How is csf created

However, the arachnoid villi act as "one way valves" In other words, the CSF acts to cushion a blow to the head and lessen the impact. Buoyancy : because the brain is immersed in fluid, the net weight of the brain is reduced from about 1, gm to about 50 gm.

Therefore, pressure at the base of the brain is reduced. Erythrocytes from subarachnoid hemorrhage are cleared in 3 to 7 days. A few neutrophils and mononuclear cells may also be present as a result of meningeal irritation. Xanthochromia blonde color of the CSF following subarachnoid hemorrhage is due to oxyhemoglobin which appears in 4 to 6 hours and bilirubin which appears in two days.

Xanthochromia may also be seen with hemorrhagic infarcts, brain tumors, and jaundice. Increased inflammatory cells pleocytosis may be caused by infectious and noninfectious processes.

Polymorphonuclear pleocytosis indicates acute suppurative meningitis. Mononuclear cells are seen in viral infections meningoencephalitis, aseptic meningitis , syphilis, neuroborreliosis, tuberculous meningitis, multiple sclerosis, brain abscess and brain tumors.

Tumor cells indicate dissemination of metastatic or primary brain tumors in the subarachnoid space. The most common among the latter is medulloblastoma. They can be best detected by cytological examination. A mononuclear inflammatory reaction is often seen in addition to the tumor cells. Oligoclonal bands are also seen occasionally in some chronic CNS infections. The type of oligoclonal bands is constant for each MS patient throughout the course of the disease.

Oligoclonal bands occur in the CSF only not in the serum. These quantitative and qualitative CSF changes indicate that in MS, there is intrathecal immunoglobulin production. MBP can be detected by radioimmunoassay. MBP is not specific for MS. It can appear in any condition causing brain necrosis, including infarcts.

Low glucose in CSF is seen in suppurative, tuberculous and fungal infections, sarcoidosis, and meningeal dissemination of tumors. Glucose is consumed by leukocytes and tumor cells. Alzheimer's disease AD.

Total-tau t-tau and phosphorylated tau p-tau are both increased in AD. Tau is an intracellular protein and p-tau is a component of neurofibrillary tangles NFTs.

Their increase in AD is thought to reflect neuronal death with release of tau into the extracellular space. Creutzfeldt-Jacob disease. The proteins the name derives from their electrophoresis pattern are a group of proteins with diverse regulatory functions present in all cells. Elevated CSF in a patient with progressive dementia of less than 2 years' duration is considered a strong indicator of CJD. A negative test does not rule out CJD. In the course of traumatic brain injury TBI , proteins from injured neurons and glial cells are released in the interstitial space and CSF and, because of damage of the BBB, make their way into the blood.

Detection of these products in CSF or serum in the early phases of TBI would be very helpful, especially because imaging studies may be inconclusive. Several such markers have been considered.

Some of these are present in settings other than TBI. Other biomarkers such as neuron specific enolase and SB protein are elevated in TBI but are not specific because they are found in tissues outside the CNS. Arterial and venous vessels running within the cortical subarachnoid space are covered with a pial cell layer, which ensheaths the vessels.

The pial sheath creates a space next to the vessel wall, which is referred to as perivascular space PVS [ 68 ]. At the site of the entrance of the cortical vessels into the VRS, their pial sheath joins with the pial cell layer covering the brain surface forming a funnel like structure, which accompanies the vessels into the VRS though for a short distance only[ 69 , 70 ].

However, the pial sheath of the arterial, but not venous, vessels extends into the VRS. Near the capillary bed, the pial sheath becomes more and more fenestrated and leaky[ 68 ]. It is important to note that the nomenclature is not used consistently. Some authors use the terms "Virchow Robin space" and "perivascular space" as synonyms[ 71 ], while others use the terms to name different spaces as discussed above[ 72 ].

Ultrastructural electron microscopic studies agree that pial membranes separate the VRS from the cortical subarachnoid space[ 65 , 68 , 70 ]. Since electron microscopy of human brain specimens shows that the VRS and the PVS are collapsed[ 68 ], it is a matter of debate whether these histologically-characterized compartments are actually open or just potential spaces. However, studies in rodents have demonstrated the VRS filled with fluid, electron microscopic dense material[ 70 ], macrophages and other blood born inflammatory cells[ 64 , 67 ].

Possibly, different fixation procedures may explain this discrepancy: rodent brains undergo intra-vital perfusion fixation, while the studies in man have to rely on specimens, which are fixed extra-corporally. Although pial cell layers obviously separate the VRS from the cortical subarachnoid space, physiologically there is strong evidence indicating that fluid circulates along the VRS Figure 2.

Following the injection of horseradish peroxidase HRP into the lateral ventricles or subarachnoid space of anesthetized cats and dogs, light microscopic examination of serial brain sections has been performed utilizing a sensitive histochemical technique tetramethylbenzidine incubation [ 73 ]. The authors reported the distribution of tracer reaction product within the VRS and along the basal laminae around capillaries.

The influx into these spaces was very rapid since the intraparenchymal microvasculature was clearly outlined 6 min after the infusion of HRP. Electron microscopy of sections incubated after 10 or 20 min of HRP circulation confirmed the paravascular location of the reaction product, which was also dispersed throughout the extracellular spaces ECS of the adjacent parenchyma.

The rapid paravascular influx of HRP could be prevented by halting or diminishing the pulsations of the cerebral arteries by aortic occlusion or by partial ligation of the brachiocephalic artery. However, it should be noted that others were not able to reproduce these findings; Krisch et al. Also, another study reported that following microinjection into the VRS or the subarachnoid space of rats, tracers e.

India ink, albumin labeled with colloidal gold, Evans blue, rhodamine remained largely in the VRS, the cortical subpial space and the core of subarachnoid trabeculae. Nevertheless, bulk flow of fluid within the VRS, around both arteries and veins, was suggested from video-densitometric measurements of fluorescently labeled albumin.

However, the observed flow was slow and its direction varied in an unpredictable way[ 71 ]. Furthermore, it was shown that, following intracerebral injection, India ink particles concentrated in the VRS, but were then rapidly ingested by perivascular cells.

Notably, very little movement of carbon-labeled perivascular cells and perivascular macrophages was seen after 2 years[ 74 ]. Diagram representing fluid movements at the Virchow Robin space. Glial blue lines and pial yellow lines cell membranes enclose the VRS and control fluid exchange. Note, that it is a matter of debate whether the VRS represents an open fluid fill space see text for discussion.

Both experimental and clinical evidence indicate the existence of a pathway along the basement membranes of capillaries, arterioles, and arteries for the drainage of ISF and solutes into the lymphatic system red lines and green arrows. It is unclear, whether the subpial perivascular spaces around arteries and veins light blue serve as additional drainage pathways. Also, the proposed glymphatic pathway connecting the arterial and venous VRS with the venous perivascular space black arrows is still a matter of debate.

Since there is obviously at least some circulation of CSF into and out of the VRS, it raises the question how fluid and tracers could cross the pial membranes separating the VRS from the subarachnoid space. Ultrastructure studies have depicted the pial barrier as a delicate, sometimes single-cell layered structure[ 75 ]. There are considerable species differences: in the mouse the pial layer was found to be extremely thin, while in man its structure was significantly thicker[ 76 ].

Notably, in man the pial barrier was still described as a delicate yet apparently continuous layer of cells, which were joined by desmosomes and gap junctions but had no obvious tight junctions[ 77 ]. According to such morphological studies, it was recognized that the pia is not impermeable to fluids[ 61 ]. Since, in a similar fashion, the ependymal cell layers covering the inner ventricular surfaces of the brain are not connected by tight junctions[ 78 ], it was suggested that "CSF communicates with the ISF across the inner ependymal and outer pial surfaces of the brain"[ 61 ].

If one assumes that the flow within the VRS depends on the pulsatility of the arteries[ 73 , 79 ], hydrostatic forces may drive fluids and solutes across the pial membranes. However, while the VRS basically allows for the bi-directional exchange between CSF and ISF, no quantitative data are available that describe the extent and kinetics of such fluid movements. Although it has been shown that pial membranes between the PVS and the SAS could prevent the exchange of larger molecules, since tracer, following intraparenchymal injection, accumulated within the PVS but was not distributed into the cisternal CSF[ 80 ].

This observation is supported by clinical findings that following aneurysmal rupture in man, red blood cells are confined to the subarachnoid space, and do not enter the VRS[ 76 ]. It has also been shown both experimentally and clinically that the PVS and possibly more importantly intramural pathways between the basement membranes of the wall of arterioles and arteries provide drainage for the ISF and waste molecules of the brain.

There is experimental evidence that the para-arterial drainage pathways are connected to the lymphatics of the exterior skull base[ 81 , 82 ]. Actually, solutes and fluid may be drained along the arteries from the brain interstitium via the VRS into the cervical lymphatics[ 81 , 83 ], reviewed by Weller[ 45 ]. Supporting this notion are the immunohistochemical and confocal microscopic observations that soluble fluorescent tracers 3 kD dextran or 40 kD ovalbumin move from the brain parenchyma along the basement membranes of capillaries and arteries following its injection of into the corpus striatum of mice.

This pathway may not serve for the transport of particles or cells, since fluospheres diameter 0. Clearance of solutes along this pathway could be prevented by cardiac arrest[ 83 ]. These findings are clinically significant since based upon observations in patients with cerebral amyloid angiopathy, beta-amyloid is deposited in the vascular wall of arterioles and arteries.

Interestingly, the extent of amyloid deposition is so prominent that it was suggested as a natural tracer for the peri-arterial drainage pathways[ 83 ]. The peri-arterial drainage of fluids and solutes has important implications not only in neurodegenerative diseases, but in addition in immunological CNS diseases, see for comprehensive reviews[ 45 , 85 , 86 ].

Similar to arteries, veins within the subarachnoid space possess a pial sheath forming a PVS[ 64 ]. As compared to arteries, it is less clear whether venous perivascular pathways serve as a drainage pathway for ISF and interstitial solutes. Notably, injections of tracers into the brain revealed no drainage along peri-venous channels unless there is disruption of flow in cerebral amyloid angiopathy when some tracer enter the peri-venous spaces[ 87 ].

However, recent findings[ 88 ] indicate a more significant contribution of the venous perivascular route for the drainage of ISF and solutes see discussion below.

Traditionally, movement of fluids through the brain interstitial space has been attributed to diffusional processes[ 89 — 91 ], which actually are slow because of the narrowness and tortuosity of the extracellular space of the brain reviewed by[ 92 ]. Today, it is commonly accepted that "the narrow spaces between cells within the neuropil are likely to be too small to permit significant bulk flow"[ 29 ]. A recent review discusses important clinical implications regarding CNS drug delivery[ 93 ].

As commented by others[ 45 , 94 ], our current understanding includes bulk flow mechanisms for the movement and drainage of ISF along white matter tracts and the perivascular spaces.

Considering the cellular architecture of pia and ependyma, it also accepted that these cellular layers represent a diffusional barrier, which actually provides a communication between ISF and CSF[ 61 ]. Experimental evidence for the existence of bulk flow mechanisms was found after microinjection of tracer into the brain. Morphological studies revealed the VRS and the perivascular spaces as channels for fluid transport, but also revealed additional spaces between fiber tracts in white matter and the subependymal layer of the ventricle.

Analysis of the kinetics of removal of three radiolabeled tracers from brain tissue e. These three test compounds differ in their diffusion coefficient by up to a factor of five but were cleared from brain according to a single exponential rate constant. This is consistent with removal by convection from a well-mixed compartment. For different regions of the brains of rats and rabbits, the ISF flow rate was estimated between 0.

Very recently it has been shown that astrocyte water transporters, i. Interestingly, such extensive water movements were indicated by earlier radiotracer experiments. For example in , following the intravenous injection of deuterium oxide a rapid distribution throughout all brain compartments was reported[ 99 ].

As a result, the significance of this work was not fully appreciated. Recently the original data on the deuterium oxide half-life in different brain compartments has been used to calculate the respective CSF fluxes by applying MRI-based volume assessments of the ventricles, the subarachnoid space and the spinal CSF spaces.

This is far greater than the traditional views of CSF physiology[ ]. CSF formation at the choroid plexus occurs in two stages: passive filtration of fluid across the highly permeable capillary endothelium and a regulated secretion across the single-layered choroidal epithelium.

The choroidal epithelium forms a fluid barrier since tight junctions are expressed at the apical, CSF facing, cell membrane[ ].

The rate of choroidal CSF formation is rather insensitive to osmotic and hydrostatic pressure changes in the CSF and therefore relatively independent of changes in intracranial pressure and plasma osmolarity.

Hence, water transport across the choroid plexus epithelium cannot be explained simply by an osmotic mechanism discussed in detail in[ 96 ]. Today there is agreement that choroidal CSF production is controlled by membrane transporters within the epithelium. Different transporters are expressed at the basolateral plasma facing and apical CSF facing membranes.

Due to its high AQP1 expression, the apical membrane has high water permeability. In contrast to this, the basolateral membrane lacks significant AQP1 expression[ ]. Together, these transporters expel water from the cell into the CSF space.

Little is known about the water transport at the basolateral membrane. The molecular mechanisms of choroidal CSF production are comprehensively reviewed in[ 96 , , ].

Traditionally the properties of the blood—brain barrier BBB are considered to be those of the capillary endothelium in brain. This endothelium contrasts with that elsewhere in the body by being sealed with tight junctions, having a high electrical resistance and a low permeability to polar solutes[ 89 ].

The modern understanding of BBB physiology was further improved by the discovery that cells surrounding the capillaries can control and modulate BBB functions. The role of astrocytes is of utmost interest with respect to CSF physiology, since astrocyte end-feet have been shown to cover the entire capillary surface, leaving intercellular clefts of less than 20 nm[ ].

The astrocytes, therefore, form an additional barrier surrounding the cerebral capillaries[ 98 ]. The role of astrocytes in brain water homeostasis is strongly supported by the finding that water transporting pores i. It is also important to recognize that contrary to earlier assumptions, the endothelial barrier carries no AQP4 transporters[ ].

Instead, water may cross the endothelium by diffusion, vesicular transport and, even against osmotic gradients, by means of co-transport with ions and glucose reviewed in[ 96 ]. The physiology of aquaporins AQPs and transporters in the brain has been comprehensively reviewed[ 96 , 98 , — ].

Here those aspects are discussed, which are relevant for the understanding of CSF circulation. Basically, in response to both passive osmotic and hydraulic pressure gradients, AQPs can transport water, solutes, and ions bi-directionally across a cell membrane. In comparison to diffusional transport, AQPs have significant biophysical differences. Diffusion is non-specific and low-capacity movement, whereas water channels like the AQPs provide rapid transport and have both a high capacity and a great selectivity for the molecules being transported[ ].

More recent data in rodents have demonstrated that the precise dynamics of the astroglia-mediated brain water regulation of the CNS is dependent on the interactions between water channels and ion channels. Their anchoring by other proteins allows for the formation of macromolecular complexes in specific cellular domains reviewed in[ ].

Currently, at least 14 different aquaporins have been identified[ 97 , ]. At least six have been reported in the brain[ , ]: AQP 1, 4, 5 specifically water permeable , AQP3 and 9 permeable for water and small solutes and AQP8 permeable for ions [ ].

Positron emission tomography techniques for imaging of AQP4 in the human brain are currently being developed[ ]. Structural and functional data suggests that the permeability of AQP channels can be regulated and that it might also be affected in brain pathologies reviewed by[ , ]. As a result of the dynamic regulation, AQP channel permeability or AQP channel subcellular localization may change within seconds or minutes leading to immediate changes in the membrane permeability.

These changes will alter AQP expression within hours or days. AQPs may be regulated under pathological conditions: For example AQP1 and AQP4 are strongly upregulated in brain tumors and in injured brain tissue[ ], AQP5 is down-regulated during ischemia but up-regulated following brain injury[ ]. Notably, AQP1 is expressed in vascular endothelial cells throughout the body but is absent in the cerebrovascular endothelium, except in the circumventricular organs[ ].

As already discussed AQP1 is found in the ventricular-facing cell plasma membrane of choroid plexus epithelial cells suggesting a role for this channel in CSF secretion. Accordingly it was discussed that AQP1-facilitated transcellular water transport accounts for only part of the total choroidal CSF production.

As a more controversial possibility, it was suggested that the choroid plexus may not be the principal site of CSF production and that extrachoroidal CSF production by the brain parenchyma may be more important[ , ]. The latter notion is supported by the observation that following its intravenous application, the penetration and steady concentration of H 2 17 O is significantly reduced in ventricular CSF in AQP4 but not in AQP1 knockout mice.

AQP4 is strongly expressed in astrocyte foot processes at the BBB, glia limitans of brain surface and VRS, as well as ventricular ependymal cells and subependymal astrocytes.

Actually, it is expressed at all borders between brain parenchyma and major fluid compartments[ 97 , , ]. Therefore, the earlier view of exchange of ISF and CSF across ependymal and glial cell layers[ ] may be in fact aquaporin-mediated water transport across these membranes[ ]. AQP4 is also localized in astrocyte end feet at the perisynaptic spaces of neurons and is found in the olfactory epithelium[ 97 ].

The precise subcellular distribution of AQP4, i. In mice lacking alpha-syntrophin, astrocyte AQP4 is displaced, being markedly reduced in the end feet membranes adjacent to the blood vessels in cerebellum and cerebral cortex, but present at higher than normal levels in membranes directly facing the neuropil[ ]. A similar effect on AQP4 localization is observed in dystrophin-null mice[ ]. Since Kir4. AQP4 is involved in water movements under pathological conditions see for details[ 97 , , , ].

There is agreement that AQP4-null mice have reduced brain swelling and improved neurological outcome in models of cellular cytotoxic cerebral edema including water intoxication, focal cerebral ischemia, and bacterial meningitis. However, brain swelling and clinical outcome are worse in AQP4-null mice in models causing a disruption of the BBB and consecutive vasogenic edema.

Impairment of AQP4-dependent brain water clearance was suggested as the mechanism of injury in cortical freeze-injury, brain tumor, brain abscess and hydrocephalus[ ]. In hydrocephalus produced by cisternal kaolin injection, AQP4-null mice demonstrated ventricular dilation and raised intracranial pressure, which were both significantly greater when compared to wild-type mice[ ].

It is a matter of ongoing research whether AQP4-mediated brain water movement is relevant under physiological conditions. Considering only the pattern of AQP4 expression at the borders between the brain and CSF compartments, it has been suggested that AQP4 facilitates or controls the flow of water into and out of the brain[ 98 ].

AQP4 deletion is associated with a sevenfold reduction in cell plasma membrane water permeability in cultured astrocytes[ ] and a tenfold reduction in BBB water permeability in mouse brain[ ]. In AQP4-null mice unaltered intracranial pressure and compliance were found[ ]. Furthermore, no changes in ventricular volume or anatomical features of two different AQP4-null mice strains were reported[ ].

However, others observed smaller ventricular sizes, reduced CSF production and increased brain water in AQP4-null mice[ ]. Considering that the deletion of AQP4 has only little or modest in vivo effects, the current view is that, under normal physiological conditions, AQP4 is not needed for relatively slow water movement conditions[ 97 ]. Mice in which a conditional knockout was driven by the glial fibrillary acidic protein promoter, showed increased basal brain water content.

It was concluded that the glial covering of the neurovascular unit limits the rate of brain water influx as well as the efflux[ ]. It is now widely accepted that water moves across the endothelium by simple diffusion and vesicular transport, and across the astrocyte foot process primarily through AQP4 channels reviewed by[ 98 ]. In addition, a variety of endothelial water-transport proteins expressed in one or both of the cell membranes luminal or apical , provide co-transport of water along with their substrates even independently of osmotic gradients.

The identification of non-aquaporin water transporters located at the endothelium was a major contribution to the understanding of water transport across the neurovascular unit not just the astrocyte or endothelial barrier.

The CSF then passes through the arachnoid villi into the superior sagittal sinus, a large vein, and is absorbed into the bloodstream.

Once in the bloodstream, it is carried away and filtered by the kidneys and liver in the same way as other bodily fluids. However, more recent research has shown that CSF is also absorbed through other pathways as well. When CSF absorption is blocked or reduced, hydrocephalus can develop. This is often referred to as communicating hydrocephalus because there is no obvious blockage within the ventricular system.

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