Cerebrospinal Fluid Has Many Functions

To work properly, the CNS needs protection not only from physical injury but also from significant variation in the local environment of its neurons. A buildup of toxins or a significant change in ionic concentration in this neuronal microenvironment could result in pathological changes in neuronal physiology.

One of the most important functions of CSF is to cushion the brain, protecting it against blows to the head. Because the specific gravities of the brain and CSF are similar, the brain floats in the fluid. Thus the force of a blow to the head is buffered by the CSF instead of being transferred directly to brain tissue.

Because the composition of the CSF is tightly controlled and it is in equilibrium with the extracellular fluid of the brain and spinal cord, the CSF also helps maintain a consistent extracellular microenvironment for the neurons and glia of the CNS. This diffusional equilibrium between the CSF and the extracellular fluid, in conjunction with the flow and multiple daily turnover of the CSF, also makes the CSF an effective waste control system that can remove potentially harmful cellular metabolites. Evidence indicates that these properties may also allow the CSF to function as a brain distribution system for some polypeptide hormones and growth factors that are secreted into the CSF.

Most Cerebrospinal Fluid Is Formed at the Choroid Plexus of the Ventricles

The ventricles are a series of interconnected cavities in the core of the brain that have an ependymal cell lining and are filled with CSF (Figure 15-2). The lateral ventricles are respectively located in the two cerebral hemispheres, the third ventricle is found at the midline of the diencephalon, and the fourth ventricle is located between the cerebellum and the dorsal surface of the hindbrain (pons and medulla) (Figure 15-3).

FIGURE 15-2 Lateral view of the ventricular cavities and their approximate spatial position within the brain.

(Modified from Fletcher TF: Spinal cord and meninges. In Evans HE, editor: Miller’s anatomy of the dog, ed 3, Philadelphia, 1993, Saunders.)

FIGURE 15-3 Midsagittal section of the brain showing portions of the ventricles and subarachnoid space, the choroid plexuses that produce CSF, and the dorsal sagittal sinus into which CSF is absorbed. The cisterna magna is a common location for the sampling of CSF. The CSF is colored light orange. III, third ventricle; IV, fourth ventricle.

(Modified from Fletcher TF: Spinal cord and meninges. In Evans HE, editor: Miller’s anatomy of the dog, ed 3, Philadelphia, 1993, Saunders.)

The majority of CSF is formed by a choroid plexus located in each of the four ventricles. These are small, cauliflower-like growths of clustered villi that form a portion of the floor or roof of each ventricle (Figure 15-3). The plexuses consist of tufts of capillaries covered by a layer of ependymal cells. These ependymal cells, unlike the cells lining the rest of the ventricle, form a selective, tight-junction barrier to the secretions of the leaky capillaries and to other surrounding fluids (e.g., CSF, extracellular fluid). Membrane transporters and selective channels regulate the passage of ions and molecules across the ependymal cell barrier, effectively controlling the composition of the CSF being synthesized in the ventricle. The active transport of sodium ions (Na⁺) contributes to a net movement of sodium chloride (NaCl) into the ventricles. This osmotic gradient regulates the water content of the CSF as water follows the NaCl passively into the ventricle. There is evidence that some potentially harmful metabolic waste products deposited in the CSF can actually be absorbed and removed by the choroid plexus.

It is important to note that CSF is formed at an almost constant rate, independent of either CSF pressure or blood pressure. Therefore, if CSF pressure or general intracranial pressure were to rise as a result of an obstruction to CSF flow or a space-occupying mass, CSF formation would continue.

Cerebrospinal Fluid Flows down a Pressure Gradient Through the Ventricular System into the Subarachnoid Space

CSF flows, by bulk, down a pressure gradient from its site of formation at the choroid plexuses through the ventricular system and subarachnoid space into the venous system. Fluid formed in the lateral ventricles passes into the third ventricle through the interventricular foramina (foramina of Monro) (see Figures 15-1, 15-2, and 15-3). The fluid mixes with fluid formed in the third ventricle and from there passes through the cerebral aqueduct (aqueduct of Sylvius) of the midbrain into the fourth ventricle. Fluid in the fourth ventricle passes into the subarachnoid space through two lateral apertures or foramina of Luschka. Some mammals have a third, medially located passageway from fourth ventricle to subarachnoid space (foramen of Magendie).

Recall that the brain and spinal cord are encased in bone (the skull and spinal canal, respectively) and covered by a series of three membranes called the meninges (see Chapter 3). From outer to inner, these membranes are the dura, arachnoid, and pia (see Figure 15-1). The subarachnoid space lies between the arachnoid and pia, and when the CSF exits the brain through the apertures (foramina) of the fourth ventricle, the CSF fills this space, spreading out over the entire outer surface of the brain and spinal cord. Thus the entire CNS is essentially floating in a fluid-filled, membranous bag. As the CSF circulates up over the dorsal convexity of the brain, it is absorbed into the venous system near the midline.

The pressure, cell count, and chemical constituents of CSF can be sampled by placing a styletted spinal needle into the subarachnoid space. Anatomically, the most convenient place to perform this varies with species. In humans it is usually performed in the lumbar spinal column because the human spinal cord tapers to a cone (conus medullaris) near the first lumbar vertebra (humans have five lumbar vertebrae) as the dura and arachnoid continue down to around the second sacral vertebra. This provides a relatively large subarachnoid space in the human midlumbar spinal column from which to sample. In most veterinary species, however, the conus medullaris extends to about the sixth or seventh lumbar vertebra, leaving only a small subarachnoid space. Therefore, most veterinary spinal taps are performed by sampling from the subarachnoid space between the skull and the first cervical vertebra in anesthetized animals. In this location the subarachnoid space, formed as the arachnoid stretches from the caudal cerebellar surface to the dorsal surface of the medulla, is called the cisterna magna (“big cistern”) and is much deeper than other portions of the subarachnoid space (see Figure 15-3). Spinal taps provide valuable information about such neuropathological lesions as intracranial space-occupying masses and inflammation.

Cerebrospinal Fluid Is Absorbed into the Venous System

CSF is absorbed into the venous system, principally into a dura-lined venous sinus (dorsal sagittal sinus) that lies between the dorsal surfaces of the cerebral hemispheres (see Figure 15-3). Most of the fluid is absorbed from the subarachnoid space into the dural sinus through arachnoid villi (Figure 15-4). These are small, fingerlike projections of the arachnoid membrane that poke through the walls of the sinus. Absorption appears to be pressure dependent and is unidirectional; CSF can flow from subarachnoid space to venous sinus, but venous blood cannot normally move from the sinus back into the subarachnoid space. The movement of CSF into the venous sinus is sometimes referred to as a “bulk flow” because all constituents of the fluid, including waste products and other foreign matter (e.g., red blood cells) move into the sinus. Whether materials cross the cells of the arachnoid villi by vesicular transport or by the formation and movement of giant, fluid-filled vacuoles is still a subject of debate. The entire volume of CSF is replaced approximately six times per day in species such as sheep and goat.

FIGURE 15-4 Transverse (coronal) section through the dorsal midline of the brain showing the absorption of CSF into the dorsal sagittal sinus, through arachnoid villi. The CSF is colored light blue. The small window on the dog’s head shows the approximate dorsoventral position of the sinus.

(Modified from Oliver JE, Lorenz MD: Handbook of veterinary neurology, ed 2, Philadelphia, 1993, Elsevier-Saunders.)

In normal animals, CSF pressure is regulated primarily by its absorption at the arachnoid villi because the rate of absorption can respond to changes in CSF pressure, whereas its formation is fairly constant and independent of changes in pressure. Therefore, any obstruction of CSF absorption into the venous sinus causes CSF pressure to rise almost immediately. In some pathological conditions, such as brain tumors or meningitis, CSF pressure can increase dramatically.

Hydrocephalus Is an Increased Volume of Cerebrospinal Fluid in the Skull

Hydrocephalus is defined as an increased CSF volume in the skull, often associated with an increased ventricular volume and increased intracranial pressure. In theory, hydrocephalus could be caused by too much fluid production at the choroid plexuses, obstruction to its flow through the ventricular system or subarachnoid space, or impaired absorption at the arachnoid villi. In practice, overproduction seems rare, whereas obstruction to flow seems more common, particularly at such vulnerable sites as the narrow cerebral aqueduct (connecting the third and fourth ventricles) and the exits from the fourth ventricle. Such blockages in the ventricular system produce a noncommunicating hydrocephalus that results in a buildup of freshly produced CSF in portions of the ventricular system behind the blockage. This causes the ventricular regions inside the brain to expand at the expense of the surrounding brain tissue, and intracranial pressure rises.

Impairment of absorption (a type of communicating hydrocephalus) can be secondary to meningitis or hemorrhage, presumably as a result of cellular debris that obstructs the transfer of CSF from subarachnoid space to venous sinus at the arachnoid villi. This can increase CSF volume in the subarachnoid space, which increases pressure on the outside surface of the brain and increases intracranial pressure.

The pathogenesis of many cases of hydrocephalus is not known. A common form of treatment in humans is surgical implantation of a tube that shunts CSF into the atria of the heart or into the peritoneal cavity, thus relieving episodes of increased CSF pressure and preventing further brain damage.

Permeability Barriers Exist Between Blood and Brain

Many dyes, once injected into the blood, stain other tissues of the body but not the brain. This suggests that the brain’s blood vessels have the ability to restrict certain substances from accessing brain tissue. This physiological property of CNS blood vessels is referred to as the blood-brain barrier (BBB). The BBB contributes to a stable environment for the neurons and glial cells of the CNS. As Claude Bernard noted more than a century ago, homeostasis, or constancy of the internal environment, is a precondition for autonomous life. It is not surprising that the brain, the “master choreographer of autonomous life,” should have special mechanisms for protecting its internal environment. Such protection from direct exposure to the blood supply is necessary because the composition of blood can significantly vary with factors such as diet, exercise, metabolic activity, illness, age, and exposure to environmental toxins. Many of the varying blood-borne nutrients, metabolites, and toxins are neuroactive and capable of affecting membrane receptors, transporters, or ion channels. In the absence of a BBB, these substances could result in unregulated and undesirable changes in neural activity and behavior.

In most capillaries, water-soluble compounds leave through open clefts between capillary endothelial cells, and exchange is relatively unrestricted. In brain capillaries, however, passage through intercellular clefts is blocked by tight junctions, and exchange of blood solutes is highly selective (Figure 15-5). As a general rule, molecules that are small, uncharged, lipid soluble, and unbound to plasma proteins (e.g., O₂, CO₂, ethanol, nicotine) can easily pass across the capillary endothelium of the BBB. Some molecules that do not fit this profile (e.g., glucose, some amino acids) are able to pass through the BBB by specific, carrier-mediated transport mechanisms. Brain capillaries have a greater number of mitochondria, which reflects the operation of such transporters. Certain degradative enzymes expressed by brain capillary endothelium (e.g., monoamine oxidase) provide a further restriction on substances that can pass the BBB. A notable feature of brain capillaries is that they are surrounded by a layer of glial astrocytic “end-feet.” these end-feet are thought to play a role in formation of the capillary endothelial tight junctions during development. evidence also indicates that the end-feet interact with the BBB-forming capillary endothelial cells and neurons to facilitate molecular homeostasis of the brain.

FIGURE 15-5 Blood-brain barrier (BBB). Unlike most capillaries of the body, cells of brain capillary walls are joined by tight junctions that restrict the passage of material between the cells. Materials leaving brain capillaries must pass through the cells forming the capillary wall. Substances that are not small, uncharged, and lipophilic must be carried across the cells by selective transport mechanisms. Astrocytic end-feet are thought to contribute to the tight-junction organization during development.

Unfortunately, for many patients, the protection afforded to the CNS by the BBB often prevents many antibiotics and other drugs from reaching the brain, particularly drugs with low lipid solubility or drugs bound to plasma proteins. Attempts to circumvent this problem have focused on temporary disruption of the BBB, direct delivery to the brain, “hitching a ride” on BBB membrane transporters, and increasing the lipid solubility of drugs.

In some parts of the brain known as the circumventricular organs, which include the hypothalamus, the brain capillaries do not form tight junctions, and the BBB is apparently not effective. This is significant because these brain regions are involved in functions such as the control of serum osmolality and glucose levels, hormonal communication, feeding, drinking, and vomiting, and therefore they need to detect the levels of many serum solutes.

Increased Intracranial Pressure

Seizures in a Foal