The meninges are three layers of connective tissue that surround and protect the soft brain and spinal cord. Cerebrospinal fluid (CSF) passes between two of the layers of the meninges and, thus, slowly circulates over the entire perimeter of the central nervous system (CNS). CSF also flows through the ventricles, which are the cavities within the brain derived from the central canal of the embryonic neural tube (Fig. 5.1).
the skull (extradural hemorrhage). An extra-dural hemorrhage could result from the bleed-ing of menbleed-ingeal vessels after a fracture of the skull. A subdural hemorrhage could be caused by the tearing of veins crossing the subdural space, which might follow after the sudden movement of the cerebral hemispheres relative to the dura and skull. A subarachnoid hemor-rhage could result from the rupture of an
aneurysm; bloody CSF obtained from a lumbar puncture is confirmatory.
VENTRICLES
The ventricular system is a series of cavities within the brain, lined by ependyma and filled with CSF. The ependyma is a simple cuboidal Figure 5.1: Midsagittal view of the meninges, ventricles, subarachnoid spaces, and cisternae.
Arrows indicate the normal direction of CSF flow.
epithelial layer of glial cells. Paired lateral ventricles, within the substance of the cerebral hemispheres, communicate with the midline third ventricle via the interventricular foram-ina of Monro (Figs. 5.3 and 5.4). The third ventricle is continuous with the tubelike cere-bral aqueduct of Sylvius (iter) in the midbrain, and the latter with the fourth ventricle in the pons and medulla (Fig. 5.1). The fourth ven-tricle, in turn, is continuous with the central canal that extends from the caudal medulla almost to the lower tip of the spinal cord, where it terminates without outlet. The central canal has a small diameter and is, for the most part, occluded. Each lateral ventricle is subdi-vided into four parts: anterior horn in the frontal lobe (rostral to foramen of Monro), body in the parietal lobe, inferior horn in the
temporal lobe, and posterior horn in the occipital lobe.
Each ventricle contains a choroid plexus, a rich network of blood vessels of the pia mater that is intimately related to the ependymal lin-ing of the ventricles. The membrane formed by the pia mater, its vascular network, connective tissue, and ependyma is called the tela choroidea. The choroid plexus of each lateral ventricle is located in the body and inferior horn; it is continuous through the foramen of Monro with the unpaired choroid plexus of the roof of the third ventricle (Fig. 5.3). The choroid plexus of the fourth ventricle is located in the roof of the medulla, in which there are three foramina through which CSF escapes from the fourth ventricle into the cisterna magna. The two lateral openings are the lateral Chapter 5 Meninges, Ventricles, and Cerebrospinal Fluid 91
Figure 5.2: Coronal section through the superior sagittal sinus and associated structures. Vac-uole transport within the villi of the arachnoid granulations (arrows on left side of midline) appears to occur via one-way bulk-flow of CSF via giant vacuoles from the subarachnoid space into the venous blood of the dural sinus. The collapsed villus lacking vacuoles (on the right side) is indica-tive of a markedly reduced bulk flow of CSF via vacuoles. The one-way flow is called bulk flow within each villus because all constituents of the CSF, including small molecules, micro-organisms, and even erythrocytes, are transported with the vacuoles. The dura mater represents the combined inner dura mater and outer dura mater.
apertures (foramina of Luschka) and the medial opening is the medial aperture (fora-men of Magendie) (Fig. 5.4).
FLUID ENVIRONMENT OF THE BRAIN
The brain and spinal cord can only function in a chemically stable homeostatic fluid envi-ronment. This comprises (1) the interstitial fluid bathing the neurons, glia, and blood ves-sels within the central nervous system and (2) the CSF. These two fluids are essentially simi-lar in composition.
The extracellular fluid occupies a space of about 15–20% of the volume of the brain. This interstitial space is greater in the gray matter than in the white matter. The former has higher water content than the latter. This fluid joins the
choroid plexus-produced CSF within the sub-arachnoid space. This CSF is constantly being renewed by production and resorption so that the total volume is replaced several times a day.
Two structures have critical roles in the formation and maintenance of this environ-ment: (1) the brain capillaries and (2) choroid plexuses. They act as selective barriers and major transfer sites of certain substances that constitute these fluids.
Tight junctions between endothelial cells of the cerebral capillaries form the so-called blood–brain barrier between the blood and the interstitial fluid. The capillaries and the ependymal epithelial cells of the choroid plexus form the blood–cerebrospinal fluid bar-rier between the blood and CSF (Figs. 5.5 and 5.6). In addition, the arachnoid is essentially impermeable to water-soluble substances and its role is largely passive.
Figure 5.3: Lateral view of the ventricles of the brain. Note in the small drawing that the choroid plexus of the lateral ventricle, the hippocampus–fornix complex, and the caudate nucleus parallel the curvature of the lateral ventricle. The caudate nucleus is cut off just behind its head in this view.
Cerebrospinal Fluid
Cerebrospinal fluid is a crystal clear, color-less solution that looks like water and is found in the ventricular system and the subarachnoid space. It consists of water, small amounts of protein, gases in solution (oxygen and carbon dioxide), sodium, potassium, magnesium, and chloride ions, glucose, and a few white cells (mostly lymphocytes).
The CSF, formed primarily by a combina-tion of capillary filtracombina-tion and active epithelial secretion, serves two major functional roles:
1. Physical Support. By acting as a “water jacket” surrounding the brain and by provid-ing buoyancy for it, the CSF protects, sup-ports, and keeps the brain afloat in a sea of fluid.
2. Homeostasis. The CSF of the ventricles and the subarachnoid space comprises a pool to which some of the endogenous water-soluble products, including unwanted substances,
drain by diffusion from extracellular fluids of the brain to the ventricles and subarach-noid space. Other products of brain metabo-lism are removed to the blood flowing through the capillaries. The CSF and capil-laries act as substitutes for the lack of a lym-phatic system in the brain and spinal cord.
The CSF along with extracellular fluids sur-rounding the neurons are the “expressions”
of state of chemical equilibrium of the neu-ral environment, called homeostasis, essen-tial for the normal functioning of the central nervous system.
The brain and spinal cord actually float in the CSF; the 1400-g brain has a net weight of about 25 g while suspended in the CSF (reduces brain weight 60-fold). The brain is
“shock mounted” in the CSF and, thus, is able to withstand the stress during sudden move-ments of the head. Illustrative of its buoyancy, removal of the CSF as was done in pneumoen-Chapter 5 Meninges, Ventricles, and Cerebrospinal Fluid 93
Figure 5.4: Frontal (A) and lateral (B) views of the ventricles of the brain.
cephalography caused intense pain and head-aches with each movement of the head, which persisted until the fluid was naturally replen-ished.
The headaches were attributed to irritation of nerve endings in the meninges and
intracra-nial blood vessels. Headaches rarely occur when a small sample of CSF is removed for chemical analysis. The volume of CSF in an adult is about 150 mL (60 mL in the ventricles and 90 mL in the subarachnoid space, includ-ing the lumbar cistern; Chap. 7). CSF is formed Figure 5.5: Relations of the leptomeninges, subarachnoid, choroid plexus, ventricle, astroglia, and neurons of the CNS. The subarachnoid space is located between the arachnoid and pia mater.
The choroid plexus is composed of an ependymal layer and a highly vascularized connective tissue core. Subarachnoid blood vessels and subarachnoid space are continuous with the core of the choroid plexus. The astrocyte has several processes: One extends to a blood capillary and termi-nates as a perivascular foot, another process extends to and contacts the pyramidal neuron, and another extends to the pia mater. The pia mater and arachnoid constitute the leptomeninges. The dura mater is called the pachymeninx.
Chapter 5 Meninges, Ventricles, and Cerebrospinal Fluid 95
Figure 5.6: Ultrastructural features in the brain, choroid plexus, pia– arachnoid layer, and ven-tricle. The continuous extracellular space is located among the glia (G), neurons or their processes (N), and the capillary. The basement lamina (also surrounds the capillary) is a porous structure.
Note the tight junctions between capillary endothelial cells and choroid plexus ependymal cells, and the gap junctions between pial cells and ependymal cells lining the ventricle.
at a rate of approximately 500 mL/day; that is, the total volume is replaced every 3-4 hours.
The interstitial fluid within the brain is read-ily exchanged with CSF. As the CSF flows through the ventricles and the subarachnoid space around the spinal cord and brain, the exchange between the two fluids occurs (1) at the leaky spaces (gap junctions; Fig. 5.6) of the ependymal layer within the ventricles and (2) at the perivascular spaces on the pial surface of the CNS.
Choroid Plexus and the Blood–Cerebrospinal Fluid Barrier
The choroid plexus comprises a single row of choroidal epithelium, arranged as villi around a core of blood vessels derived from the pia mater and connective tissue Figs. 5.5 and 5.6). The choroidal epithelium is continuous with the ependyma of the ventricles. The exten-sive vascular network of the plexus is an expression of its active metabolic activity. The ventricular surface of each choroidal cell has a brush border comprised of microvilli, a feature of epithelial cells noted for fluid transport.
These cells contain many oxidative enzymes, which are indicative of their role in the active transport of electrolytes and other solutes.
Tight junctions join adjacent endothelial cells of the brain and the choroid plexus, adjacent choroidal epithelial cells, and adjacent cells of the arachnoid membrane. These tight junctions are a barrier to the passage of macromolecules (1) from the blood to the ventricular CSF (CSF secretion) and (2) from the CSF to the capillary blood (absorption by the choroid plexus). The mechanism of CSF secretion and absorption from the CSF can be summarized as follows.
The hydrostatic pressure within the choroidal capillaries initiates the passage of water and ions across the endothelial cells to the intersti-tial connective tissue and then to the choroidal epithelium. The completion of the transfer to the CSF takes two routes; (1) transcellular movement through the epithelial choroidal cells and across the plasma membrane into the ven-tricular cavity and (2) paracellular movement across the tight junction to the ventricular
cav-ity. Both of these transfers are thought to be dependent on ion pumps. The details of the means for the transfer of molecules from the ventricular CSF to the capillaries have not been fully resolved.
The choroid plexuses of the four ventricles where the blood–cerebrospinal fluid barrier is located continuously secrete most of the CSF.
Impermeable tight junctions join the endothe-lial cells and also the cuboidal ependymal cells of the choroid plexus (Fig. 5.6). These junc-tional barriers prevent the serum proteins from entering the CNS and inhibit the free diffusion of water-soluble molecules. The formation of the CSF by the choroid plexus involves capil-lary filtration and active transport by the ependymal cells. Flow of molecules across the cells of the choroid plexus occurs via active transport (energy required), facilitated diffu-sion (no energy required), and facilitated exchanges of ions (e.g., sodium, potassium, and chloride ions). Although the CSF is char-acterized as a cell-free, low-protein ultrafiltrate of blood and that the CSF and blood plasma are in osmotic equilibrium, some small but signifi-cant differences do exist between the two flu-ids. As compared to the blood plasma, CSF contains less potassium, bicarbonate, calcium, and glucose and more magnesium and chlo-ride; its pH is lower.
The choroid plexus acts as a “kidney” of the brain that maintains the chemical stability of the CSF in a similar fashion as the kidney maintains the chemical stability of the blood. A key difference in this comparison is that the kidney removes waste products from the blood, whereas the choroid plexus pumps some
“waste products” (byproducts of metabolic activity) from the CNS into the blood.
These barriers consist of permeability barri-ers that comprise systems whose primary roles are to preserve homeostasis in the central nerv-ous system. They facilitate the entry of essen-tial substances and metabolites and they block the entry or facilitate the removal of toxic sub-stances and unnecessary metabolites. In many neurologic diseases, the blood–brain barrier breaks down and does not function as usual,
with some substances normally excluded pass-ing through the barrier. This occurs in some infections, strokes, brain tumors, and trauma.
Flow of CSF
After its formation at the choroid plexuses and in the ventricular surfaces, there is bulk flow of CSF through the ventricular system, the subarachnoid spaces, and cisterns surrounding the CNS before it enters the systemic blood cir-culation. The CSF travels from the lateral ven-tricles through the foramina of Monro into the third ventricle, through the narrow cerebral aqueduct into the fourth ventricle, through the paired apertures of Luschka and the median aperture of Magendie within the tela choroidea in the roof of the fourth ventricle into the cis-terna magna, and then slowly circulates ros-trally through the subarachnoid space to the region of the superior sagittal venous sinus at the top of the skull (Fig. 5.1). Most of the CSF appears to enter the venous blood by a one-way
bulk flow via vacuole (some of giant size) transport from the subarachnoid space through the cells of the arachnoid villi (pacchionian granulations) into the dural venous sinuses (Fig. 5.2). This one-way passage is called bulk flow because all constituents leave with the CSF including small molecules, micro-organ-isms, and even, at times, erythrocytes. These villi are grossly visible spongelike herniations of the arachnoid that penetrate into the lumen of the superior sagittal sinus. CSF also extends into and fills the tubular extensions of the arachnoid and subarachnoid space that form the sleeves around the roots of the spinal nerves (Fig. 5.7). These numerous microscopically visible arachnoid villi associated with spinal veins of the spinal roots absorb some CSF.
CSF Pressure
Cerebrospinal fluid pressure is lower than blood pressure. In an individual lying side-ways, the pressure varies from 65 to 195 mm of Chapter 5 Meninges, Ventricles, and Cerebrospinal Fluid 97
Figure 5.7: Dorsal view of a dorsal root ganglion and dorsal root illustrating an arachnoid vil-lus adjacent to the dorsal root (spinal cord to the right of figure). The arachnoid, CSF, and sub-arachnoid space of the spinal canal extend as sleeves that surround the ganglion and roots of each spinal nerve. The arachnoid of this sleeve protrudes into a spinal root (radicular) vein to form an arachnoid villus from which some CSF can pass into a vein. (Adapted from Fishman., 1992)
water throughout the subarachnoid space. In a seated subject, the pressure may rise to between 200 and 300 mm of water in the lum-bar cistern, reach zero in the cisterna magna, and go below atmospheric pressure in the ven-tricles. Fluctuations in the pressure occur in response to phases of the heartbeat and the res-piratory cycle. These shifts occur because the rigid box of dura and skull does not yield, so that the intracranial pressure changes if addi-tions or subtracaddi-tions to the intracranial contents occur (Monro–Kellie doctrine).
An obstruction to the normal passage of CSF results in a backup of CSF and an increase in intracranial pressure. Because the CSF extends to the optic disk (optic nerve head, blind spot) of the subarachnoid space within the dural sleeve along the optic nerve, an ele-vated CSF pressure results in dilated retinal veins and forward thrust of the optic disk beyond the level of the retina. This papilledema, or so-called “choked disk”, can be observed during an inspection of the fundus of the eye with an ophthalmoscope. A persistent papilledema could result in damaged optic nerve fibers.
CIRCUMVENTRICULAR (PERIVENTRICULAR) ORGANS Adjacent to the median ventricular cavities (third ventricle, cerebral aqueduct, and fourth ventricle) are several specialized regions of ependymal origin called circumventricular organs (Fig. 21.5). The common vascular, ependymal, and neural organization of these structures differs from that found in typical brain tissue. They are referred to as “being in the brain, but not of it,” in part because their capillaries are lined by fenestrated endothelial cells indicative of a defective blood–brain bar-rier to macromolecules. In humans, these anatomically well-defined organs include (1) the median eminence of the tuber cinereum (hypothalamus), the neurohypophysis, and the pineal body, all of which have a role in neu-roendocrine regulation (Chap. 21), and (2) the
subcommissural organ, organum vasculosum of the lamina terminalis, subfornical organ, and area postrema (Chap. 21). The functional roles of the latter group are largely unknown.
The area postrema is a chemoreceptive struc-ture activated by blood-borne substances that elicit vomiting and its removal causes refrac-toriness to some but not all forms of emetic stimuli.
HYDROCEPHALUS
An increase in the volume of CSF within the skull is known as hydrocephalus. Several types exist. In compensating hydrocephalus, there is no increase in pressure; this usually occurs when cerebral atrophy associated with a pri-mary CNS disease is compensated with an increase in CSF volume. In obstructive hydro-cephalus and communicating hydrohydro-cephalus, there is both an increase in volume and in pres-sure of the CSF. Obstructive hydrocephalus occurs when there is an obstruction to the flow of CSF within the ventricles, cerebral aque-duc,t or the apertures in the roof of the fourth ventricle. The blockage results in an increase in the volume of CSF above the obstruction, which might be caused by a tumor, develop-mental anomaly, or some inflammatory process. In communicating hydrocephalus, the ventricular CSF can readily flow into the sub-arachnoid space; the hydrocephalus results either from an obstruction to its flow within the subarachnoid space or from an alteration in the rate of formation and absorption of the CSF.
CLINICAL ASPECTS OF CEREBROSPINAL FLUID
Cerebrospinal fluid is used for diagnostic testing. Samples of CSF for examination are usually obtained by a lumbar puncture (spinal tap) into the spinal cistern; this is done by inserting a long needle in the midline between the spines of vertebrae L3 and L4, or L4 and L5, with the patient lying curled up on one side.
There is no risk to injuring the spinal cord because it terminates above these levels. The nerve roots of the cauda equina are usually deflected by the needle and, thus, rarely injured.
With the relaxed patient lying sideways, the normal pressure as indicated ranges from 65 to 195 mm of water. The pulsations of the cere-bral arteries are registered as small oscillations on the manometer. Compression on the internal jugular veins draining blood from the brain results in a brisk rise in the CSF pressure. A lumbar puncture is contraindicated in the pres-ence of an elevated intracranial pressure or an obstruction in the subarachnoid space. In such cases, removal of CSF from the lumbar cistern would lower pressure below blockage, with several possible results: herniation of (1) uncus of temporal lobe through the tentorium or (2) cerebellar tonsils into the foramen magnum.
The former, through pressure on the midbrain, can result in coma and the latter, through pres-sure on the medulla, can cause death from malfunctioning of the cardiac and respiratory centers.
The removed CSF is examined for the pres-ence of cells (lymphocytes and erythrocytes), plasma protein, gamma globulins, and glucose.
Special tests are carried out for specific dis-eases.
SUGGESTED READINGS
Blaas HG, Eik-Nes SH, Kiserud T, Berg S, Angelsen B, Olstad B. Three-dimensional imaging of the brain cavities in human embryos. Ultrasound Obstet. Gynecol. 1995;5:228–232.
Davson H. Formation and drainage of the cere-brospinal fluid. In Shapiro K, Marmarou A, Port-noy H, eds. Hydrocephalus. New York, NY:
Raven; 1984:p 1–40.
Davson H, Segal MB. Physiology of the CSF and Blood–Brain Barriers. Boca Raton, FL: CRC;
1996.
Davson H, Welch K, Segal MB. Physiology and Pathophysiology of the Cerebrospinal Fluid.
New York, NY: Churchill Livingstone; 1987.
Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia, PA: Saun-ders; 1992.
Laterra J, Goldstein G. Ventricular organization of the cerebrospinal fluid, blood-brain barrier, brain edema, and hydrocephalus. In: Kandel ER, Schwartz JH, Jessel T., eds. Principles of Neural Science, 4th ed. New York: McGraw-Hill, 2002;
1288–1301.
McConnell H, Bianchine JR. Cerebrospinal Fluid in Neurology and Psychiatry. New York, NY: Chap-man & Hall; 1994.
Walz W. The Neuronal Environment: Brain Home-ostasis in Health and Disease. Totowa, NJ:
Humana; 2002.
Chapter 5 Meninges, Ventricles, and Cerebrospinal Fluid 99
Individuals are as old as their neurons in the sense that almost all neurons are generated by early postnatal life and are not generally replaced by new ones during a lifetime. The genetically driven development of the complex circuitry of the nervous system continues throughout life, tempered and honed by a com-bination of constraints readjustments and responses to the influences and demands from both the internal and external environments.
The cardiovascular system and the nervous system are the first organ systems to function during embryonic life. In humans, the heart begins to beat late in the third week after fertil-ization. Before the heart begins to beat, the nervous system commences to differentiate and change in shape. Growth in size occurs after the heart commences to pulsate and blood slowly circulates to bring oxygen and essential nutrients to the developing nervous system.
During the second month, when stimuli are applied to the upper lip of the embryo, there is
an avoidance reflex withdrawal of the head. A mother might feel life as early as the 12th pre-natal week.
From a relatively few primordial cells pres-ent several weeks after fertilization of the ovum, the nervous system undergoes a remark-able change to attain its complex and intricate organization. Once a neuroblast leaves the ven-tricular layer of the neural tube, not only is it committed to differentiate into a neuron but also it will never divide again. To generate the estimated 100–200 billion neurons in the mature brain requires a calculated production of more than 2500 neurons per minute during the entire prenatal period. The brain of a 1-year-old child has as many neurons as it will ever have. Throughout life, cells are continu-ously lost at an estimated rate of 200,000 per day in humans. The estimate is based on the observation of the 5 to 10% loss of brain tissue with age. Assuming that there is a 7% loss of neurons over a life-span of 100 years and with