Cerebrospinal fluid (CSF) is a clear, colorless body fluid found in the brain and spine. It is produced in the choroid plexuses of the ventricles of the brain. It acts as a cushion or buffer for the brain's cortex, 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.
The brain produces roughly 500 mL of cerebrospinal fluid per day. This fluid is constantly reabsorbed, so that only 100-160 mL is present at any one time.
Ependymal cells of the choroid plexus produce more than two thirds of CSF. The choroid plexus is a venous plexus contained within the four ventricles of the brain, hollow structures inside the brain filled with CSF. The remainder of the CSF is produced by the surfaces of the ventricles and by the lining surrounding the subarachnoid space.
Ependymal cells secrete sodium into the lateral ventricles. This creates osmotic pressure and draws water into the CSF space. Chloride, with a negative charge, moves with the positively charged sodium and a neutral charge is maintained. As a result, CSF contains a higher concentration of sodium and chloride than blood plasma, but less potassium, calcium and glucose and protein.
The Orešković and Klarica hypothesis suggests that the 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 (ISF) of the surrounding brain tissue, regulated by AQP-4.
Circulation or movement
CSF circulates within the ventricular system of the brain. The ventricles are a series of cavities filled with CSF, inside the brain. 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. The fourth ventricle is an outpouching on the posterior part of the brainstem. From the fourth ventricle, the fluid passes through three openings to enter the subarachnoid space – these are the median aperture, and the lateral apertures. The subarachnoid space covers the brain and spinal cord. 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, based on more than thirty years of continuous experimental research, suggests that there is no unidirectional CSF circulation, but cardiac cycle-dependent bi-directional systolic-diastolic to-and-fro cranio-spinal CSF movements. This is based on the fact that, in the upright position, the hydrostatic pressure gradient was observed and it was found that there is a long-lasting sub-atmospheric intracranial pressure, zero CSF pressure in the cervical region and +30 cm H2O in the lumbar region, and CSF can only flow from a region of higher to a region of lower CSF pressure. The team concluded that the term "circulation" should be avoided and a more appropriate term "movement" of CSF would be advisable.
The CSF moves in a pulsatile manner throughout the CSF system with a nearly zero net flow, as shown on an MRI.
It had been thought that CSF returns to the vascular system by entering the dural venous sinuses via the arachnoid granulations (or villi). However, some have suggested that CSF flow along the cranial nerves and spinal nerve roots allow it into the lymphatic channels; this flow may play a substantial role in CSF reabsorbtion, in particular in the neonate, in which arachnoid granulations are sparsely distributed. The flow of CSF to the nasal submucosal lymphatic channels through the cribriform plate seems to be especially important. The Orešković and Klarica hypothesis, on the other hand, suggests that the CSF does not flow unidirectionally to cortical SAS to be passively absorbed through arachnoid villi, but is being permanently produced and absorbed inside the entire CSF system, as a consequence of water filtration and reabsorption through the capillary walls into the interstitial fluid (ISF) of the surrounding brain tissue.
The CSF is created from blood plasma and is largely similar to it, except that CSF is nearly protein-free compared with plasma and has some modified electrolyte levels. CSF contains approximately 0.3% plasma proteins, or approximately 15 to 40 mg/dL, depending on sampling site, and it is produced at a rate of 500 ml/day. Since the subarachnoid space around the brain and spinal cord can contain only 135 to 150 ml, large amounts are drained primarily into the blood through arachnoid granulations in the superior sagittal sinus. Thus the CSF turns over about 3.7 times a day. This continuous flow into the venous system dilutes the concentration of larger, lipid-insoluble molecules penetrating the brain and CSF.
|Water Content (%)||99||93|
CSF pressure, as measured by lumbar puncture (LP), 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 cerebrospinal fluid as estimated by lumbar puncture is similar to the intracranial pressure.
There are quantitative differences in the distributions of a number of proteins in the CSF. In general, globular proteins and albumin are in lower concentration in ventricular CSF compared to lumbar or cisternal fluid. 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.
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|Substance||Lower limit||Upper limit||Unit||Corresponds to % of that in plasma[clarification needed]|
|Substance||Lower limit||Upper limit||Unit||Corresponds to % of that in plasma|
|2.2, 2.8||3.9, 4.4||mmol/L|
|Albumin||7.8||40||mg/dL||0 - 0.7%
- corresponding to an albumin (CSF/serum) quotient of 0 to 7x10−3
|Substance||Lower limit||Upper limit||Unit||Corresponds to % of that in blood plasma|
|RBCs||n/a||0 / negative||cells/µL or
Around the third week of development, the embryo is a three-layered disc, covered on the dorsal surface by a layer of endoderm. In the middle of this surface is a linear structure called the notochord. As the endoderm proliferates, the notochord is dragged into the middle of the developing embryo and becomes the neural canal.
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, releasing CSF. The CSF quickly fills the neural canal.
CSF serves several purposes:
- Buoyancy: The actual mass of the human brain is about 1400 grams; however, the net weight of the brain suspended in the CSF is equivalent to a mass of 25 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. In certain situations such as motor vehicle crashes or sports injuries, the CSF cannot protect the brain from forced contact with the skull case, causing hemorrhaging, brain damage, and sometimes death.
- Chemical stability: 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.
- 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.
- Clearing waste: 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 (ISF). 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".
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.
CSF connections with the lymphatic system have been demonstrated in several mammalian systems. Preliminary data suggest that these CSF-lymph connections form around the time that the CSF secretory capacity of the choroid plexus is developing (in utero). There may be some relationship between CSF disorders, including hydrocephalus and impaired CSF lymphatic transport.
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.
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 is colloquially termed as "water on the brain" and is of medical importance. Hydrocephalus may cause increased intracranial pressure inside the skull. It may lead to enlargement of the cranium 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.
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. Cells in the fluid are counted, as are the levels of protein and glucose. These parameters alone may be extremely beneficial in the diagnosis of subarachnoid hemorrhage and central nervous system infections (such as meningitis). Moreover, a CSF culture examination may yield the microorganism that has caused the infection. By using more sophisticated methods, such as the detection of the oligoclonal bands, an ongoing inflammatory condition (for example, multiple sclerosis) can be recognized. A beta-2 transferrin assay is highly specific and sensitive for the detection of CSF leakage.
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.
About one third of people experience a headache after lumbar puncture.
This fluid has an importance in anesthesiology. Baricity refers to the density of a substance compared to the density of human cerebrospinal fluid. Baricity is used in anesthesia to determine the manner in which a particular drug will spread in the intrathecal space.
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.
Wang et al. in their article show the utility of tapping CSF to identify somatic mutations causing Central Nervous System (CNS) tumors.
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.
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, 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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