Cerebrospinal fluid

Circulation In humans, there is about 125–150 mL of CSF at any one time. CSF moves in a single outward direction from the ventricles, but multidirectionally in the subarachnoid space. 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. In general, globular proteins and albumin are in lower concentration in ventricular CSF compared to lumbar or cisternal fluid. This continuous flow into the venous system dilutes the concentration of larger, lipid-insoluble molecules penetrating the brain and CSF. CSF is normally free of red blood cells and at most contains fewer than 5 white blood cells per mm3 (if the white cell count is higher than this it constitutes pleocytosis and can indicate inflammation or infection). ==Development==

At around the fifth week of its development, the embryo is a 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. 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. 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. ==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. 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. Metabolic waste products diffuse rapidly into CSF and are removed into the bloodstream as CSF is absorbed. When this goes awry, CSF can become toxic, such as in amyotrophic lateral sclerosis, the most common form of motor neuron disease. Production The brain produces roughly 500 mL of cerebrospinal fluid per day at a rate of about 20 mL an hour. This transcellular fluid is constantly reabsorbed, so that only 125–150 mL is present at any one time. Additionally, the larger CSF volume may be one reason as to why children have lower rates of postdural puncture headache. Most (about two-thirds to 80%) of CSF is produced by the choroid plexus. CSF is mostly produced by the lateral ventricles. CSF is produced by the choroid plexus in two steps. Firstly, a filtered form of plasma moves from fenestrated capillaries in the choroid plexus into an interstitial space, Cilia on the apical surfaces of the ependymal cells beat to help transport the CSF. 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. As a result, to maintain 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. Choroid plexuses also secrete growth factors, iodine, vitamins B1, B12, C, folate, beta-2 microglobulin, arginine vasopressin and nitric oxide into CSF. 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. 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. Reabsorption CSF returns to the vascular system by entering the dural venous sinuses via arachnoid granulations. particularly those surrounding the nose via drainage along the olfactory nerve through the cribriform plate. The pathway and extent are currently not known, but may involve CSF flow along some cranial nerves and be more prominent in the neonate. CSF turns over at a rate of three to four times a day. CSF has also been seen to be reabsorbed through the sheathes of cranial and spinal nerve sheathes, and through the ependyma. Regulation The composition and rate of CSF generation are influenced by hormones and the content and pressure of blood and CSF. 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. 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. Changes in the 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. ==Clinical significance==

Pressure CSF pressure, as measured by lumbar puncture, is 10–18 cmH2O (8–15 mmHg or 1.1–2 kPa) with the patient lying on the side and 20–30 cmH2O (16–24 mmHg or 2.1–3.2 kPa) with the patient sitting up. In newborns, CSF pressure ranges from 8 to 10 cmH2O (4.4–7.3 mmHg or 0.78–0.98 kPa). Most variations are due to coughing or internal compression of jugular veins in the neck. When lying down, the CSF pressure as estimated by lumbar puncture is similar to the intracranial pressure. Hydrocephalus is an abnormal accumulation of CSF in the ventricles of the brain. Hydrocephalus can occur because of obstruction of the passage of CSF, such as from an infection, injury, mass, or congenital abnormality. Hydrocephalus is usually treated through the insertion of a shunt, such as a ventriculo-peritoneal shunt, which diverts fluid to another part of the body. 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 swollen optic disc. 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. Caffeine, given either orally or intravenously, often offers symptomatic relief. 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. 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. 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. 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. ==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. 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. 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. 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. In 1869 Gustav Schwalbe proposed that CSF drainage could occur via lymphatic vessels. 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. In 1912, a neurologist William Mestrezat gave the first accurate description of the chemical composition of CSF. In 1914, Harvey W. Cushing published conclusive evidence that CSF is secreted by the choroid plexus. ==Other animals==

During phylogenesis, CSF is present within the neuraxis before it circulates. In humans and other mammals, cerebrospinal fluid turns over at a rate of 3–5 times a day. Problems with CSF circulation, leading to hydrocephalus, can occur in other animals as well as humans. == See also ==