CSF is mostly produced by specializedependymal cells in thechoroid plexuses of the ventricles of the brain, and absorbed in thearachnoid granulations. It is also produced by ependymal cells in the lining of the ventricles. In humans, there is about 125 mL of CSF at any one time, and about 500 mL is generated every day. CSF acts as a shock absorber, cushion or buffer, providing basic mechanical andimmunological protection to the brain inside theskull. CSF also serves a vital function in thecerebral autoregulation ofcerebral blood flow.
Although noted byHippocrates, it was forgotten for centuries, though later was described in the 18th century byEmanuel Swedenborg.[1] In 1914,Harvey Cushing demonstrated that CSF is secreted by the choroid plexus.[2]
CSF moves in a single outward direction from the ventricles, but multidirectionally in the subarachnoid space.[6][5] The flow of cerebrospinal fluid is pulsatile, driven by thecardiac cycle.[7] The flow of CSF through perivascular spaces in the brain (surrounding thecerebral arteries) is obtained through the pumping movements of the walls of the arteries.[7]
CSF is derived fromblood plasma and is largely similar to it, except that CSF is nearly protein-free compared with plasma and has some differentelectrolyte levels. Due to the way it is produced, CSF has a lowerchloride level than plasma, and a highersodium level.[4][8]
CSF contains approximately 0.59% plasma proteins, or approximately 15 to 40 mg/dL, depending on sampling site.[9] In general, globular proteins and albumin are in lower concentration in ventricular CSF compared to lumbar or cisternal fluid.[10] This continuous flow into thevenous system dilutes the concentration of larger, lipid-insoluble molecules penetrating the brain and CSF.[11] CSF is normally free ofred blood cells and at most contains fewer than 5white blood cells per mm3 (if the whitecell count is higher than this it constitutespleocytosis and can indicate inflammation or infection).[12]
At around the fifth week of itsdevelopment, theembryo is athree-layered disc, covered withectoderm,mesoderm andendoderm. A tube-like formation develops in the midline, called thenotochord. The notochord releases extracellular molecules that affect the transformation of the overlying ectoderm into nervous tissue.[13] Theneural tube, forming from the ectoderm, contains CSF prior to the development of the choroid plexuses.[5] The openneuropores of the neural tube close after the first month of development, and CSF pressure gradually increases.[5]
By the fourth week of embryonic development thebrain has begun to develop. Three swellings (primary brain vesicles), have formed within the embryo around the canal, near to where the head will develop. These swellings represent different components of thecentral nervous system: theprosencephalon (forebrain),mesencephalon (midbrain), andrhombencephalon (hindbrain).[13] Subarachnoid spaces are first evident around the 32nd day of development near the rhombencephalon; circulation is visible from the 41st day.[5] At this time, the first choroid plexus can be seen, found in the fourth ventricle, although the time at which they first secrete CSF is not yet known.[5]
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 achoroid plexus develops, producing and releasing CSF.[13] CSF quickly fills the neural canal.[13] Arachnoid villi are formed around the 35th week of development, with arachnoid granulations noted around the 39th, and continuing developing until 18 months of age.[5]
Thesubcommissural organ secretesSCO-spondin, which formsReissner's fiber within CSF assisting movement through the cerebral aqueduct. It is present in early intrauterine life but disappears during early development.[5]
Buoyancy: The actualmass of thehuman brain is about 1400–1500 grams, but its netweight suspended in CSF is equivalent to a mass of 25–50 g.[14][3] The brain therefore exists inneutral buoyancy, which allows the brain to maintain itsdensity without being impaired by its own weight, which would cut off blood supply and killneurons in the lower sections without CSF.[8]
Protection: CSF protects the brain tissue from injury when jolted or hit, by providing a fluid buffer that acts as ashock absorber from some forms of mechanical injury.[3][8]
Prevention of brain ischemia: The prevention ofbrain ischemia is aided by decreasing the amount of CSF in the limited space inside the skull. This decreases totalintracranial pressure and facilitates bloodperfusion.[3]
The brain produces roughly 500 mL of cerebrospinal fluid per day at a rate of about 20 mL an hour.[20] Thistranscellular fluid is constantly reabsorbed, so that only 125–150 mL is present at any one time.[3]
CSF volume is higher on a mL per kg body weight basis in children compared to adults. Infants have a CSF volume of 4 mL/kg, children have a CSF volume of 3 mL/kg, and adults have a CSF volume of 1.5–2 mL/kg. A high CSF volume is why a larger dose of local anesthetic, on a mL/kg basis, is needed in infants.[21] Additionally, the larger CSF volume may be one reason as to why children have lower rates of postdural puncture headache.[22]
CSF is produced by the choroid plexus in two steps. Firstly, a filtered form ofplasma moves fromfenestrated capillaries in the choroid plexus into an interstitial space,[3] with movement guided by a difference in pressure between the blood in the capillaries and the interstitial fluid.[5] This fluid then needs to pass through theepithelium cells lining the choroid plexus into the ventricles, an active process requiring the transport ofsodium,potassium andchloride that draws water into CSF by creatingosmotic pressure.[5] Unlike blood passing from the capillaries into the choroid plexus, the epithelial cells lining the choroid plexus containtight junctions between cells, which act to prevent most substances flowing freely into CSF.[24]Cilia on the apical surfaces of the ependymal cells beat to help transport the CSF.[25]
Water andcarbon dioxide from the interstitial fluid diffuse into the epithelial cells. Within these cells,carbonic anhydrase converts the substances intobicarbonate andhydrogen ions. These are exchanged for sodium and chloride on the cell surface facing the interstitium.[5] Sodium, chloride, bicarbonate and potassium are then actively secreted into the ventricular lumen.[4][5] This creates osmotic pressure and draws water into CSF,[4] facilitated byaquaporins.[5] CSF contains many fewer protein anions than blood plasma. Protein in the blood is primarily composed of anions where each anion has many negative charges on it.[26] As a result, to maintainelectroneutrality blood plasma has a much lower concentration of chloride anions than sodium cations. CSF contains a similar concentration of sodium ions to blood plasma but fewer protein cations and therefore a smaller imbalance between sodium and chloride resulting in a higher concentration of chloride ions than plasma. This creates an osmotic pressure difference with the plasma. CSF has less potassium, calcium, glucose and protein.[8] Choroid plexuses also secrete growth factors,iodine,[27]vitamins B1,B12,C,folate,beta-2 microglobulin,arginine vasopressin andnitric oxide into CSF.[5] ANa-K-Cl cotransporter andNa/K ATPase found on the surface of the choroid endothelium, appears to play a role in regulating CSF secretion and composition.[5][3]It has been hypothesised 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 byAQP-4.[28]
There are circadian variations in CSF secretion, with the mechanisms not fully understood, but potentially relating to differences in the activation of theautonomic nervous system over the course of the day.[5]
CSF returns to the vascular system by entering thedural venous sinuses viaarachnoid granulations.[4] These are outpouchings of thearachnoid mater into the venous sinuses around the brain, with valves to ensure one-way drainage.[4] This occurs because of a pressure difference between the arachnoid mater and venous sinuses.[5] CSF has also been seen to drain intolymphatic vessels,[31] particularly those surrounding the nose via drainage along theolfactory nerve through thecribriform plate. The pathway and extent are currently not known,[3] but may involve CSF flow along some cranial nerves and be more prominent in theneonate.[5] CSF turns over at a rate of three to four times a day.[4] CSF has also been seen to be reabsorbed through the sheathes ofcranial andspinal nerve sheathes, and through the ependyma.[5]
The composition and rate of CSF generation are influenced by hormones and the content and pressure of blood and CSF.[5] For example, when CSF pressure is higher, there is less of a pressure difference between the capillary blood in choroid plexuses and CSF, decreasing the rate at which fluids move into the choroid plexus and CSF generation.[5] Theautonomic nervous system influences choroid plexus CSF secretion, with activation of thesympathetic nervous system decreasing secretion and theparasympathetic nervous system increasing it.[5] Changes in thepH of the blood can affect the activity ofcarbonic anhydrase, and some drugs (such asfurosemide, acting on theNa-K-Cl cotransporter) have the potential to impact membrane channels.[5]
CSF pressure, as measured bylumbar 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.[32] In newborns, CSF pressure ranges from 8 to 10cmH2O (4.4–7.3 mmHg or 0.78–0.98 kPa). Most variations are due to coughing or internal compression ofjugular veins in the neck. When lying down, the CSF pressure as estimated by lumbar puncture is similar to theintracranial pressure.
Idiopathic intracranial hypertension is a condition of unknown cause characterized by a rise in CSF pressure. It is associated with headaches,double vision, difficulties seeing, and aswollen optic disc.[33] It can occur in association with the use of vitamin A andtetracycline antibiotics, or without any identifiable cause at all, particularly in youngerobese women.[33] Management may include ceasing any known causes, acarbonic anhydrase inhibitor such asacetazolamide, repeated drainage via lumbar puncture, or the insertion of a shunt such as a ventriculo-peritoneal shunt.[33]
CSF can leak from thedura as a result of different causes such as physical trauma or a lumbar puncture, or fromno known cause when it is termed aspontaneous cerebrospinal fluid leak.[36] It is usually associated withintracranial hypotension: low CSF pressure.[35] It can cause headaches, made worse by standing, moving and coughing,[35] as the low CSF pressure causes the brain to "sag" downwards and put pressure on its lower structures.[35] If a leak is identified, abeta-2 transferrin test of the leaking fluid, when positive, is highly specific and sensitive for the detection for CSF leakage.[36]Medical imaging such as CT scans and MRI scans can be used to investigate for a presumed CSF leak when no obvious leak is found but low CSF pressure is identified.[37]Caffeine, given either orally orintravenously, often offers symptomatic relief.[37] Treatment of an identified leak may include injection of a person's blood into the epidural space (anepidural blood patch),spinal surgery, orfibrin glue.[37]
CSF can be tested for the diagnosis of a variety ofneurological diseases, usually obtained by a procedure called lumbar puncture.[38] Lumbar puncture is carried out under sterile conditions by inserting a needle into the subarachnoid space, usually between the third and fourthlumbar vertebrae. CSF is extracted through the needle, and tested.[36] About one third of people experience a headache after lumbar puncture,[36] 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.[3]
Lumbar puncture can also be performed to measure theintracranial pressure, which might be increased in certain types ofhydrocephalus. 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 fatalbrain herniation.[36]
Someanesthetics andchemotherapy drugs are injectedintrathecally into the subarachnoid space, where they spread around CSF, meaning substances that cannot cross theblood–brain barrier can still be active throughout the central nervous system.[39][40]Baricity refers to the density of a substance compared to the density of human cerebrospinal fluid and is used inregional anesthesia to determine the manner in which a particular drug will spread in theintrathecal space.[39]
Liquorpheresis is the process of filtering the CSF in order to clear it from endogen or exogen pathogens. It can be achieved by means of fully implantable or extracorporeal devices, though the technique remains experimental today.[41]
CSF drug delivery refers to a number of methods designed to administer therapeutic agents directly into the CSF, bypassing the BBB to achieve higher drug concentrations in the CNS. This technique is particularly beneficial for treating neurological disorders such as brain tumors, infections, and neurodegenerative diseases. Intrathecal injection, where drugs are injected directly into the CSF via the lumbar region, and intracerebroventricular injection, targeting the brain's ventricles, are common approaches. These methods ensure that drugs can reach the CNS more effectively than systemic administration, potentially improving therapeutic outcomes and reducing systemic side effects. Advances in this field are driven by ongoing research into novel delivery systems and drug formulations, enhancing the precision and efficacy of treatments.Intrathecal pseudodelivery refers to a particular drug delivery method where the therapeutic agent is introduced into a reservoir connected to the intrathecal space, rather than being released into the CSF and distributed throughout the CNS. In this approach, the drug interacts with its target within the reservoir, allowing for changing the composition of the CSF without systemic release. This method can be advantageous for maximizing efficacy and minimizing systemic side effects.[42]
Various comments by ancient physicians have been read as referring to CSF.Hippocrates discussed "water" surrounding the brain when describing congenitalhydrocephalus, andGalen 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 remained unmentioned in the literature. This is perhaps because of the prevailing autopsy technique, which involved cutting off the head, thereby removing evidence of CSF before the brain was examined.[43]
The modern rediscovery of CSF is credited toEmanuel 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.[43]
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.[43]François 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 thepia mater.[43]
Thomas Willis (noted as the discoverer of thecircle of Willis) made note of the fact that the consistency of CSF is altered in meningitis.[43] In 1869Gustav Schwalbe proposed that CSF drainage could occur via lymphatic vessels.[3]
In 1891,W. Essex Wynter began treating tubercular meningitis by removing CSF from the subarachnoid space, andHeinrich Quincke began to popularize lumbar puncture, which he advocated for both diagnostic and therapeutic purposes.[43] In 1912, a neurologist William Mestrezat gave the first accurate description of the chemical composition of CSF.[43] In 1914,Harvey W. Cushing published conclusive evidence that CSF is secreted by thechoroid plexus.[43]
Duringphylogenesis, CSF is present within theneuraxis before it circulates.[5] The CSF ofteleost fish, which do not have a subarachnoid space, is contained within the ventricles of their brains.[5] In mammals, where a subarachnoid space is present, CSF is present in it.[5] Absorption of CSF is seen inamniotes and more complex species, and as species become progressively more complex, the system of absorption becomes progressively more enhanced, and the role of spinal epidural veins in absorption plays a progressively smaller and smaller role.[5]
The amount of cerebrospinal fluid varies by size and species.[44] In humans and othermammals, cerebrospinal fluid turns over at a rate of 3–5 times a day.[44] Problems with CSF circulation, leading to hydrocephalus, can occur in other animals as well as humans.[44]
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