Image showing the location of CSF highlighting the brain's ventricular system
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found in the brain and spinal cord. It is produced in the choroid plexuses of the ventricles of the brain. It acts as a cushion or buffer for the brain, providing basic mechanical and immunological protection to the brain inside the skull. The CSF also serves a vital function in cerebral autoregulation of cerebral blood flow.
The CSF occupies the subarachnoid space (between the arachnoid mater and the pia mater) and the ventricular system around and inside the brain and spinal cord. It constitutes the content of the ventricles, cisterns, and sulci of the brain, as well as the central canal of the spinal cord.
There is about 125-150mL of CSF at any one time. This CSF circulates within the ventricular system of the brain. The ventricles are a series of cavities filled with CSF. The majority of CSF is produced from within the two lateral ventricles. From here, the CSF passes through the interventricular foramina to the third ventricle, then the cerebral aqueduct to the fourth ventricle. From the fourth ventricle, the fluid passes into the subarachnoid space through four openings – the central canal of the spinal cord, the median aperture, and the two lateral apertures. CSF is present within the subarachnoid space, which covers the brain, spinal cord, and stretches below the end of the spinal cord to the sacrum. There is connection from the subarachnoid space to the bony labyrinth of the inner ear making the cerebrospinal fluid continuous with the perilymph.
A new hypothesis (2014) by Klarica and Oreskovic poses that there is no unidirectional CSF circulation, but cardiac cycle-dependent bi-directional systolic-diastolic to-and-fro cranio-spinal CSF movements.
The CSF is derived from blood plasma and is largely similar to it, except that CSF is nearly protein-free compared with plasma and has some different electrolyte levels. Owing to the way it is produced, CSF has a higher chloride level than plasma, and an equivalent sodium level.
CSF contains approximately 0.3% plasma proteins, or approximately 15 to 40 mg/dL, depending on sampling site. In general, globular proteins and albumin are in lower concentration in ventricular CSF compared to lumbar or cisternal fluid. This continuous flow into the venous system dilutes the concentration of larger, lipid-insoluble molecules penetrating the brain and CSF. CSF is normally free of red blood cells, and at most contains only a few white blood cells. Any white blood cell count higher than this constitutes pleocytosis.
Around the third week of development, the embryo is a three-layered disc, covered on the dorsal surface by a layer of ectoderm (so called presumptive epidermis). In the middle of this surface is a linear structure called the notochord, a tube-like formation derived from the dorsal mesoderm. The notochord releases extracellular molecules that affect the transformation of the overlying ectoderm into nervous tissue.
As the brain develops, by the fourth week of embryological development three swellings have formed within the embryo around the canal, near where the head will develop. These swellings represent different components of the central nervous system: the prosencephalon, mesencephalon and rhombencephalon.
The developing forebrain surrounds the neural cord. As the forebrain develops, the neural cord within it becomes a ventricle, ultimately forming the lateral ventricles. Along the inner surface of both ventricles, the ventricular wall remains thin, and a choroid plexus develops, producing and releasing CSF. The CSF quickly fills the neural canal.
CSF serves several purposes:
- Buoyancy: The actual mass of the human brain is about 1400 - 1500 grams; however, the net weight of the brain suspended in the CSF is equivalent to a mass of 25 - 50 grams. The brain therefore exists in neutral buoyancy, which allows the brain to maintain its density without being impaired by its own weight, which would cut off blood supply and kill neurons in the lower sections without CSF.
- Protection: CSF protects the brain tissue from injury when jolted or hit, by providing a fluid buffer that acts as a shock absorber from some forms of mechanical injury.
- Prevention of brain ischemia: The prevention of brain ischemia is made by decreasing the amount of CSF in the limited space inside the skull. This decreases total intracranial pressure and facilitates blood perfusion.
- Homeostasis: CSF flows throughout the inner ventricular system in the brain and is absorbed back into the bloodstream, rinsing the metabolic waste from the central nervous system through the blood–brain barrier. This allows for homeostatic regulation of the distribution of neuroendocrine factors, to which slight changes can cause problems or damage to the nervous system. For example, high glycine concentration disrupts temperature and blood pressure control, and high CSF pH causes dizziness and syncope. To use Davson's term, the CSF has a "sink action" by which the various substances formed in the nervous tissue during its metabolic activity diffuse rapidly into the CSF and are thus removed into the bloodstream as CSF is absorbed.
- Clearing waste: CSF provides a mechanism for the removal of waste products from the brain, CSF has been shown by the research group of Maiken Nedergaard to be critical in the brain's glymphatic system, which plays an important role in flushing metabolic toxins or waste from the brain's tissues' cellular interstitial fluid. CSF flushing of wastes from brain tissue is further increased during sleep, which results from the opening of extracellular channels controlled through the contraction of glial cells, which allows for the rapid influx of CSF into the brain. These findings indicate that CSF may play a large role during sleep in clearing metabolic waste, like beta amyloid, that are produced by the activity in the awake brain. Results of Klarica et al. suggest that efflux transport at the capillary endothelium is much more important for brain homeostasis than the removal of potential toxic brain metabolites by CSF "circulation".
|Water Content (%)||99||93|
The brain produces roughly 500 mL of cerebrospinal fluid per day, at a rate of about 25mL an hour. This transcellular fluid is constantly reabsorbed, so that only 125-150 mL is present at any one time.
Most (about two-thirds to 80%) of CSF is produced by the choroid plexus. The choroid plexus is a network of blood vessels present within sections of the four ventricles of the brain. It is present throughout the ventricular system except for the cerebral aqueduct, frontal horn of the lateral ventricle, and occipital horn of the lateral ventricle. CSF is also produced by the single layer of column-shaped ependymal cells which line the ventricles; by the lining surrounding the subarachnoid space; and a small amount directly from the tiny spaces surrounding blood vessels around the brain.
CSF is produced by the choroid plexus in two steps. A filtered form of plasma leaks from the fenestrated capillaries in the choroid plexus. The lining of the choroid plexus are similar to ependymal cells around them, but possess tight junctions between them, which act to prevent most substances flowing freely into the CSF. To create the fluid, the lining cells of the choroid plexus actively secrete sodium into the ventricles. This creates osmotic pressure and draws water into the CSF. Chloride, with a negative charge, moves with the positively charged sodium and an electroneutral charge is maintained. Potassium, glucose and bicarbonate are all also transported out of the cell. As a result, CSF contains a higher concentration of sodium and chloride than blood plasma, but less potassium, calcium and glucose and protein. At a molecular level, an Na/K ATPase transporter found on the surface of the choroid lining cells facing the CSF, appears to play a critical role. Other molecules likely to play a role include Aquaporins, channels involved in the transport of water,the Na-K-Cl cotransporter, and the intracellular carbonic anhydrase enzyme, found within choroid plexus cells.
Orešković and Klarica hypothesise that CSF is not primarily produced by the choroid plexus, but is being permanently produced inside the entire CSF system, as a consequence of water filtration through the capillary walls into the interstitial fluid of the surrounding brain tissue, regulated by AQP-4.
CSF returns to the vascular system by entering the dural venous sinuses via arachnoid granulations. These are outpouchings of the arachnoid mater into the venous sinuses around the brain, with valves to ensure one-way drainage. CSF has also been seen to drain into lymphatic vessels, particularly those surrounding the nose; however the pathway and extent are currently not known, but may involve CSF flow along some cranial nerves and be more prominant in the neonate. CSF turns over at a rate of three to four times a day.
Elevated CSF pressure
When CSF pressure is elevated, cerebral blood flow may be constricted. When disorders of CSF flow occur, they may therefore affect not only CSF movement but also craniospinal compliance and the intracranial blood flow, with subsequent neuronal and glial vulnerabilities. The venous system is also important in this equation. Infants and patients shunted as small children may have particularly unexpected relationships between pressure and ventricular size, possibly due in part to venous pressure dynamics. This may have significant treatment implications, but the underlying pathophysiology needs to be further explored.
Lumbar puncture can also be performed to measure the intracranial pressure, which might be increased in certain types of hydrocephalus. However, a lumbar puncture should never be performed if increased intracranial pressure is suspected due to certain situations such as a tumour, because it can lead to brain herniation and ultimately death.
CSF pressure, as measured by lumbar puncture, is 10–18 cmH2O (8–15 mmHg or 1.1–2 kPa) with the patient lying on the side and 20–30 cmH2O (16–24 mmHg or 2.1–3.2 kPa) with the patient sitting up. In newborns, CSF pressure ranges from 8 to 10 cmH2O (4.4–7.3 mmHg or 0.78–0.98 kPa). Most variations are due to coughing or internal compression of jugular veins in the neck. When lying down, the CSF pressure as estimated by lumbar puncture is similar to the intracranial pressure.
Hydrocephalus is an abnormal accumulation of cerebrospinal fluid (CSF) in the ventricles of the brain and can be caused by an impaired flow of cerebrospinal fluid, reabsorption, or excessive production of CSF. Hydrocephalus may cause increased intracranial pressure inside the skull. It may lead to enlargement of the skull and head if hydrocephalus occurs during fetal development. It is usually accompanied by mental disability, sometimes by convulsive episodes and also tunnel vision. Hydrocephalus may become fatal if it is not corrected quickly. It is more common in infants, and in older adults.
CSF can leak from the dura as a result of different causes such as physical trauma or a lumbar puncture, or from no known cause when it is termed spontaneous cerebrospinal fluid leak. The leakage can cause a lack of CSF pressure and volume which can allow the brain to descend through the foramen magnum in the occipital bone where the lower portion of the brain may impact on cranial nerve complexes causing a variety of sensory symptoms.
CSF can be tested for the diagnosis of a variety of neurological diseases, usually obtained by a procedure called lumbar puncture. Lumbar puncture is carried out under sterile conditions by inserting a needle into the subarachnoid space, usually between the third and fourth lumbar vertebrae. CSF is extracted through the needle, and tested. About one third of people experience a headache after lumbar puncture, and pain or discomfort at the needle entry site is common. Rarer complications may include bruising, meningitis or ongoing post lumbar-puncture leakage of CSF.
Testing often includes a measurement of CSF pressure, counting and identifying cells such as whites and red blood cells; measuring protein and glucose levels; and culturing the fluid. Results may assist in subarachnoid hemorrhage with elevated red blood cells and xanthochromia, and central nervous system infections such as meningitis, with elevated white blood cells. A CSF culture may yield the microorganism that has caused the infection. Investigation for types of proteins - oligoclonal bands - may reveal point to specific diseases, including multiple sclerosis, paraneoplastic syndromes, systemic lupus erythematosus, neurosarcoidosis, cerebral angiitis; and specific antibodies such as Aquaporin 4 may be tested for to assist in the diagnosis of autoimmune conditions. A lumbar puncture that drains CSF may also be used as part of treatment for some conditions, including idiopathic intracranial hypertension and normal pressure hydrocephalus.
This fluid has an importance in anesthesia. Baricity refers to the density of a substance compared to the density of human cerebrospinal fluid. Baricity is used in general anesthesia to determine the manner in which a particular drug will spread in the intrathecal space.
The IgG index of cerebrospinal fluid is a measure of the immunoglobulin G content, and is elevated in multiple sclerosis. It is defined as IgG index = (IgGCSF / IgGserum ) / (albuminCSF / albuminserum). A cutoff value has been suggested to be 0.73, with a higher value indicating presence of multiple sclerosis.
A 2010 study showed analysis of CSF for three protein biomarkers that can indicate the presence of Alzheimer's disease. The three biomarkers are CSF amyloid beta 1–42, total CSF tau protein and P-Tau181P. In the study, the biomarker test showed good sensitivity, identifying 90% of persons with Alzheimer's disease, but poor specificity, as 36% of control subjects were positive for the biomarkers. The researchers suggested the low specificity may be explained by developing but not yet symptomatic disease in controls.
Various comments by ancient physicians have been read as referring to CSF. Hippocrates discussed "water" surrounding the brain when describing congenital hydrocephalus, and Galen referred to "excremental liquid" in the ventricles of the brain, which he believed was purged into the nose. But for some 16 intervening centuries of ongoing anatomical study, CSF remains unmentioned in the literature. This is perhaps because of the prevailing autopsy technique, which involved cutting off the head, thereby removing evidence of the CSF before the brain was examined. The modern rediscovery of CSF is now credited to Emanuel Swedenborg. In a manuscript written between 1741 and 1744, unpublished in his lifetime, Swedenborg referred to CSF as "spirituous lymph" secreted from the roof of the fourth ventricle down to the medulla oblongata and spinal cord. This manuscript was eventually published in translation in 1887.
Albrecht von Haller, a Swiss physician and physiologist, made note in his 1747 book on physiology that the "water" in the brain was secreted into the ventricles and absorbed in the veins, and when secreted in excess, could lead to hydrocephalus.
Francois Magendie studied the properties of CSF by vivisection. He discovered the foramen Magendie, the opening in the roof of the fourth ventricle, but mistakenly believed that CSF was secreted by the pia mater.
Thomas Willis (noted as the discoverer of the circle of Willis) made note of the fact that the consistency of the CSF is altered in meningitis. In 1869 Gustav Schwalbe proposed that CSF drainage could occur via lymphatic vessels.
In 1891, W. Essex Wynter began treating tubercular meningitis by tapping the subarachnoid space, and Heinrich Quincke began to popularize lumbar puncture, which he advocated for both diagnostic and therapeutic purposes. In 19th and early 20th century literature, particularly German medical literature, liquor cerebrospinalis was a term used to refer to CSF.
In 1912, a neurologist William Mestrezat gave the first accurate description of the chemical composition of the CSF. In 1914, Harvey W. Cushing published conclusive evidence that the CSF is secreted by the choroid plexus.
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