Cerebrospinal Fluid and the Blood-Brain Barrier

1. Cerebrospinal fluid has many functions.

2. Most cerebrospinal fluid is formed at the choroid plexus of the ventricles.

3. Cerebrospinal fluid flows down a pressure gradient through the ventricular system into the subarachnoid space.

4. Cerebrospinal fluid is absorbed into the venous system.

5. Hydrocephalus is an increased volume of cerebrospinal fluid in the skull.

6. Permeability barriers exist between blood and brain.

Cerebrospinal fluid (CSF) is a clear fluid present in the ventricles (core cavities) of the brain, in the central canal that runs through the core of the spinal cord, and in the subarachnoid space that surrounds the entire outer surface of the brain and spinal cord (Figure 15-1). The CSF contains almost no blood cells, little protein, and differs from plasma with respect to the concentration of various ions. Its rates of formation, flow, and absorption are sufficiently high to cause its replacement several times daily. Sampling its pressure, cell count, and levels of various biochemical constituents is a common diagnostic procedure for central nervous system pathology called a spinal tap. Injecting radiopaque dyes into the CSF of the subarachnoid space is the basis of a common neuroradiographic technique called myelography, often used in conjunction with computerized tomography (CT scan), which can assess the integrity of the spinal canal. Obstruction of the flow of CSF produces a condition called hydrocephalus. An understanding of the formation, flow, and absorption of CSF is essential for understanding these diagnostic procedures and the pathophysiology of hydrocephalus.

FIGURE 15-1 Schematic diagram of the relationships among the central nervous system, ventricles, cerebrospinal fluid (CSF), and meninges. The CSF is colored pink. *LV,* Lateral ventricle; *III,* third ventricle; *IV,* fourth ventricle; *solid curved arrow,* interventricular foramen; *solid straight arrow,* cerebral aqueduct; *dashed curved arrow,* lateral aperture of the fourth ventricle. (Modified from Behan M: Organization of the nervous system. In Reece WO, editor: *Duke’s physiology of domestic animals,* ed 12, Ithaca, NY, 2004, Comstock Publishing.)

The blood-brain barrier (BBB) refers to the selective nature of central nervous system (CNS) blood vessels with respect to the materials that can move across their walls, compared with blood vessels in other parts of the body. Understanding the BBB helps clarify how the brain is protected from potentially harmful neuroactive chemicals in the blood, and why it is difficult to deliver certain drugs effectively to the brain.

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. *Arrows* represent the flow of cerebrospinal fluid through and ultimately out from the ventricles at the lateral apertures. (From deLahunta A and Glass E: *Veterinary neurology and clinical neurology,* ed 3, St. Louis, 2009, 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 (see 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 are 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 the subarachnoid 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 (lumbar cistern) 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 in the spinal column. Therefore, most veterinary spinal taps are performed by sampling from the subarachnoid space region that is accessed between the skull and the first cervical vertebra (atlas) in anesthetized animals (Figure 15-4). 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”; also called cerebellomedullary 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.