View source for Cerebrospinal fluid

{{short description|Clear, colorless bodily fluid found in the brain and spinal cord}}
{{good article}}
{{Anatomy-terms}}{{Infobox anatomy
| Name = Cerebrospinal fluid
| Image = 1317 CFS Circulation.jpg
| Caption = The cerebrospinal fluid circulates in the [[subarachnoid space]] around the [[brain]] and [[spinal cord]], and in the [[ventricular system|ventricles]] of the brain.
| Image2 = Blausen 0216 CerebrospinalSystem.png 
| Caption2 = Image showing the location of CSF highlighting the brain's [[ventricular system]]
| acronym = CSF
|Latin = liquor cerebrospinalis
}}

'''Cerebrospinal fluid''' ('''CSF''') is a clear, colorless [[Extracellular fluid#Transcellular fluid|transcellular body fluid]] found within the [[meninges|meningeal tissue]] that surrounds the [[vertebrate]] [[brain]] and [[spinal cord]], and in the [[ventricular system|ventricles]] of the brain.

CSF is mostly produced by specialized [[Ependyma|ependymal cells]] in the [[choroid plexus]]es of the ventricles of the brain, and absorbed in the [[arachnoid granulation]]s. It is also produced by ependymal cells in the lining of the ventricles. In humans, there is about 125&nbsp;mL of CSF at any one time, and about 500&nbsp;mL is generated every day. CSF acts as a shock absorber, cushion or buffer, providing basic mechanical and [[immune system|immunological protection]] to the brain inside the [[Human skull|skull]]. CSF also serves a vital function in the [[cerebral autoregulation]] of [[cerebral blood flow]].

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 fills the [[ventricular system|ventricles]] of the brain, [[subarachnoid cisterns|cisterns]], and [[Sulcus (neuroanatomy)|sulci]], as well as the [[central canal]] of the spinal cord. There is also a connection from the subarachnoid space to the [[bony labyrinth]] of the [[inner ear]] via the [[perilymphatic duct]] where the [[perilymph]] is continuous with the cerebrospinal fluid. The ependymal cells of the choroid plexus have multiple [[Cilium#Motile cilia|motile cilia]] on their apical surfaces that beat to move the CSF through the ventricles.

A sample of CSF can be taken from around the spinal cord via [[lumbar puncture]]. This can be used to test the [[intracranial pressure]], as well as indicate diseases including [[encephalitis|infections of the brain]] or the surrounding [[meningitis|meninges]].

Although noted by [[Hippocrates]], it was forgotten for centuries, though later was described in the 18th century by [[Emanuel Swedenborg]].<ref>{{cite journal |url=https://nah.sen.es/vmfiles/abstract/NAHV5N32017105_113EN.pdf |title=The history of cerebrospinal fluid: from Classical Antiquity to the late modern period |author=M. A. Tola Arribas |journal=Neurosciences and History |year=2017 |volume=5 |issue=3 |pages=105–113 |accessdate=2025-03-15}}</ref> In 1914, [[Harvey Cushing]] demonstrated that CSF is secreted by the choroid plexus.<ref>{{cite web |url=https://www.americanscientist.org/article/the-early-years-of-brain-imaging |title=The Early Years of Brain Imaging |author=David Warmflash |website=[[American Scientist]] |date=7 February 2023 |accessdate=2025-03-15}}</ref>

== Structure ==
===Circulation===
[[File:NPH MRI 272 GILD.gif|thumb|MRI showing pulsation of CSF]][[File:dist vent.png|thumb|Distribution of CSF|350x350px]]

In humans, there is about 125–150&nbsp;mL of CSF at any one time.<ref name="WRIGHT2012" /> 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, CSF passes through the [[Interventricular foramina (neuroanatomy)|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{{snd}}the [[central canal]] of the spinal cord, the [[median aperture]], and the two [[lateral aperture]]s.<ref name="WRIGHT2012" /> CSF is present within the subarachnoid space, which covers the brain and spinal cord, and stretches below the end of the spinal cord to the [[sacrum]].<ref name="WRIGHT2012" /><ref name=GH2005/> There is a connection from the subarachnoid space to the [[bony labyrinth]] of the [[inner ear]] making the cerebrospinal fluid continuous with the [[perilymph]] in 93% of people.<ref name="SAKKA2011">{{cite journal | vauthors = Sakka L, Coll G, Chazal J | title = Anatomy and physiology of cerebrospinal fluid | journal = European Annals of Otorhinolaryngology, Head and Neck Diseases | volume = 128 | issue = 6 | pages = 309–16 | date = December 2011 | pmid = 22100360 | doi = 10.1016/j.anorl.2011.03.002 | doi-access = free }}</ref>

CSF moves in a single outward direction from the ventricles, but multidirectionally in the subarachnoid space.<ref name="Proulx2021">{{cite journal |last1=Proulx |first1=Steven T. |title=Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics |journal=Cellular and Molecular Life Sciences |date=March 2021 |volume=78 |issue=6 |pages=2429–2457 |doi=10.1007/s00018-020-03706-5|pmid=33427948 |pmc=8004496 }}</ref><ref name="SAKKA2011"/> The flow of cerebrospinal fluid is pulsatile, driven by the [[cardiac cycle]].<ref name="Mestre2018">{{cite journal |vauthors=Mestre H, Tithof J, Du T, Song W, Peng W, Sweeney AM, Olveda G, Thomas JH, Nedergaard M, Kelley DH |title=Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension |journal=Nat Commun |volume=9 |issue=1 |article-number=4878 |date=November 2018 |pmid=30451853 |pmc=6242982 |doi=10.1038/s41467-018-07318-3 |bibcode=2018NatCo...9.4878M |url=}}</ref> The flow of CSF through perivascular spaces in the brain (surrounding the [[cerebral arteries]]) is obtained through the pumping movements of the walls of the arteries.<ref name="Mestre2018"/>

===Contents===
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. Due to the way it is produced, CSF has a lower [[chloride]] level than plasma, and a higher [[sodium]] level.<ref name=GH2005/><ref name=SALADIN2012 />

CSF contains approximately 0.59% plasma proteins, or approximately 15 to 40&nbsp;mg/dL, depending on sampling site.<ref name="pmid4456012">{{cite journal | vauthors = Felgenhauer K | title = Protein size and cerebrospinal fluid composition | journal = Klinische Wochenschrift | volume = 52 | issue = 24 | pages = 1158–64 | date = December 1974 | pmid = 4456012 | doi = 10.1007/BF01466734 | s2cid = 19776406 }}</ref> In general, globular proteins and albumin are in lower concentration in ventricular CSF compared to lumbar or cisternal fluid.<ref>{{cite journal | vauthors = Merril CR, Goldman D, Sedman SA, Ebert MH | title = Ultrasensitive stain for proteins in polyacrylamide gels shows regional variation in cerebrospinal fluid proteins | journal = Science | volume = 211 | issue = 4489 | pages = 1437–8 | date = March 1981 | pmid = 6162199 | doi = 10.1126/science.6162199 | bibcode = 1981Sci...211.1437M }}</ref> {{anchor|IgG index}} This continuous flow into the [[venous system]] dilutes the concentration of larger, lipid-insoluble molecules penetrating the brain and CSF.<ref name="pmid10027064">{{cite journal | vauthors = Saunders NR, Habgood MD, Dziegielewska KM | title = Barrier mechanisms in the brain, I. Adult brain | journal = Clinical and Experimental Pharmacology & Physiology | volume = 26 | issue = 1 | pages = 11–9 | date = January 1999 | pmid = 10027064 | doi = 10.1046/j.1440-1681.1999.02986.x | s2cid = 34773752 | doi-access =  }}</ref> CSF is normally free of [[red blood cell]]s and at most contains fewer than 5 [[white blood cell]]s per mm<sup>3</sup> (if the white [[cell counting|cell count]] is higher than this it constitutes [[pleocytosis]] and can indicate inflammation or infection).<ref>{{cite book| vauthors  = Jurado R, Walker HK |title=Clinical Methods: The History, Physical, and Laboratory Examinations|date=1990|publisher=Butterworths|isbn=978-0409900774|edition=3rd|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK398/|chapter=Cerebrospinal Fluid|pmid=21250239}}</ref>

==Development==
At around the fifth week of its [[human embryonic development|development]], the [[embryo]] is a [[Trilaminar embryonic disc|three-layered disc]], covered with [[ectoderm]], [[mesoderm]] and [[endoderm]]. A tube-like formation develops in the midline, called the [[notochord]]. The notochord releases extracellular molecules that affect the transformation of the overlying ectoderm into nervous tissue.<ref name=LARSEN2009/> The [[neural tube]], forming from the ectoderm, contains CSF prior to the development of the choroid plexuses.<ref name="SAKKA2011"/> The open [[neuropore]]s of the neural tube close after the first month of development, and CSF pressure gradually increases.<ref name="SAKKA2011"/>

By the fourth week of embryonic development the [[Brain#Development|brain 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 the [[central nervous system]]: the [[prosencephalon]] (forebrain), [[mesencephalon]] (midbrain), and [[rhombencephalon]] (hindbrain).<ref name=LARSEN2009/> Subarachnoid spaces are first evident around the 32nd day of development near the rhombencephalon; circulation is visible from the 41st day.<ref name="SAKKA2011"/> 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.<ref name="SAKKA2011"/>

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.<ref name=LARSEN2009 /> CSF quickly fills the neural canal.<ref name=LARSEN2009>{{cite book |first1=Gary C. |last1=Schoenwolf |first2=William James |last2=Larsen | name-list-style = vanc |title=Larsen's human embryology |year=2009 |publisher=Churchill Livingstone/Elsevier |location=Philadelphia |isbn=978-0-443-06811-9 |chapter=Development of the Brain and Cranial Nerves |edition=4th}}{{page needed|date=July 2014}}</ref> 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.<ref name="SAKKA2011"/>

The [[subcommissural organ]] secretes [[SCO-spondin]], which forms [[Reissner's fiber]] within CSF assisting movement through the cerebral aqueduct. It is present in early intrauterine life but disappears during early development.<ref name="SAKKA2011"/>

==Physiology==

===Function===
CSF serves several purposes:

#'''Buoyancy:''' The actual [[mass]] of the [[human brain]] is about 1400–1500 grams, but its net [[weight]] suspended in CSF is equivalent to a mass of 25–50 g.<ref>{{cite book |title= The Human Nervous System |last1 = Noback |first1 = Charles | first2 = Norman L. | last2 = Strominger | first3 = Robert J. | last3 = Demarest | first4 = David A. | last4 = Ruggiero | name-list-style = vanc |year= 2005 |publisher= Humana Press  |isbn= 978-1-58829-040-3 |page= 93}}</ref><ref name="WRIGHT2012">{{cite journal | vauthors = Wright BL, Lai JT, Sinclair AJ | title = Cerebrospinal fluid and lumbar puncture: a practical review | journal = Journal of Neurology | volume = 259 | issue = 8 | pages = 1530–45 | date = August 2012 | pmid = 22278331 | doi = 10.1007/s00415-012-6413-x | s2cid = 2563483 }}</ref> 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 [[neuron]]s in the lower sections without CSF.<ref name=SALADIN2012 />
#'''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.<ref name=WRIGHT2012 /><ref name=SALADIN2012 />
#'''Prevention of brain ischemia:''' The prevention of [[brain ischemia]] is aided by decreasing the amount of CSF in the limited space inside the skull. This decreases total [[intracranial pressure]] and facilitates blood [[perfusion]].<ref name="WRIGHT2012" />
#'''Regulation:''' CSF allows for the [[Homeostasis|homeostatic regulation]] of the distribution of substances between cells of the brain,<ref name="SAKKA2011"/>  and [[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 (medicine)|fainting]].<ref name="SALADIN2012" />
#'''Clearing waste:''' CSF allows for the removal of waste products from the brain,<ref name=WRIGHT2012 /> and is critical in the brain's [[lymphatic system]], called the [[glymphatic system]].<ref name=Iliff>{{cite journal | vauthors = Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M | display-authors = 6 | title = A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β | journal = Science Translational Medicine | volume = 4 | issue = 147 | pages = 147ra111 | date = August 2012 | pmid = 22896675 | pmc = 3551275 | doi = 10.1126/scitranslmed.3003748 }}</ref> Metabolic waste products [[diffusion|diffuse]] rapidly into CSF and are removed into the bloodstream as CSF is absorbed.<ref>{{Cite book |last1=Ropper |first1=Allan H. |title=Adams and Victor's principles of neurology |last2=Adams |first2=Raymond D. |last3=Victor |first3=Maurice |last4=Brown |first4=Robert H. |date=2005 |publisher=McGraw-Hill Medical Pub. Division |isbn=978-0-07-141620-7 |edition=8 |location=New York |pages=530 |chapter=Chapter 30 |oclc=61409790}}</ref>  When this goes awry, CSF can become toxic, such as in [[amyotrophic lateral sclerosis]], the most common form of [[motor neuron disease]].<ref>{{Cite journal| vauthors = Kwong KC, Gregory JM, Pal S, Chandran S, Mehta AR |title=Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis: a systematic review of in vitro studies|url= |journal=Brain Communications|year=2020|volume=2|issue=2|article-number=fcaa121|language=en|doi=10.1093/braincomms/fcaa121|pmid=33094283|pmc=7566327|doi-access=free}}</ref><ref>{{cite journal | vauthors = Ng Kee Kwong KC, Mehta AR, Nedergaard M, Chandran S | title = Defining novel functions for cerebrospinal fluid in ALS pathophysiology | journal = Acta Neuropathologica Communications | volume = 8 | issue = 1 | article-number = 140 | date = August 2020 | pmid = 32819425 | pmc = 7439665 | doi = 10.1186/s40478-020-01018-0 | doi-access = free }}</ref>

===Production===
{|class="wikitable floatright"
|+ Comparison of serum and cerebrospinal fluid
|-
! Substance || CSF || Serum
|-
| Water content (% wt) || 99 || 93 
|-
| Protein (mg/dL) || 35 || 7000
|-
| Glucose (mg/dL) || 60 || 90 
|-
| Osmolarity (mOsm/L) || 295 || 295 
|-
| [[Sodium]] (mEq/L) || 138 || 138
|-
| [[Potassium]] (mEq/L) || 2.8 || 4.5
|-
| [[Calcium]] (mEq/L) || 2.1 || 4.8
|-
| [[Magnesium]] (mEq/L) || 2.0–2.5<ref>{{Cite book|url=https://books.google.com/books?id=o6SoJYPnyTQC|title=Cerebrospinal Fluid in Clinical Practice |first=David N. |last=Irani | name-list-style = vanc |date=14 April 2018|publisher=Elsevier Health Sciences|access-date=14 April 2018|via=Google Books|isbn=9781416029083}}</ref> || 1.7
|-
| [[Chloride]] (mEq/L) || 119 || 102
|-
| pH || 7.33 || 7.41
|-
|colspan=3| {{Further-text|[[List of reference ranges for cerebrospinal fluid|List of reference ranges<br>for cerebrospinal fluid]]}}
|}
The brain produces roughly 500&nbsp;mL of cerebrospinal fluid per day at a rate of about 20&nbsp;mL an hour.<ref name="Czarniak">{{cite journal |vauthors=Czarniak N, Kamińska J, Matowicka-Karna J, Koper-Lenkiewicz OM |title=Cerebrospinal Fluid-Basic Concepts Review |journal=Biomedicines |volume=11 |issue=5 |date=May 2023 |page=1461 |pmid=37239132 |pmc=10216641 |doi=10.3390/biomedicines11051461 |url= |doi-access=free }}</ref> This [[transcellular fluid]] is constantly reabsorbed, so that only 125–150&nbsp;mL is present at any one time.<ref name="WRIGHT2012" />

CSF volume is higher on a mL per kg body weight basis in children compared to adults. Infants have a CSF volume of 4&nbsp;mL/kg, children have a CSF volume of 3&nbsp;mL/kg, and adults have a CSF volume of 1.5–2&nbsp;mL/kg. A high CSF volume is why a larger dose of local anesthetic, on a mL/kg basis, is needed in infants.<ref>{{Cite journal |last1=Thiele |first1=Eryn L. |last2=Nemergut |first2=Edward C. |date=June 2020 |title=Miller's Anesthesia, 9th ed |url=http://dx.doi.org/10.1213/ane.0000000000004780 |journal=Anesthesia & Analgesia |volume=130 |issue=6 |pages=e175–e176 |doi=10.1213/ane.0000000000004780 |issn=0003-2999|url-access=subscription }}</ref>  Additionally, the larger CSF volume may be one reason as to why children have lower rates of postdural puncture headache.<ref name="pmid12655411">{{cite journal | vauthors = Janssens E, Aerssens P, Alliët P, Gillis P, Raes M | title = Post-dural puncture headaches in children. A literature review | journal = European Journal of Pediatrics | volume = 162 | issue = 3 | pages = 117–121 | date = March 2003 | pmid = 12655411 | doi = 10.1007/s00431-002-1122-6 | s2cid = 20716137 }}</ref>

<!--Sites of production-->Most (about two-thirds to 80%) of CSF is produced by the [[choroid plexus]].<ref name="WRIGHT2012" /><ref name=GH2005/> The choroid plexus is a network of blood vessels present within sections of the [[Ventricular system|four ventricles]] of the brain. It is present throughout the [[ventricular system]] except for the [[cerebral aqueduct]], and the  [[Lateral ventricles#Structure|frontal and occipital horns of the lateral ventricles]].<ref name=Young292>{{cite book|last=Young|first=Paul A. | name-list-style = vanc |title=Basic clinical neuroscience|year=2007|publisher=Lippincott Williams & Wilkins|location=Philadelphia, Pa.|isbn=978-0-7817-5319-7|page=292|edition=2nd}}</ref> CSF is mostly produced by the [[lateral ventricles]].<ref name="Czarniak"/> CSF is also produced by the [[simple columnar epithelium|single layer of column-shaped]] [[ependymal cell]]s which line the ventricles; by the lining surrounding the [[subarachnoid space]]; and a small amount directly from the [[perivascular space|tiny spaces surrounding blood vessels]] around the brain.<ref name=GH2005>{{cite book |first1=Arthur C. |last1=Guyton |first2=John Edward |last2=Hall | name-list-style = vanc |title=Textbook of medical physiology |year=2005 |publisher=W.B. Saunders |location=Philadelphia |isbn=978-0-7216-0240-0 |edition=11th |pages=764–7}}</ref>

<!--Mechanism of production in choroid plexi-->CSF is produced by the choroid plexus in two steps. Firstly, a filtered form of [[blood plasma|plasma]] moves from [[Capillary#Fenestrated|fenestrated capillaries]] in the choroid plexus into an interstitial space,<ref name="WRIGHT2012" /> with movement guided by a difference in pressure between the blood in the capillaries and the interstitial fluid.<ref name="SAKKA2011"/> This fluid then needs to pass through the [[epithelium]] cells lining the choroid plexus into the ventricles, an active process requiring the transport of [[sodium]], [[potassium]] and [[chloride]] that draws water into CSF by creating [[osmotic pressure]].<ref name="SAKKA2011"/> Unlike blood passing from the capillaries into the choroid plexus, the epithelial cells lining the choroid plexus contain [[tight junctions]] between cells, which act to prevent most substances flowing freely into CSF.<ref name="Hall">{{cite book|title=Guyton and Hall textbook of medical physiology|date=2011|publisher=Saunders/Elsevier|isbn=978-1-4160-4574-8|edition=12th|location=Philadelphia, Pa.|page=749|last1=Hall|first1=John | name-list-style = vanc }}</ref> [[Cilium#Motile cilia|Cilia]] on the apical surfaces of the ependymal cells beat to help transport the CSF.<ref name="Kishimoto">{{cite journal | vauthors = Kishimoto N, Sawamoto K | title = Planar polarity of ependymal cilia | journal = Differentiation; Research in Biological Diversity | volume = 83 | issue = 2 | pages = S86-90 | date = February 2012 | pmid = 22101065 | doi = 10.1016/j.diff.2011.10.007 }}</ref>

<!--Second step-->[[Water]] and [[carbon dioxide]] from the interstitial fluid diffuse into the epithelial cells. Within these cells, [[carbonic anhydrase]] converts the substances into [[bicarbonate]] and [[hydrogen ions]]. These are exchanged for sodium and chloride on the cell surface facing the interstitium.<ref name="SAKKA2011"/> Sodium, chloride, bicarbonate and potassium are then actively secreted into the ventricular lumen.<ref name=GH2005/><ref name="SAKKA2011"/> This creates osmotic pressure and draws water into CSF,<ref name=GH2005/> facilitated by [[aquaporin]]s.<ref name="SAKKA2011"/> 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.<ref>{{cite journal |last1=Staempfli |first1=Henry R. |last2=Constable |first2=Peter D. |title=Experimental determination of net protein charge and Atot and Ka of nonvolatile buffers in human plasma |journal=Journal of Applied Physiology |date=1 August 2023 |volume=95 |issue=2 |pages=620–630 |doi=10.1152/japplphysiol.00100.2003 |pmid=12665532 |url=https://journals.physiology.org/doi/full/10.1152/japplphysiol.00100.2003 |access-date=18 August 2023|url-access=subscription }}</ref> 
As a result, to maintain [[Pauling's principle of electroneutrality|electroneutrality]] 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.<ref name=SALADIN2012>{{cite book |last1=Saladin |first1=Kenneth | name-list-style = vanc |title=Anatomy and Physiology |edition=6th |publisher=McGraw Hill |year=2012 |pages=519–20}}</ref> Choroid plexuses also secrete growth factors, [[iodine]],<ref>{{Cite journal | vauthors = Venturi S, Venturi M |title=Iodine, PUFAs and Iodolipids in Health and Disease: An Evolutionary Perspective |journal=Human Evolution |volume= 29 |issue= 1–3 |pages=185–205 |year=2014 }}</ref> [[vitamin B1|vitamins B<sub>1</sub>]], [[Vitamin B12|B<sub>12</sub>]], [[Vitamin C|C]], [[folate]], [[beta-2 microglobulin]], [[arginine vasopressin]] and [[nitric oxide]] into CSF.<ref name="SAKKA2011"/> A [[Na-K-Cl cotransporter]] and [[Na/K ATPase]] found on the surface of the choroid endothelium, appears to play a role in regulating CSF secretion and composition.<ref name="SAKKA2011"/><ref name="WRIGHT2012" />
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 by [[Aquaporin 4|AQP-4]].<ref name="pmc4118619">{{cite journal | vauthors = Orešković D, Klarica M | title = A new look at cerebrospinal fluid movement | journal = Fluids and Barriers of the CNS | volume = 11 | pages = 16 | year = 2014 | pmid = 25089184 | pmc = 4118619 | doi = 10.1186/2045-8118-11-16 | doi-access = free }}</ref>

There are circadian variations in CSF secretion, with the mechanisms not fully understood, but potentially relating to differences in the activation of the [[autonomic nervous system]] over the course of the day.<ref name="SAKKA2011"/>

Choroid plexus of the lateral ventricle produces CSF from the arterial blood provided by the [[anterior choroidal artery]].<ref>{{cite journal | vauthors = Zagórska-Swiezy K, Litwin JA, Gorczyca J, Pityński K, Miodoński AJ | title = Arterial supply and venous drainage of the choroid plexus of the human lateral ventricle in the prenatal period as revealed by vascular corrosion casts and SEM | journal = Folia Morphologica | volume = 67 | issue = 3 | pages = 209–13 | date = August 2008 | pmid = 18828104 | url = https://journals.viamedica.pl/folia_morphologica/article/view/15975 }}</ref> In the fourth ventricle, CSF is produced from the arterial blood from the [[anterior inferior cerebellar artery]] (cerebellopontine angle and the adjacent part of the lateral recess), the [[posterior inferior cerebellar artery]] (roof and median opening), and the [[superior cerebellar artery]].<ref>{{cite journal | vauthors = Sharifi M, Ciołkowski M, Krajewski P, Ciszek B | title = The choroid plexus of the fourth ventricle and its arteries | journal = Folia Morphologica | volume = 64 | issue = 3 | pages = 194–8 | date = August 2005 | pmid = 16228955 }}</ref>

===Reabsorption===
CSF returns to the vascular system by entering the [[dural venous sinuses]] via [[arachnoid granulation]]s.<ref name=GH2005/> These are outpouchings of the [[arachnoid mater]] into the venous sinuses around the brain, with valves to ensure one-way drainage.<ref name=GH2005/> This occurs because of a pressure difference between the arachnoid mater and venous sinuses.<ref name="SAKKA2011"/> CSF has also been seen to drain into [[lymph]]atic vessels,<ref name="pmid15624320">{{cite journal | vauthors = Johnston M | title = The importance of lymphatics in cerebrospinal fluid transport | journal = Lymphatic Research and Biology | volume = 1 | issue = 1 | pages = 41–4; discussion 45 | year = 2003 | pmid = 15624320 | doi = 10.1089/15396850360495682 }}</ref> particularly those surrounding the nose via drainage along the [[olfactory nerve]] through the [[cribriform plate]]. The pathway and extent are currently not known,<ref name="WRIGHT2012" /> but may involve CSF flow along some cranial nerves and be more prominent in the [[neonate]].<ref name="SAKKA2011"/> CSF turns over at a rate of three to four times a day.<ref name=GH2005/> CSF has also been seen to be reabsorbed through the sheathes of [[cranial nerves|cranial]] and [[spinal nerve]] sheathes, and through the ependyma.<ref name="SAKKA2011"/>

===Regulation===
The composition and rate of CSF generation are influenced by hormones and the content and pressure of blood and CSF.<ref name="SAKKA2011"/> 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.<ref name="SAKKA2011"/> The [[autonomic nervous system]] influences choroid plexus CSF secretion, with activation of the [[sympathetic nervous system]] decreasing secretion and the [[parasympathetic nervous system]] increasing it.<ref name="SAKKA2011"/> Changes in the [[pH#pH of various body fluids|pH of the blood]] can affect the activity of [[carbonic anhydrase]], and some drugs (such as [[furosemide]], acting on the [[Na-K-Cl cotransporter]]) have the potential to impact membrane channels.<ref name="SAKKA2011"/>

==Clinical significance==
===Pressure===
{{Further|Cerebral shunt}}
'''CSF pressure''', as measured by [[lumbar puncture]], is 10–18&nbsp;[[Centimetre of water|cmH<sub>2</sub>O]] (8–15&nbsp;[[mmHg]] or 1.1–2&nbsp;[[kilopascal|kPa]]) with the patient lying on the side and 20–30 cmH<sub>2</sub>O (16–24&nbsp;mmHg or 2.1–3.2&nbsp;kPa) with the patient sitting up.<ref>{{cite web|url=http://neuropathology-web.org/chapter14/chapter14CSF.html|title=Chapter 14 – Cerebrospinal Fluid :THE NORMAL CSF|date=May 2011|publisher=Northeast Ohio Medical University|work=Neuropathology| first = Dimitri | last = Agamanolis | name-list-style = vanc |access-date=2014-12-25}}</ref> In newborns, CSF pressure ranges from 8 to 10 [[centimetre of water|cmH<sub>2</sub>O]] (4.4–7.3&nbsp;mmHg or 0.78–0.98&nbsp;kPa). Most variations are due to coughing or internal compression of [[jugular vein]]s 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 CSF in the ventricles of the brain.<ref name=DAVIDSONS2010B>{{cite book |editor1-first=Nicki R. |editor1-last=Colledge |editor2-first=Brian R. |editor2-last=Walker |editor3-first=Stuart H. |editor3-last=Ralston | name-list-style = vanc |title=Davidson's principles and practice of medicine |year=2010 |publisher=Churchill Livingstone/Elsevier |location=Edinburgh |isbn=978-0-7020-3084-0 |edition=21st |pages=1220–1}}</ref> Hydrocephalus can occur because of [[obstructive hydrocephalus|obstruction]] of the passage of CSF, such as from an infection, injury, mass, or [[congenital abnormality]].<ref name=DAVIDSONS2010B /><ref name=NIH2017 /> [[normal pressure hydrocephalus|Hydrocephalus without obstruction associated with normal CSF pressure]] may also occur.<ref name=DAVIDSONS2010B /> Symptoms can include [[gait dysfunction|problems with gait]] and [[Motor coordination|coordination]], [[urinary incontinence]], [[nausea]] and [[vomiting]], and progressively impaired [[cognition]].<ref name=NIH2017 /> In infants, hydrocephalus can cause an enlarged head, as the bones of the skull have not yet fused, seizures, irritability and drowsiness.<ref name=NIH2017 /> A [[CT scan]] or [[MRI scan]] may reveal enlargement of one or both lateral ventricles, or causative masses or lesions,<ref name=DAVIDSONS2010B /><ref name=NIH2017 /> and [[lumbar puncture]] may be used to demonstrate and in some circumstances relieve high intracranial pressure.<ref name=HARRISONS2015>{{cite book |last1=Kasper |first1=Dennis |last2=Fauci |first2=Anthony |last3=Hauser |first3=Stephen |last4=Longo |first4=Dan |last5=Jameson |first5=J. |last6=Loscalzo |first6=Joseph | name-list-style = vanc |title=Harrison's Principles of Internal Medicine|date=2015|publisher=McGraw-Hill Professional|isbn=978-0-07-180215-4|edition=19|pages=2606–7}}</ref> Hydrocephalus is usually treated through the insertion of a [[Cerebral shunt|shunt]], such as a [[ventriculo-peritoneal shunt]], which diverts fluid to another part of the body.<ref name=DAVIDSONS2010B /><ref name="NIH2017">{{cite web|title=Hydrocephalus Fact Sheet|url=https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Hydrocephalus-Fact-Sheet|archive-url=https://web.archive.org/web/20161223060842/https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Hydrocephalus-Fact-Sheet|url-status=dead|archive-date=December 23, 2016|website=www.ninds.nih.gov|publisher=National Institute of Neurological Disorders and Stroke|access-date=19 May 2017}}</ref>

[[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 a [[Papilledema|swollen optic disc]].<ref name=DAVIDSONS2010B /> It can occur in association with the use of vitamin A and [[tetracycline]] antibiotics, or without any identifiable cause at all, particularly in younger [[obese]] women.<ref name=DAVIDSONS2010B /> Management may include ceasing any known causes, a [[carbonic anhydrase inhibitor]] such as [[acetazolamide]], repeated drainage via lumbar puncture, or the insertion of a shunt such as a ventriculo-peritoneal shunt.<ref name=DAVIDSONS2010B />

===CSF leak===
{{main|Cerebrospinal fluid leak}}
CSF can leak from the [[dura mater|dura]] as a result of different causes such as physical trauma or a lumbar puncture, or from [[idiopathy|no known cause]] when it is termed a [[spontaneous cerebrospinal fluid leak]].<ref name=DAVIDSONS2010 /> It is usually associated with [[intracranial hypotension]]: low CSF pressure.<ref name=HARRISONS2015 /> It can cause headaches, made worse by standing, moving and coughing,<ref name=HARRISONS2015 /> as the low CSF pressure causes the brain to "sag" downwards and put pressure on its lower structures.<ref name=HARRISONS2015 /> If a leak is identified, a [[beta-2 transferrin]] test of the leaking fluid, when positive, is highly specific and sensitive for the detection for CSF leakage.<ref name=DAVIDSONS2010>{{cite book |editor1-first=Nicki R. |editor1-last=Colledge |editor2-first=Brian R. |editor2-last=Walker |editor3-first=Stuart H. |editor3-last=Ralston | name-list-style = vanc |title=Davidson's principles and practice of medicine |year=2010 |publisher=Churchill Livingstone/Elsevier |location=Edinburgh |isbn=978-0-7020-3084-0 |edition=21st |pages=1147–8}}</ref> [[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.<ref name="PALDINO2003">{{cite journal | vauthors = Rosen CL | title = Meningiomas: the role of preoperative angiography and embolization | journal = Neurosurgical Focus | volume = 15 | issue = 4 | pages = 1 p following ECP4 | date = October 2003 | pmid = 15376362 | doi = 10.3171/foc.2003.15.6.8 | doi-access = free }}</ref> [[Caffeine]], given either orally or [[intravenous]]ly, often offers symptomatic relief.<ref name=PALDINO2003 /> Treatment of an identified leak may include injection of a person's blood into the epidural space (an [[epidural blood patch]]), [[spinal surgery]], or [[fibrin glue]].<ref name=PALDINO2003 />

===Lumbar puncture===
[[Image:4 vials of human cerebrospinal fluid.jpg|thumb|Vials containing human cerebrospinal fluid]]
{{Main|Lumbar puncture}}
CSF can be tested for the diagnosis of a variety of [[neurological disease]]s, usually obtained by a procedure called lumbar puncture.<ref name=AMP2003>{{cite journal | vauthors = Seehusen DA, Reeves MM, Fomin DA | title = Cerebrospinal fluid analysis | journal = American Family Physician | volume = 68 | issue = 6 | pages = 1103–8 | date = September 2003 | pmid = 14524396 | url = http://www.aafp.org/afp/20030915/1103.html | access-date = 2009-03-05 | archive-date = 2008-05-15 | archive-url = https://web.archive.org/web/20080515204056/http://www.aafp.org/afp/20030915/1103.html | url-status = dead }}</ref> 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.<ref name=DAVIDSONS2010 /> About one third of people experience a headache after lumbar puncture,<ref name=DAVIDSONS2010 /> 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.<ref name=WRIGHT2012/>

Testing often includes observing the colour of the fluid, measuring CSF pressure, and counting and identifying [[white blood cell|white]] and [[red blood cell]]s within the fluid; measuring protein and glucose levels; and [[Microbiological culture|culturing]] the fluid.<ref name=DAVIDSONS2010 /><ref name="AMP2003" /> The presence of red blood cells and [[xanthochromia]] may indicate [[subarachnoid hemorrhage]]; whereas [[central nervous system]] infections such as [[meningitis]], may be indicated by elevated white blood cell levels.<ref name=AMP2003/> A CSF culture may yield the [[microorganism]] that has caused the infection,<ref name="DAVIDSONS2010"/> or [[Polymerase chain reaction|PCR]] may be used to identify a viral cause.<ref name="AMP2003" /> Investigations to the total type and nature of proteins reveal point to specific diseases, including [[multiple sclerosis]], [[paraneoplastic syndrome]]s, [[systemic lupus erythematosus]], [[neurosarcoidosis]], [[cerebral angiitis]];<ref name="WRIGHT2012" /> and specific [[antibodies]] such as [[aquaporin-4]] may be tested for to assist in the diagnosis of [[autoimmune]] conditions.<ref name=WRIGHT2012/> 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]].<ref name=WRIGHT2012/>

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 fatal [[brain herniation]].<ref name=DAVIDSONS2010 />

===Anesthesia and chemotherapy===
{{See also|Blood–cerebrospinal fluid barrier}}
Some [[anesthetic]]s and [[chemotherapy]] drugs are injected [[intrathecal]]ly into the subarachnoid space, where they spread around CSF, meaning substances that cannot cross the [[blood–brain barrier]] can still be active throughout the central nervous system.<ref name=HOCKING2004/><ref>{{cite web|title=Intrathecal Chemotherapy for Cancer Treatment {{!}} CTCA|url=http://www.cancercenter.com/treatments/intrathecal-chemotherapy/|website=CancerCenter.com|access-date=22 May 2017|archive-date=1 January 2018|archive-url=https://web.archive.org/web/20180101135319/https://www.cancercenter.com/treatments/intrathecal-chemotherapy/|url-status=dead}}</ref>  [[Baricity]] refers to the density of a substance compared to the density of human cerebrospinal fluid and is used in [[regional anesthesia]] to determine the manner in which a particular drug will spread in the [[intrathecal]] space.<ref name="HOCKING2004">{{cite journal | vauthors = Hocking G, Wildsmith JA | title = Intrathecal drug spread | journal = British Journal of Anaesthesia | volume = 93 | issue = 4 | pages = 568–78 | date = October 2004 | pmid = 15220175 | doi = 10.1093/bja/aeh204 | doi-access = free }}</ref>

===Liquorpheresis===

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.<ref>{{Cite book |last=Menendez-Gonzalez |first=Manuel |title=Liquorpheresis: Cerebrospinal Fluid Filtration to Treat CNS Conditions |publisher=Springer Cham |year=2023 |isbn=978-3-031-43481-5 |edition=First |location=London |publication-date=November 2023 |pages=1–67 |language=English}}</ref>
===CSF drug delivery===
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. 
<ref>{{Cite journal |last1=Sun |first1=Wujin |last2=Gu |first2=Zhen |date=2016-03-03 |title=ATP-Responsive Drug Delivery Systems |journal=Expert Opinion on Drug Delivery |language=en |volume=13 |issue=3 |pages=311–314 |doi=10.1517/17425247.2016.1140147 |issn=1742-5247 |pmc=4998835 |pmid=26745457}}</ref>

==History==
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 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.<ref name=CSFhistory />

The modern rediscovery of CSF is 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.<ref name=CSFhistory>{{cite journal | vauthors = Hajdu SI | title = A note from history: discovery of the cerebrospinal fluid | journal = Annals of Clinical and Laboratory Science | volume = 33 | issue = 3 | pages = 334–6 | year = 2003 | pmid = 12956452 | url = http://www.annclinlabsci.org/content/33/3/334.long }}</ref>

[[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.<ref name=CSFhistory/> [[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 the [[pia mater]].<ref name=CSFhistory/>

[[Thomas Willis]] (noted as the discoverer of the [[circle of Willis]]) made note of the fact that the consistency of CSF is altered in meningitis.<ref name=CSFhistory/> In 1869 [[Gustav Albert Schwalbe|Gustav Schwalbe]] proposed that CSF drainage could occur via lymphatic vessels.<ref name="WRIGHT2012" />

In 1891, [[W. Essex Wynter]] began treating tubercular meningitis by removing CSF from the subarachnoid space, and [[Heinrich Quincke]] began to popularize lumbar puncture, which he advocated for both diagnostic and therapeutic purposes.<ref name=CSFhistory/> In 1912, a neurologist William Mestrezat gave the first accurate description of the chemical composition of CSF.<ref name=CSFhistory/> In 1914, [[Harvey W. Cushing]] published conclusive evidence that CSF is secreted by the [[choroid plexus]].<ref name=CSFhistory/>

==Other animals==
During [[phylogenesis]], CSF is present within the [[neuraxis]] before it circulates.<ref name="SAKKA2011"/> The CSF of [[teleost]] fish, which do not have a subarachnoid space, is contained within the ventricles of their brains.<ref name="SAKKA2011"/> In mammals, where a subarachnoid space is present, CSF is present in it.<ref name="SAKKA2011"/> Absorption of CSF is seen in [[amniote]]s 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.<ref name="SAKKA2011"/>

The amount of cerebrospinal fluid varies by size and species.<ref name="REECE2013">{{cite book|last1=Reece|first1=William O. | name-list-style = vanc |title=Functional Anatomy and Physiology of Domestic Animals|date=2013|publisher=John Wiley & Sons|isbn=978-1-118-68589-1|page=118|url=https://books.google.com/books?id=C_q3Q-IpkNMC&q=cerebrospinal+fluid+and+animals&pg=PA118|language=en}}</ref> In humans and other [[mammal]]s, cerebrospinal fluid turns over at a rate of 3–5 times a day.<ref name=REECE2013 /> Problems with CSF circulation, leading to hydrocephalus, can occur in other animals as well as humans.<ref name=REECE2013 />

== See also ==
* [[Neuroglobin]]
* [[Pandy's test]]
* [[Reissner's fiber]]
* [[Syrinx (medicine)]]

== References ==
{{Reflist}}

== External links ==
{{Commons category|Cerebrospinal fluid}}
* [https://web.archive.org/web/20150105122521/http://www.aboutkidshealth.ca/En/HowTheBodyWorks/IntroductiontotheBrain/WhatisCerebrospinalFluidCSF/Pages/CirculationofCerebrospinalFluidCSF.aspx Circulation of Cerebrospinal Fluid (CSF)]{{snd}} interactive tool
* [https://neuropathology-web.org/chapter14/chapter14CSF.html Cerebrospinal fluid]{{snd}} course material in neuropathology
* [https://web.archive.org/web/20171106060813/http://www.control.tfe.umu.se/Ian/CSF/ Identification of the Cerebrospinal Fluid System Dynamics]

{{Ventricular system}}
{{Authority control}}

{{DEFAULTSORT:Cerebrospinal Fluid}}
[[Category:Body fluids]]
[[Category:Ventricular system]]
[[Category:Neurology]]
[[Category:Reference intervals]]