Cerebrospinal Fluid
Formation
About 70% of the CSF present in the brain and spinal cord is produced by the choroid plexuses. The remaining 30% of CSF, which is secreted by the parenchyma of the brain, crosses the ependyma (a single layer of ciliated columnar epithelial cells lining the ventricular system) and enters the ventricles. The formation of CSF is an active process involving the enzyme carbonic anhydrase and specific transport mechanisms.
The formation of the CSF first involves filtration of the blood through the fenestrations of the endothelial cells that line the choroidal capillaries. However, the movement of peptides, proteins, and other larger molecules from this filtrate into the CSF is prevented by the tight junctions that exist in the neighboring epithelial cells that form the outer layer of the choroid plexus. Energy-dependent active transport mechanisms are present in the choroidal epithelium for transporting Na+ and Mg2+ ions into the CSF and for removing K+ and Ca2+ ions from the CSF. Water flows across the epithelium for maintaining the osmotic balance. Normally, the rate of formation of CSF is about 500 mL/day and the total volume of CSF is 90 to 140 mL, of which about 23 mL is in the ventricles, and the remaining is in the subarachnoid space.
Circulation
The movement of CSF is pulsatile. It flows from the lateral ventricles into the third ventricle through the foramina of Monro (Fig. 3-3A [the direction of flow is indicated by arrows]) where it mixes with more CSF. Then, it flows through the cerebral aqueduct (aqueduct of Sylvius) into the fourth ventricle, where additional CSF is secreted. The fluid leaves the ventricular system via the foramina of Luschka and Magendie and enters the cere-bellomedullary cistern (cisterna magna). The CSF then travels rostrally over the cerebral hemisphere where it enters the arachnoid villi (Fig. 3-1A). The arachnoid villi allow flow of CSF into the dural venous sinuses but do not allow flow in the opposite direction because the pressure in the subarachnoid space is higher (about 200 mm H2O) compared with the pressure in the dural venous sinuses (about 80 mm H2O). The CSF in the cer-ebellomedullary cistern also flows downward into the spinal subarachnoid space and then ascends along the ventral surface of the spinal cord into the basal part of the brain where it courses dorsally to empty into the dural sinuses (Fig. 3-1A).
Functions
There are four main functions of the CSF. (1) The brain and spinal cord float in the CSF because the specific gravities of these central nervous system (CNS) structures are approximately the same. This buoyant effect of the CSF results in reduction of traction exerted upon the nerves and blood vessels connected with the CNS. (2) The CSF provides a cushioning effect on the CNS and dampens the effects of trauma. (3) The CSF also serves as a vehicle for removal of metabolites from the CNS. (4) Under normal conditions, the CSF provides a stable ionic environment for the CNS. However, the chemical composition of the CSF may change in certain situations such as administration of drugs that cross the blood-brain barrier.
Composition
Normally, very little protein is present in the CSF, and this is the primary difference between CSF and blood serum.
TABLE 3-1 CompositionofNormalSeru
|
Constituent |
Serum |
CSF |
|
Protein (g/L) |
60-78 |
0.15-0.45 |
|
Glucose (mmol/L) |
3.9-5.8 |
2.2-3.9 |
|
Ca2+ (mmol/L) |
2.1-2.5 |
1-1.35 |
|
K+ (mmol/L) |
4-5 |
2.8-3.2 |
|
Na+ (mmol/L) |
136-146 |
147-151 |
|
Cl- (mmol/L) |
98-106 |
118-132 |
|
Mg2+ (mmol/L) |
0.65-1.05 |
0.78-1.26 |
CSF = cerebrospinal fluid.
The concentrations of glucose, as well as Ca2+ and K+ ions, are slightly smaller in the CSF, and the concentrations of Na+, Cl-, and Mg2+ ions are slightly greater when compared with that of serum (Table 3-1).
Alteration of the Cerebrospinal Fluid in Pathological Conditions
Normally, the CSF is a clear and colorless fluid. However, it may be colored in pathological states. For example, xan-thochromia (yellow color) of the CSF results several hours after subarachnoid hemorrhage when red blood cells (RBCs) undergo lysis and the liberated hemoglobin is broken down into bilirubin, which imparts a yellow color to the CSF. Because CSF is sterile, the results of microbiological studies on normal CSF should be negative, with a normal sample of CSF containing up to 5 lymphocytes/|L and no RBCs. Thus, an increased white blood cell (WBC) count in CSF is indicative of disease (e.g., bacterial meningitis or viral encephalitis). Gamma globulin levels are elevated in CSF of patients with multiple sclerosis (a disorder associated with localized areas of demyelination in the white matter of the CNS) or chronic infections of the CNS. CSF glucose level is low in acute bacterial and chronic fungal infections of the CNS. Increased glycolysis by polymorphonuclear leukocytes in these conditions may be responsible for decreased glucose levels. In contrast, CSF glucose levels are commonly normal in viral infections of the CNS. Alterations in the composition of CSF in some pathological states are listed in the Summary Table at the end of the topic.
The Blood-Brain Barrier and Blood-CSF Barrier
Large molecules cannot pass from the blood into the interstitial fluid of the CNS. This is due to the existence of the blood-brain barrier, which is located at the interface between the capillary wall and brain tissue. The blood-brain barrier consists of: (1) endothelial cells lining the capillary wall with tight junctions between them, (2) processes of astrocytes abutting on the capillaries as perivascu-lar end-feet and (3) a capillary basement membrane. This arrangement of different cells or their processes prevents the passage of large molecules from the blood into the extracellular space between the neurons and neuroglia and forms the anatomical basis of the blood-brain barrier. One of the beneficial functions of the blood-brain barrier is to prevent entry of blood-borne foreign substances into the brain tissue. However, the existence of this blood-brain barrier also presents a problem when the goal is to deliver drugs into the CNS. In other organs, tight junctions do not exist between the neighboring endothelial cells lining the capillaries.
Large molecules cannot pass from the blood into the CSF. This is due to the presence of a blood-CSF barrier. In the choroid plexus, tight junctions do not exist between the neighboring endothelial cells lining the capillary wall. Unlike in other parts of the CNS, the capillary endothelium in the choroid plexuses is fenestrated. Therefore, large molecules can pass from blood through the capillary endothelium of the choroid plexus. However, the choroi-dal plexus has an outermost layer of epithelial cells. Tight junctions exist between choroidal epithelial cells that prevent large molecules in the blood from entering the CSF.
There are seven structures in the CNS that lack a blood-brain barrier. Called circumventricular organs, they are the area postrema, pineal body, subcommissural organ, subfornical organ, OVLT, neurohypophysis (the posterior pituitary gland), and the median eminence (Fig. 3-3B). They lack tight junctions in their capillaries. Instead, they have fenestrated capillaries, capillary loops, and large perivascular spaces that permit the passage of larger circulating molecules into the adjacent brain tissue. It is believed that some circulating hormones consisting of large molecules reach their target areas in the brain via the circumventricular organs. For example, the subfornical organ lies in the roof of the third ventricle. Blood-borne angiotensin II reaches the subfornical organ readily because of the lack of the blood-brain barrier in this organ and induces thirst for overall regulation of fluid balance and cardiovascular homeostasis.
Disorders Associated With Meninges
Meningitis
Infection of the meninges, meningitis, can be life-threatening if it is not treated promptly. In leptomeningitis, the arachnoid and pia mater are infected. Most commonly meningitis is caused by bacterial, viral, or fungal infection. Bacterial meningitis is most serious and needs prompt treatment. It is most commonly caused by Streptococcus penumoniae and Neisseria meningitidis. In acute meningitis, the symptoms develop rapidly (within 24 hours) and last for several days. In subacute meningitis, the onset of symptoms is slow and the course of disease is longer (weeks). Most prominent symptoms include headache, fever, chills, stiff neck, vomiting, photophobia (fear of bright lights), and confusion and about one third of such patients suffer from seizures. Accompanying these symptoms is an increase in CSF pressure; the CSF is cloudy and contains increased protein levels, WBCs, and bacteria. Treatment of bacterial meningitis includes administration of an appropriate antibiotic (intravenous route) for treating the infection, corticosteroids (e.g., dexamethasone) to reduce inflammation and increased CSF pressure, acetaminophen to reduce fever, and an anticonvulsant (e.g., phenytoin) to prevent seizures. In viral meningitis the onset of symptoms is slow (several days). There is no drug treatment for viral meningitis. Typically medications for fever and pain are administered and the patient recovers within 1 to 2 weeks. A vaccine is available for meningitis caused by Neisseria meningitidis. The pneumonia vaccine can provide protection against meningitis caused by Streptococcus penumonia.
Meningiomas
Tumors arising from the meninges are called meningiomas. They are generally slow-growing tumors. They are classified as benign (typical), atypical, or malignant meningi-omas. Benign meningiomas consist of slow-growing cells, atypical meningiomas contain rapidly reproducing cells, and malignant meningiomas contain aggressively growing cells. The exact cause of meningiomas is not known. However, many patients with meningiomas have abnormalities in chromosome 22, which normally suppresses tumor growth. Abnormalties in other genes have also been reported in these patients. For example, extra copies of platelet-derived growth factor receptor and epidermal growth factor receptor have been detected in meningioma tissue. Treatment of meningiomas includes surgical removal or radiosurgery (external beam radiation is aimed at the tumor and a small region surrounding it).
Epidural Hematoma
Head injury may result in loosening of the periosteal dura from the cranium, and an artery (e.g., middle meningeal artery) may be damaged leading to extravasation of blood to form an epidural hematoma. The patient usually experiences headache, disorientation, and lethargy.
Subdural Hematoma
Normally, there is no space at the junction of dura and subarachnoid mater; branches of veins pass through the subarachnoid space to enter the dural sinuses. Head injury may damage these veins, causing extravasation of blood, which creates a space between the dura and subachnoid to form a subdural hematoma.
Subarachnoid Hemorrhage
Head trauma may cause rupture of an intracranial aneu-rysm (local dilatation of an artery or vein resulting in a bulge and weakening of the vessel wall) resulting in extravasation of blood into the subarachnoid space. The aneurysms may be congenital or caused by pathological processes. The extravasated blood may be sequestered in the subarachnoid space or it may collect in cisterns. Sub-arachnoid hemorrhage is associated with intense headache, nausea and vomiting, and, finally, unconsciousness.
Disorders of the Cerebrospinal Fluid System
Hydrocephalus
Dilation of the ventricles (or hydrocephalus) occurs when the circulation of CSF is blocked or its absorption is impeded, while the CSF formation continues to occur at a constant rate. This results in an increase in ventricular pressure that, in turn, causes ventricular dilation. The ventricular dilation exerts pressure on the adjacent tissue, causing impairment of such structures as the corticobulbar and corticospinal tracts. Therefore, a progressive loss of motor function ensues. Hydrocephalus may occur before birth and is usually noted during the first few months of life.
When movement of CSF out of the ventricular system is impeded (e.g., by blockage at the cerebral aqueduct or foramina of the fourth ventricle), the ensuing hydrocephalus is classified as a noncommunicating hydrocephalus. If the movement of the CSF into the dural venous sinuses is impeded or blocked by an obstruction at the arachnoid villi, hydrocephalus developed in this manner is called a communicating hydrocephalus. In communicating hydrocephalus, a tracer dye injected into the lateral ventricle appears in the lumbar CSF, indicating that there is no obstruction to the flow of CSF in the ventricular or extra-ventricular pathways. On the other hand, in noncommunicating hydrocephalus, a tracer dye injected into the lateral ventricle does not appear in the lumbar CSF, indicating that there is an obstruction to the flow of CSF in the ventricular pathways.
Increase in Intracranial Pressure
The craniovertebral cavity and its dural lining form a closed space. An increase in the size or volume of any constituent of the cranial cavity results in an increase in ICR For example, the ICP may increase in the following situations: (1) when the total volume of brain tissue is increased by diffuse cerebral edema; (2) when regional increase in the volume of brain tissue results from an intracerebral hemorrhage or tumors; (3) when the CSF volume increases due to an obstruction in its flow; and (4) when a venous obstruction causes an increase in blood volume in the brain tissue.
The following symptoms may accompany increased ICP: headache (due to stretching of cranial pain-sensitive mechanisms), nausea and vomiting (due to the activation of a chemoreceptor trigger zone located near the area postrema), bradycardia (due to the increased pressure on the nucleus ambiguus and dorsal motor nucleus of vagus in the medulla), an increase in systemic blood pressure (due to the increased pressure on the ventrolateral medulla where vasomotor centers are located), and loss of consciousness. The nucleus ambiguus and the dorsal motor nucleus of vagus contain preganglionic parasympathetic neurons whose axons travel in the vagus nerve and provide parasympathetic innervation to the heart. An elevation and blurring of the optic disk margin (papilledema) may occur due to increased pressure in the subarachnoid space along the optic nerve.
Clinical Case
History
Charles is a 77-year-old man who has been having gait problems and urinary incontinence for the past 6 months. Although he was reluctant to see a physician, his daughter persevered and brought him to a neurologist. His daughter believed that his condition was worsening because, in the past month or so, she noticed that his short-term memory was deteriorating and that he was receiving notices from collection agencies for unpaid or incorrectly paid bills. The gait problem manifested itself as difficulty with climbing stairs and frequent, unexplained falls. During the Korean War, Charles had suffered a subarachnoid hemorrhage as a result of his close proximity to an exploding grenade. The neurologist was informed by the patient’s daughter that, until the recent events, Charles had been an active, healthy, intelligent, and coherent person.
Examination
When the neurologist asked Charles to remember three random, unrelated objects, he was unable to recall any of them after 5 minutes. He did not know how many quarters are in $1.75, and he incorrectly spelled the word "world." A grasp reflex (squeezing the examiner’s hand as a reflex reaction to stroking of the palm) was present. Although motor strength was normal in his arms and legs bilaterally, when asked to walk, Charles took many steps in the same place without moving forward and then started to fall. His cranial nerve, sensory, and cerebellar examinations were normal.
Explanation
This case is an example of a condition called normal pressure hydrocephalus. Various meningeal and ependymal conditions, such as chronic meningitis and prior subarachnoid hemorrhages, may cause this condition by initially blocking cerebrospinal fluid (CSF) absorption. As a result, formation of CSF diminishes slightly, but so does its absorption.The ventricles compensate by enlarging due to the initial higher pressure, as well as the larger volume of CSF, and a new equilibrium is attained. If there is continued obstruction, this process will repeat itself. As a result, the force exerted by the larger ventricles causes hydrostatic impairment to the nerve fiber tracts in the central white matter surrounding the ventridesJhe frontal lobe white matter absorbs maximal ventricular expansion with preservation of the cortical gray matter and subcortical structures. As a result, patients with normal pressure hydrocephalus have abnormal frontal lobe function, including gait apraxia (dysfunction of gait not explained by weakness, cerebellar problems, or sensory problems), urinary incontinence without bladder dysfunction, and dementia. Frontal lobe dysfunction may also cause the reappearance of primitive reflexes, which normally disappear shortly after birth, such as the grasp reflex, because this brain region normally suppresses them. Later, urinary incontinence may also manifest itself in a manner similar to that in a young child, in which the patient may be indifferent to it. Headaches are rare in this particular type of hydrocephalus because ventricular expansion is slow and increased intracranial pressure is transient. The symptoms of this disorder (e.g., incontinence, gait apraxia, and dementia) are commonly referred to as the"3Ws" (wet, wobbly, and weird).
Normal pressure hydrocephalus is usually diagnosed through a neurologic examination, computed tomography, or magnetic resonance imaging of the brain and neuropsychological testing. The imaging studies of the brain show enlarged ventricles and, occasionally, interstitial fluid within the white matter adjacent to the lateral ventricles. Measurement of CSF pressures with a lumbar puncture (normal) and radionuclide cisternography (a procedure where a radionuclide is injected into the CSF and distribution is observed over a period of 24 hours) may be helpful but are not always necessary. Occasionally, shunting procedures allowing the CSF to drain into the peritoneal cavity or the bloodstream are helpful if performed early in the course of this condition.
SUMMARY TABLE
Alterations in Cerebrospinal Fluid Composition in Some Pathological Conditions
|
Pathological Condition |
Protein |
Glucose |
Cells |
|
Subarachnoid hemorrhage |
Increased (+) |
Normal |
Presence of RBCs |
|
Guillain-Barre syndrome |
Increased (++) |
Normal |
Presence of a few WBCs |
|
Metastatic cancer in the meninges |
Increased (+) |
Normal or decreased |
Presence of increased number of WBCs (lymphocytes) Tumor cells |
|
Viral meningitis |
Increased (+) |
Normal |
Presence of excessive number of WBCs (lymphocytes) |
|
Tubercular meningitis |
Increased (+) |
Decreased |
Presence of increased number of WBCs (lymphocytes) |
|
Bacterial meningitis |
Increased (+) |
Decreased |
Presence of increased number of WBCs (polymorphonuclear leukocytes) |
CSF = cerebrospinal fluid; RBC = red blood cell; WBC = white blood cell. Plus sign (+) indicates increase. Relatively greater increase is shown by two plus signs (++).
