Cerebrospinal fluid is formed at a rate of about 500 milliliters each day, which is three to four times as much as the total volume of fluid in the entire cerebrospinal fluid system. About two thirds or more of this fluid originates as secretion from the choroid plexuses in the four ventricles, mainly in the two lateral ventricles. Additional small amounts of fluid are secreted by the ependymal surfaces of all the ventricles and by the arachnoidal membranes. A small amount comes from the brain through the peri vascular spaces that surround the blood vessels passing through the brain.
The arrows in Figure 1 show that the main channels of fluid flow from the choroid plexuses and then through the cerebrospinal fluid system. The fluid secreted in the lateral ventricles passes first into the third ventricle; then, after addition of minute amounts of fluid from the third ventricle, it flows downward along the aqueduct of Sylvius into the fourth ventricle, where still another minute amount of fluid is added. Finally, the fluid passes out of the fourth ventricle through three small openings, two lateral foramina of Luschka and a midline foramen of Magendie, entering the cisterna magna, a fluid space that lies behind the medulla and beneath the cerebellum.
Fig1. The arrows show the pathway of cerebrospinal fluid flow from the choroid plexuses in the lateral ventricles to the arachnoidal villi protruding into the dural sinuses.
The cisterna magna is continuous with the subarachnoid space that surrounds the entire brain and spinal cord. Almost all the cerebrospinal fluid then flows upward from the cisterna magna through the subarachnoid spaces surrounding the cerebrum. From here, the fluid flows into and through multiple arachnoidal villi that project into the large sagittal venous sinus and other venous sinuses of the cerebrum. Thus, any extra fluid empties into the venous blood through pores of these villi.
Secretion by the Choroid Plexus. The choroid plexus, a section of which is shown in Figure 2, is a cauliflower-like growth of blood vessels covered by a thin layer of epithelial cells. This plexus projects into the temporal horn of each lateral ventricle, the posterior portion of the third ventricle, and the roof of the fourth ventricle.
Fig2. Choroid plexus in a lateral ventricle.
Secretion of fluid into the ventricles by the choroid plexus depends mainly on active transport of sodium ions through the epithelial cells lining the outside of the plexus. The sodium ions in turn pull along large amounts of chloride ions as well because the positive charge of the sodium ion attracts the chloride ion’s negative charge. The two ions combined increase the quantity of osmotically active sodium chloride in the cerebrospinal fluid, which then causes almost immediate osmosis of water through the membrane, thus providing the fluid of the secretion.
Less important transport processes move small amounts of glucose into the cerebrospinal fluid and both potassium and bicarbonate ions out of the cerebrospinal fluid into the capillaries. Therefore, the resulting characteristics of the cerebrospinal fluid become the following: osmotic pressure, approximately equal to that of plasma; sodium ion concentration, also approximately equal to that of plasma; chloride ion, about 15 percent greater than in plasma; potassium ion, approximately 40 percent less; and glucose, about 30 percent less.
Absorption of Cerebrospinal Fluid Through the Arachnoidal Villi. The arachnoidal villi are microscopic fingerlike inward projections of the arachnoidal membrane through the walls and into the venous sinuses. Conglomerates of these villi form macroscopic structures called arachnoidal granulations that can be seen protruding into the sinuses. The endothelial cells covering the villi have been shown by electron microscopy to have vesicular passages directly through the bodies of the cells large enough to allow relatively free flow of (1) cerebrospinal fluid, (2) dissolved protein molecules, and (3) even particles as large as red and white blood cells into the venous blood.
Perivascular Spaces and Cerebrospinal Fluid. The large arteries and veins of the brain lie on the surface of the brain but their ends penetrate inward, carrying with them a layer of pia mater, the membrane that covers the brain, as shown in Figure 3. The pia is only loosely adherent to the vessels, so a space, the perivascular space, exists between it and each vessel. Therefore, perivascular spaces follow both the arteries and the veins into the brain as far as the arterioles and venules go.
Fig3. Drainage of a perivascular space into the subarachnoid space. (Modified from Ranson SW, Clark SL: Anatomy of the Nervous System. Philadelphia: WB Saunders, 1959.)
Lymphatic Function of the Perivascular Spaces. As is true elsewhere in the body, a small amount of protein leaks out of the brain capillaries into the interstitial spaces of the brain. Because no true lymphatics are present in brain tissue, excess protein in the brain tissue leaves the tissue flowing with fluid through the perivascular spaces into the subarachnoid spaces. Upon reaching the sub arachnoid spaces, the protein then flows with the cere brospinal fluid, to be absorbed through the arachnoidal villi into the large cerebral veins. Therefore, perivascular spaces, in effect, are a specialized lymphatic system for the brain.
In addition to transporting fluid and proteins, the perivascular spaces transport extraneous particulate matter out of the brain. For instance, whenever infection occurs in the brain, dead white blood cells and other infectious debris are carried away through the perivascular spaces.
Cerebrospinal Fluid Pressure
The normal pressure in the cerebrospinal fluid system when one is lying in a horizontal position averages 130 mm of water (10 mm Hg), although this pressure may be as low as 65 mm of water or as high as 195 mm of water even in the normal healthy person.
Regulation of Cerebrospinal Fluid Pressure by the Arachnoidal Villi. The normal rate of cerebrospinal fluid formation remains nearly constant, so changes in fluid formation are seldom a factor in pressure control. Conversely, the arachnoidal villi function like “valves” that allow cerebrospinal fluid and its contents to flow readily into the blood of the venous sinuses while not allowing blood to flow backward in the opposite direction. Normally, this valve action of the villi allows cerebrospinal fluid to begin to flow into the blood when cerebrospinal fluid pressure is about 1.5 mm Hg greater than the pressure of the blood in the venous sinuses. Then, if the cerebrospinal fluid pressure rises still higher, the valves open more widely. Under normal conditions, the cerebrospinal fluid pressure almost never rises more than a few millimeters of mercury higher than the pressure in the cerebral venous sinuses.
In disease states, the villi sometimes become blocked by large particulate matter, by fibrosis, or by excesses of blood cells that have leaked into the cerebrospinal fluid in brain diseases. Such blockage can cause high cerebrospinal fluid pressure, as described in the following section.
High Cerebrospinal Fluid Pressure in Pathological Conditions of the Brain. Often a large brain tumor elevates the cerebrospinal fluid pressure by decreasing reabsorption of the cerebrospinal fluid back into the blood. As a result, the cerebrospinal fluid pressure can rise to as much as 500 mm of water (37 mm Hg) or about four times normal.
The cerebrospinal fluid pressure also rises considerably when hemorrhage or infection occurs in the cranial vault. In both these conditions, large numbers of red and/or white blood cells suddenly appear in the cerebrospinal fluid and can cause serious blockage of the small absorption channels through the arachnoidal villi. This also sometimes elevates the cerebrospinal fluid pressure to 400 to 600 mm of water (about four times normal).
Some babies are born with high cerebrospinal fluid pressure, which is often caused by abnormally high resistance to fluid reabsorption through the arachnoidal villi, resulting either from too few arachnoidal villi or from villi with abnormal absorptive properties. This is discussed later in connection with hydrocephalus.
Measurement of Cerebrospinal Fluid Pressure. The usual procedure for measuring cerebrospinal fluid pressure is simple: First, the person lies exactly horizontally on his or her side so that the fluid pressure in the spinal canal is equal to the pressure in the cranial vault. A spinal needle is then inserted into the lumbar spinal canal below the lower end of the cord, and the needle is connected to a vertical glass tube that is open to the air at its top. The spinal fluid is allowed to rise in the tube as high as it will. If it rises to a level 136 mm above the level of the needle, the pressure is said to be 136 mm of water pressure—or, upon dividing this number by 13.6, which is the specific gravity of mercury, about 10 mm Hg pressure.
Obstruction to Flow of Cerebrospinal Fluid Can Cause Hydrocephalus. “Hydrocephalus” means excess water in the cranial vault. This condition is frequently divided into communicating hydrocephalus and noncommunicating hydrocephalus. In communicating hydrocephalus, fluid flows readily from the ventricular system into the sub arachnoid space, whereas in noncommunicating hydro cephalus, fluid flow out of one or more of the ventricles is blocked.
Usually the noncommunicating type of hydrocephalus is caused by a block in the aqueduct of Sylvius, resulting from atresia (closure) before birth in many babies or from blockage by a brain tumor at any age. As fluid is formed by the choroid plexuses in the two lateral and the third ventricles, the volumes of these three ventricles increase greatly, which flattens the brain into a thin shell against the skull. In neonates, the increased pressure also causes the whole head to swell because the skull bones have not yet fused.
The communicating type of hydrocephalus is usually caused by blockage of fluid flow in the subarachnoid spaces around the basal regions of the brain or by blockage of the arachnoidal villi where the fluid is normally absorbed into the venous sinuses. Fluid therefore collects both on the outside of the brain and to a lesser extent inside the ventricles. This will also cause the head to swell tremendously if it occurs in infancy when the skull is still pliable and can be stretched, and it can damage the brain at any age. A therapy for many types of hydrocephalus is surgical placement of a silicone tube shunt all the way from one of the brain ventricles to the peritoneal cavity where the excess fluid can be absorbed into the blood.
Blood–Cerebrospinal Fluid and Blood-Brain Barriers
It has already been pointed out that the concentrations of several important constituents of cerebrospinal fluid are not the same as in extracellular fluid elsewhere in the body. Furthermore, many large molecules hardly pass at all from the blood into the cerebrospinal fluid or into the interstitial fluids of the brain, even though these same sub stances pass readily into the usual interstitial fluids of the body. Therefore, it is said that barriers, called the blood cerebrospinal fluid barrier and the blood-brain barrier, exist between the blood and the cerebrospinal fluid and brain fluid, respectively.
Barriers exist both at the choroid plexus and at the tissue capillary membranes in essentially all areas of the brain parenchyma except in some areas of the hypothalamus, pineal gland, and area postrema, where substances diffuse with greater ease into the tissue spaces. The ease of diffusion in these areas is important because they have sensory receptors that respond to specific changes in the body fluids, such as changes in osmolality and in glucose concentration, as well as receptors for peptide hormones that regulate thirst, such as angiotensin II. The blood-brain barrier also has specific carrier molecules that facilitate transport of hormones, such as leptin, from the blood into the hypothalamus where they bind to specific receptors that control other functions such as appetite and sympathetic nervous system activity.
In general, the blood-cerebrospinal fluid and blood brain barriers are highly permeable to water, carbon dioxide, oxygen, and most lipid-soluble substances such as alcohol and anesthetics; slightly permeable to electrolytes such as sodium, chloride, and potassium; and almost totally impermeable to plasma proteins and most non-lipid- soluble large organic molecules. Therefore, the blood cerebrospinal fluid and blood-brain barriers often make it impossible to achieve effective concentrations of therapeutic drugs, such as protein antibodies and non-lipid-soluble drugs, in the cerebrospinal fluid or parenchyma of the brain.
The cause of the low permeability of the blood cerebrospinal fluid and blood-brain barriers is the manner in which the endothelial cells of the brain tissue capillaries are joined to one another. They are joined by so-called tight junctions. That is, the membranes of the adjacent endothelial cells are tightly fused rather than having large slit pores between them, as is the case for most other capillaries of the body.
Brain Edema
One of the most serious complications of abnormal cerebral fluid dynamics is the development of brain edema. Because the brain is encased in a solid cranial vault, accumulation of extra edema fluid compresses the blood vessels, often causing seriously decreased blood flow and destruction of brain tissue.
The usual cause of brain edema is either greatly increased capillary pressure or damage to the capillary wall that makes the wall leaky to fluid. A common cause is a serious blow to the head, leading to brain concussion, in which the brain tissues and capillaries are traumatized and capillary fluid leaks into the traumatized tissues.
Once brain edema begins, it often initiates two vicious circles because of the following positive feedbacks:
1. Edema compresses the vasculature, which in turn decreases blood flow and causes brain ischemia. The ischemia in turn causes arteriolar dilation with still further increase in capillary pressure. The increased capillary pressure then causes more edema fluid, so the edema becomes progressively worse.
2. The decreased cerebral blood flow also decreases oxygen delivery, which increases the permeability of the capillaries, allowing still more fluid leakage. It also turns off the sodium pumps of the neuronal tissue cells, thus allowing these cells to swell in addition.
Once these two vicious circles have begun, heroic measures must be used to prevent total destruction of the brain. One such measure is to infuse intravenously a concentrated osmotic substance, such as a concentrated mannitol solution, which pulls fluid by osmosis from the brain tissue and breaks up the vicious circles. Another procedure is to remove fluid quickly from the lateral ventricles of the brain by means of ventricular needle puncture, thereby relieving the intracerebral pressure.
