The cerebrospinal fluid (CSF) is produced from arterial blood by the choroid plexuses of the lateral and fourth ventricles by a combined process of diffusion, pinocytosis and active transfer. A small amount is also produced by ependymal cells. The choroid plexus consists of tufts of capillaries with thin fenestrated endothelial cells. These are covered by modified ependymal cells with bulbous microvilli. The total volume of CSF in the adult ranges from140 to 270 ml. The volume of the ventricles is about 25 ml. CSF is produced at a rate of 0.2 - 0.7 ml per minute or 600-700 ml per day. The circulation of CSF is aided by the pulsations of the choroid plexus and by the motion of the cilia of ependymal cells. CSF is absorbed across the arachnoid villi into the venous circulation and a significant amount probably also drains into lymphatic vessels around the cranial cavity and spinal canal. The arachnoid villi act as one-way valves between the subarachnoid space and the dural sinuses. The rate of absorption correlates with the CSF pressure. CSF acts as a cushion that protects the brain from shocks and supports the venous sinuses (primarily the superior sagittal sinus, opening when CSF pressure exceeds venous pressure). It also plays an important role in the homeostasis and metabolism of the central nervous system.
CSF from the lumbar region contains 15 to 45 mg/dl protein (lower in childen) and 50-80 mg/dl glucose (two-thirds of blood glucose). Protein concentration in cisternal and ventricular CSF is lower. Normal CSF contains 0-5 mononuclear cells. The CSF pressure, measured at lumbar puncture (LP), is 100-180 mm of H2O (8-15 mm Hg) with the patient lying on the side and 200-300 mm with the patient sitting up.
Astrocytic processes around capillary
Brain capillary. A:astrocytic processes; E:endothelium; Arrowheads:vasular basement membrane.
Astrocytic processes around vessel
Astrocytic processes around a brain vessel. GFAP
Unlike other organs and tissues, the endothelial cells that line brain capillaries have no fenestrations or pinocytotic (transportation) vesicles and have tight
and adherens junctions that almost fuse adjacent endothelial cells. Moreover, these endothelial cells have different receptors and ion channels on their surface facing the lumen than on the surfaces facing the brain, an arrangement that facilitates transcellular transport. This anatomy is the basis of the blood-brain
barrier (BBB). The endothelial cells are surrounded by a basement membrane made up of collagens, laminins, and proteoglycans. A discontinuous layer of pericytes are embedded in this basement membrane. Astrocytic processes cover the capillaries. The space between them and the capillary basement membrane contains a few perivascular macrophages and rare lymphocytes that cross the BBB (passing through endothelial cells rather than between them) and survey this space. The same types of cells are present in the perivascular (Virchow-Robin) space (see below). Brain endothelial cells do not express leukocyte adhesion molecules (LAMs) on their luminal surface and this limits the entry of leukocytes into brain tissue. In non-diseased states, no immune cells or molecules are found deeper in brain interstitial space, resulting in an “immune privileged” status. During development, astrocytes induce brain endothelial cells to develop in this special leak-proof fashion.
The BBB separates plasma from the interstitial space of the CNS and is key to maintaining homeostasis in the CNS. It controls the traffic of molecules, including ions and water in and out of the brain and plays an important role in supplying the brain with nutrients and getting rid of waste and toxic products. The ability to exclude certain substances from brain interstitial space has to do not only with the vascular anatomy, but also with lipid solubility and selective transcellular transport by endothelial cells. Lipophilic compounds cross the BBB easier than hydrophilic ones do, and small lipophilic molecules such as O2 and CO2 diffuse freely. Hydrophilic substances can only get across brain capillaries through endothelial cells rather than between them. Some hydrophilic molecules, including glucose and amino acids, enter endothelial cells with the help of transporters, and larger molecules, including proteins, enter via receptor-mediated endocytosis and exit along the opposite surface by exocytosis. GLUT1 is the glucose transporter. The ATP-binding cassette (ABC) transporters are important for transport of lipophilic substanses and efflux of toxic metabolites. The BBB protects the brain from toxic substances but also impedes the entry of drugs. Circulating leukocytes enter the brain by passing through endothelial cells rather than between them. Astrocytes cover almost the entire surface of brain capillaries; they are interposed between the vasculature and neurons thus linking neuronal activity to BBB function. Hypertonic stimuli and chemical substances including glutamate and certain cytokines can open the BBB.
A wide variety of disorders including stroke, trauma, CNS infections, demyelinative diseases, metabolic disorders, degenerative diseases, and malignant brain tumors are associated with BBB dysfunction. The common end result of BBB dysfunction in many of these disorders is increased vascular permeability leading to vasogenic edema. For instance, blood vessels in glioblastom and other malignant brain tumors do not have tight junctions, explaining the fluid leakage and cerebral edema that accompanies these tumors. Cytokines generated during infectious and inflammatory processes enhance transmigration of circulating leukocytes and may even loosen tight junctions, thus facilitating the migration of inflammatory cells into the brain. HIE disrupts the BBB. More subtle BBB dysfunction may result in impaired glucose transport and accumulation of Aβ.
Glia limitans. A condensation of astrocytic processes on the surface of the brain. GFAP
The interstitial space of the brain is separated from the ventricular CSF by the ependymal lining and from the subarachnoid CSF by the glia limitans. The glia limitans is a thick layer of interdigitating astrocytic processes with an overlying basement membrane. This layer seals the surface of the CNS and dips into brain tissue along the perivascular space (see below). External to it is the pia matter, a thin layer of connective tissue cells with a small amount of collagen. The ependymal barrier is far more permeable than the BBB.
The major cerebral arteries and veins traverse the subarachnoid space and penetrate into the brain, where they branch into smaller vessels and eventually capillaries. Capillaries are in contact with astrocytic processes. Vessels larger than capillaries are separated from the surrounding brain tissue by a space (the perivascular or Virchow-Robin space), which is an extension of the subarachnoid space. The perivascular space is a component of the “glymphatic” system which facilitates exchange of molecules between the CSF and the interstitial fluid (ISF) of the brain. CSF flows into brain tissue and ISF effluxes from brain tissue into the CSF along perivascular spaces. The glymphatic system helps rid the brain of waste products. Such products are filtered through the arachnoid villi and removed by the venous circulation. Additionally, it has become apparent in recent years that there is a system of lymphatic vessels closely associated with the dural sinuses. This system may also be important for clearing waste products and for immune surveillance.
Perivascular (Virchow-Robin) space around a small artery. The VRS is exaggerated in paraffin-processed specimens.
The outer surface of this perivascular space (PVS) is formed by the glia limitans. The inner surface is the vascular basement membrane. Postcapillary venules are also surrounded by a PVS. The PVS that surrounds postcapillary venules is the portal of entry of leukocytes into the brain in the normal state and during inflammation. Circulating monocytes and lymphocytes normally traverse postcapillary venules and enter the PVS. In the course of inflammation, such as MS, this entry is increased because of leukocyte interactions with inflamed endothelial cells. Furthermore, leukocytes penetrate the glia limitans and enter into the CNS. The latter move is facilitated by matrix metalloproteinases (MMPs) produced by macrophages, which loosen the glia limitans.
Blood: Blood may be spilled into the CSF by accidental puncture of a leptomeningeal vein during entry of the LP needle. Such blood stains the fluid that is drawn initially and clears gradually. If it does not clear, blood indicates subarachnoid hemorrhage. Erythrocytes from subarachnoid hemorrhage are cleared in 3 to 7 days. A few neutrophils and mononuclear cells may also be present as a result of meningeal irritation. Xanthochromia (blonde color) of the CSF following subarachnoid hemorrhage is due to oxyhemoglobin which appears in 4 to 6 hours and bilirubin which appears in two days. Xanthochromia may also be seen with hemorrhagic infarcts, brain tumors, and jaundice.
Increased inflammatory cells (pleocytosis) may be caused by infectious and noninfectious processes. Polymorphonuclear pleocytosis indicates acute suppurative meningitis. Mononuclear cells are seen in viral infections (meningoencephalitis, aseptic meningitis), syphilis, neuroborreliosis, tuberculous meningitis, multiple sclerosis, brain abscess and brain tumors.
Leukemic cells in the CSF
Tumor cells indicate dissemination of metastatic or primary brain tumors in the subarachnoid space. The most common among the latter is medulloblastoma. They can be best detected by cytological examination. A mononuclear inflammatory reaction is often seen in addition to the tumor cells.
Increased protein: In bacterial meningitis, CSF protein may rise to 500 mg/dl. A more moderate increase (150-200 mg/dl) occurs in inflammatory diseases of meninges (meningitis, encephalitis), intracranial tumors, subarachnoid hemorrhage, and cerebral infarction. A more severe increase occurs in the Guillain-Barré syndrome and acoustic and spinal schwannoma. In multiple sclerosis, CSF protein is normal or mildly increased, but there is often an elevation of IgG in CSF, but not in serum, expressed as an elevation of the CSF IgG/albumin index (normally 10:1). In addition, 90% of MS patients have oligoclonal IgG bands in the CSF. Oligoclonal bands are also seen occasionally in some chronic CNS infections. The type of oligoclonal bands is constant for each MS patient throughout the course of the disease. Oligoclonal bands occur in the CSF only (not in the serum). These quantitative and qualitative CSF changes indicate that in MS, there is intrathecal immunoglobulin production. In addition, the CSF in MS often contains myelin fragments and myelin basic protein (MBP). MBP can be detected by radioimmunoassay. MBP is not specific for MS. It can appear in any condition causing brain necrosis, including infarcts.
Low glucose in CSF is seen in suppurative, tuberculous and fungal infections, sarcoidosis, and meningeal dissemination of tumors. Glucose is consumed by leukocytes and tumor cells.
Alzheimer's disease (AD). In AD, total CSF beta amyloid (Aβ) is not significantly different from controls but Aβ42 is decreased probably because it is deposited in plaques and is not available in a diffusible form. Total-tau (t-tau) and phosphorylated tau (p-tau) are both increased in AD. Tau is an intracellular protein and p-tau is a component of neurofibrillary tangles (NFTs). Their increase in AD is thought to reflect neuronal death with release of tau into the extracellular space. T-tau is also increased in other conditions with neuronal death including Creutzfeldt-Jacob disease(CJD), however, p-tau is not elevated in CJD presumably because there are no NFTs in that condition.
Creutzfeldt-Jacob disease. In addition to elevated t-tau (see above), the most widely used CSF biomarker for CJD is the 14-3-3-protein. The 14-3-3 proteins (the name derives from their electrophoresis pattern) are a group of proteins with diverse regulatory functions present in all cells. Elevated CSF 14-3-3 in a patient with progressive dementia of less than 2 years' duration is considered a strong indicator of CJD. 14-3-3 is also elevated in patients with acute stroke, encephalitis, and other conditions with extensive brain damage. A negative 14-3-3 test does not rule out CJD. It has been reported recently that CSF transferrin (Tf) is significantly decreased in sporadic CJD and, combined with t-tau may be a useful biomarker for CJD.
S100B is a member of the S100 family of proteins. It is produced primarily by astrocytes. It exerts autocrine and paracrine effects on glia, neurons, and microglia and is thought to be involved in a variety of biological processes. S100B is elevated in CSF and blood in acute brain injury caused by trauma and stroke, and its concentration correlates with the severity of injury and clinical outcome. In these clinical settings, S100B probably leaks from injured cells, but it may also be actively secreted as part of the cellular response to injury and is thought to exert neuroprotective-trophic and toxic actions. CSF levels of S100B are increased premature infants with HIE and germinal matrix hemorrhage and in amniotic fluid in pregnancies with intrauterine death and CNS abnormalities. Blood and CSF S100B is elevated in melanoma (S100B is made by the tumor cells) and in brain tumors and has been regarded as a predictor of brain metastases. It is also elevated in neurodegenerative disorders such as Alzheimer’s disease and frontotemporal lobar degeneration, and in neuroinflammatory disorders such as MS.
Defective resorption of CSF into the superior sagittal sinus due to sinovenous thrombosis accounts for some cases of the syndrome of pseudotumor cerebri, which is characterized by headache, papilledema, increased CSF pressure and normal size ventricles. These symptoms and signs are caused by intracranial hypertension. This syndrome has many other causes, including meningeal pathology, tumors, toxic and metabolic disorders, and conditions that cause marked elevation of CSF protein, such as the Guillain-Barré syndrome. In many cases, no specific etiology is identified (idiopathic intracranial hypertension).
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Updated: August, 2016