as a colloid cyst of the third ventricle, an ependymoma of the fourth ventricle, or the intraventricular racemose form of cysticercosis. Masses obstructing CSF outflow cause sudden headaches, ataxia, and loss of consciousness. Diagnosis may be difficult in patients with colloid cysts when the symptoms are intermittent because of the ball-valve effect of the mass.

Cerebellar hemorrhage and cerebellar infarction with edema cause an acute hydrocephalus by compression of the brainstem, occluding the cerebral aqueduct and fourth ventricle outflow pathways and causing noncommunicating hydrocephalus and acute elevation in intraventricular pressure. Patients with cerebellar hemorrhage usually have a history of hypertension. Increasing drowsiness and difficulty walking often follow the acute onset of headache. Hemiparesis and brainstem findings evolve after the ataxia, providing a clue that the origin of the problem is in the posterior fossa. The expanding hemorrhagic mass in the posterior fossa, if it is encroaching on the brainstem, requires urgent neurosurgical attention, with placement of a ventricular catheter to decompress the lateral and third ventricles, followed by posterior fossa craniectomy to remove the mass and reduce pressure on the brainstem (Fisher et al., 1965; Ott et al., 1974). In patients with cerebellar infarction, the progression is generally slower, since the maximum swelling takes place in 24 to 48 hours, but the consequences of the enlarging posterior fossa mass are the same as with hemorrhage, and surgery may be necessary to remove the necrotic tissues and restore normal CSF flow. CT is helpful to show enlargement of the ventricle, but MRI is better for imaging the cerebellar infarction (Fig. 59.12).

Fig. 59.12 Cerebellar infarct with secondary hydrocephalus. A, Initial diffusion-weighted image with cerebellar infarct in the territory of the left posterior inferior cerebellar artery. B, Initial axial T2-weighted magnetic resonance imaging shows normal ventricular size. C, Diffusion-weighted image 3 days later, showing swelling of the infarction in the cerebellum. D, Echo-planar T2 axial image shows enlargement of the ventricles prior to surgery for hydrocephalus.

Treatment of adult hydrocephalus involves an operation to insert a tube to shunt CSF from the ventricles to the peritoneal cavity. These devices have one-way valves that respond to pressure. In an emergency, hydrocephalic ventricles can be assessed readily owing to the increase in their size. Shunt malfunction may cause abrupt decompensation. Symptoms of acute increased ICP from a shunt malfunction resemble those seen with onset of the hydrocephalic process.

Adult-onset hydrocephalus that is communicating may be due to a tumor in the basal cisterns, subarachnoid bleeding, or infection or inflammation of the meninges. In the preantibiotic era, syphilis, tuberculosis, and fungal infections were a common cause of hydrocephalus due to chronic obstruction of subarachnoid pathways (McHugh, 1964). CSF cultures are indicated in the elderly patient with enlarged ventricles, and searching for other sources of infection in lungs and other organs may be helpful in establishing the type of infection.

Normal-Pressure Hydrocephalus

Chronic hydrocephalus in the adult can produce symptoms of gait disturbance, incontinence, and memory loss, with or without symptoms and signs of raised ICP including headache, papilledema, and false localizing signs (Adams et al., 1965). Causes of chronic hydrocephalus include post subarachnoid hemorrhage, chronic meningeal infections (e.g., fungal, tuberculosis, syphilis), and slow-growing tumors blocking the CSF pathways.

Normal-pressure hydrocephalus (NPH) is a term commonly used to describe chronic communicating adult-onset hydrocephalus (Marmarou et al., 2005). Typically, patients with NPH have the triad of mental impairment, gait disturbance, and incontinence. NPH can develop secondary to trauma, infection, or subarachnoid hemorrhage, but in about one-third of patients, no etiology is found. Enlarged ventricles are seen on CT, and MRI shows both the enlarged ventricles and transependymal CSF absorption. By definition, LP generally reveals a normal or minimally elevated CSF pressure. Normal pressure is an unfortunate term, because patients who have undergone long-term monitoring with this syndrome have intermittently elevated pressures, often during the night.

The presenting symptoms may be related to gait or mental function. When gait is the presenting factor, the prognosis for treatment is better. NPH causes an apraxic gait, which is an inability to lift the legs, as if they were stuck to the floor. Motor strength is intact, reflexes are usually normal or slightly increased, and Babinski signs are absent. In some patients, attempts to elicit a Babinski sign will result in a grasp response of the toes, suggestive of frontal lobe damage. Patients may be misdiagnosed as having Parkinson disease, because the gait disorder is similar in the two syndromes, suggesting that the etiology of the problem in the hydrocephalic patient lies in the basal ganglia. Because many of these patients also have hypertension, and some have small or large strokes, such patients may have other neurological findings including spasticity and hyperreflexia with Babinski signs.

NPH leads to a reduction in intellect, which at times may be subtle. The dementia is of the subcortical type and involves slowing of verbal and motor responses, with preservation of cortical functions such as language and spatial resolution. Neuropsychological testing quantifies the decline in intellect and the degree of dementia. Patients are apathetic and appear depressed. Incontinence of urine may occur early in the course, particularly in patients with prominent gait disturbance. In the early stages of the illness, presumably as the ventricles are undergoing enlargement, patients can experience drop attacks or brief loss of consciousness. Headache and papilledema are generally not part of the syndrome.

Diagnosis of adult-onset hydrocephalus and selection of patients for placement of a ventriculoperitoneal shunt has been difficult. Many of these patients have hypertensive vascular disease with lacunar infarcts. Features of Parkinson disease were noted in earlier reports of the syndrome, and it is now recommended that all patients with Parkinson disease have scans to rule out hydrocephalus. CT and MRI have aided in separating Parkinson disease, lacunar state, and NPH, although NPH may occasionally coexist with these diseases. Patients diagnosed with vascular diseases such as lacunar state or subcortical arteriosclerotic encephalopathy (Binswanger disease) along with the hydrocephalus respond poorly to shunting, and if there is a positive response, it may be transient as the underlying disease progresses (Boon et al., 1999; Tullberg et al., 2002). Selection of patients for shunting requires a combination of clinical findings and diagnostic test results, because no test can totally predict whether a patient will likely benefit from an operation.

There may be a correlation between improvement in gait after a large volume of CSF is removed, which suggests that the patient would benefit from a shunt. Cisternography has been used in diagnosis; it is a procedure that involves injecting a radiolabeled tracer into the CSF, then monitoring its absorption for 3 days. Normally the radiolabeled material fails to enter the ventricles, moving over the convexity of the brain and leaving the CSF space within 12 to 24 hours. In patients with large ventricles due to atrophy, there may be a delay in circulation time, with some isotope being seen in the ventricles during the first 24 hours (Benson et al., 1970). Communicating hydrocephalus with abnormal CSF circulation shows persistent ventricular filling for more than 48 hours. In patients with NPH, there is reflux of the tracer into the cerebral ventricles by 24 hours and retention in the ventricles for 48 to 72 hours. This suggests that transependymal absorption is occurring and that periventricular white matter has become an alternate route of CSF absorption. A positive cisternogram is seen in some patients with hypertensive cerebrovascular disease and Binswanger encephalopathy because of the overlap in the three syndromes.

Infusion of artificial CSF into the lumbar sac at a constant rate shows increased resistance to absorption of CSF, presumably across the arachnoid granulations, in patients with NPH (Katzman and Hussey, 1970). Variations on the infusion test are used, and some investigators report usefulness of the test in making treatment decisions. There is a revival of interest in determining both the resistance to absorption and the compliance or elasticity of the ventricles as an aid in selecting shunt patients.

Neuroimaging in patients with NPH has shown an enlargement of the temporal horns of the lateral ventricle, with a disproportionate amount of cortical atrophy than anticipated for the age of the patient. This is in contrast to patients with hydrocephalus ex vacuo due to a degenerative disease such as Alzheimer disease, in which there is atrophy of the cerebral gyri and enlargement of both the sulci and ventricles. Another useful finding on proton-density MRI is the presence of presumed transependymal fluid in the frontal and occipital periventricular regions. Quantitative cisternography using single-photon emission CT has been successfully used to predict the results of a shunt. Other proposed diagnostic methods, including measuring the rate of absorption of CSF by infusion of saline or artificial CSF into the thecal sac, clinical improvement after CSF removal, or the prolonged monitoring of ICP, have been used with some success to select patients for surgery. Decreased cerebral blood flow has been reported in NPH; regional cerebral blood flow is reduced in both cortical and subcortical regions. Patients who show clinical improvement with shunting have a concomitant increase in cerebral blood flow. Removal of CSF may result in an increase in cerebral blood flow in patients in whom NPH is likely to respond to shunt therapy.

A large number of patients underwent placement of ventriculoperitoneal shunts after the initial report of NPH and the subsequent enthusiasm that this would cure dementia (Adams et al., 1965). As the number of patients that showed no improvement with shunts grew and the complication rates of placing a shunt in an elderly patient became evident, the number of patients undergoing shunt operations at most centers declined. This trend may be reversing with the improvements in patient selection. However, none of the currently available tests by themselves identifies the patients who will benefit from shunting. Most helpful is a combination of clinical signs and judiciously chosen laboratory tests.

Various success rates for shunt placement have been reported; some reports describe improvement in approximately 80% of treated patients, while others report lower rates. In the early days of treatment of NPH patients with shunts, a high rate of shunt failure occurred, with complications of shunting being a major problem (Katzman and Wells, 1977). Serious complications occurred in as many as one-fourth of the patients, including infection and subdural hematomas. More recently, the rates of correct diagnosis and complication-free treatments have improved, but the definitive diagnostic test and complication-free treatment remain elusive goals (Marmarou et al., 2005). Clearly, more information is needed to aid in the diagnosis and management of patients with this potentially treatable syndrome.