Cerebrospinal fluid

Cerebrospinal fluid is a clear, colorless transcellular body fluid found within the meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricles of the brain.
CSF is mostly produced by the epithelial cells in the choroid plexuses of the ventricles of the brain, and absorbed in the arachnoid granulations. 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 and immunological protection to the brain inside the skull. CSF also serves a vital function in the cerebral autoregulation of cerebral blood flow.
CSF occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord. It fills the ventricles of the brain, cisterns, and 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 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 infections of the brain or the surrounding meninges.
Although noted by Hippocrates, it was forgotten for centuries, though later was described in the 18th century by Emanuel Swedenborg. In 1914, Harvey Cushing demonstrated that CSF is secreted by the choroid plexus.

Structure

Circulation

In humans, there is about 125–150 mL of CSF at any one time. 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 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 openingsthe central canal of the spinal cord, the median aperture, and the two lateral apertures. 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. 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.
CSF moves in a single outward direction from the ventricles, but multidirectionally in the subarachnoid space. The flow of cerebrospinal fluid is pulsatile, driven by the cardiac cycle. The flow of CSF through perivascular spaces in the brain is obtained through the pumping movements of the walls of the arteries.

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.
CSF contains approximately 0.59% plasma proteins, or approximately 15 to 40 mg/dL, depending on sampling site. 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.

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. The neural tube, forming from the ectoderm, contains CSF prior to the development of the choroid plexuses. The open neuropores of the neural tube close after the first month of development, and CSF pressure gradually increases.
By the fourth week of embryonic development the brain has begun to develop. Three swellings, 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, mesencephalon, and rhombencephalon. Subarachnoid spaces are first evident around the 32nd day of development near the rhombencephalon; circulation is visible from the 41st day. 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.
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. CSF quickly fills the neural canal. 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.
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.
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.
Regulation: CSF allows for the homeostatic regulation of the distribution of substances between cells of the brain, 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 fainting.
Clearing waste: CSF allows for the removal of waste products from the brain, and is critical in the brain's lymphatic system, called the glymphatic system. 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.
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. Additionally, the larger CSF volume may be one reason as to why children have lower rates of postdural puncture headache.
Most of CSF is produced by the choroid plexus. The choroid plexus is a network of blood vessels present within sections of the four ventricles of the brain. It is present throughout the ventricular system except for the cerebral aqueduct, and the frontal and occipital horns of the lateral ventricles. CSF is mostly produced by the lateral ventricles. CSF is also produced by the single layer of column-shaped ependymal cells which line the ventricles; by the lining surrounding the subarachnoid space; and a small amount directly from the tiny spaces surrounding blood vessels around the brain.
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, with movement guided by a difference in pressure between the blood in the capillaries and the interstitial fluid. 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. 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. 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. Sodium, chloride, bicarbonate and potassium are then actively secreted into the ventricular lumen. This creates osmotic pressure and draws water into CSF, facilitated by aquaporins. 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.
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. 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.
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 AQP-4.
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.
Choroid plexus of the lateral ventricle produces CSF from the arterial blood provided by the anterior choroidal artery. In the fourth ventricle, CSF is produced from the arterial blood from the anterior inferior cerebellar artery, the posterior inferior cerebellar artery, and the superior cerebellar artery.