Editing Cerebrospinal fluid (section)

==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|pages=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 | pages = 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}}</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}}</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"/>