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. It is important to recognize that all these transport mechanism are bi-directional and represent a dynamic process. This implies that large water fluxes may take place continuously, although the net flow may be small.
This would explain the fast and extensive passage of deuterium oxide from blood to brain[ 99 ]. As a process independent of net flow, the finding could be understood as a result of a dynamic bidirectional mixing of water between the blood, ISF and the CSF compartments.
The bidirectional transport could also generate net-flux. Actually, the neurovascular unit may not only be involved in the production but also in the absorption of CSF and ISF. This is suggested by recent experiments in which tritiated water was infused into the ventricle of cats.
During a three-hour infusion, the concentration in blood sampled from the cerebral venous sinuses rapidly increased up to 5 times higher than in samples of cisternal CSF and arterial blood.
However, following the infusion of 3 H-inulin, the cisternal concentration increased sharply during the observation period of three hours. At the same time venous and arterial concentrations were near background activity. It was concluded that 3 H-water, but not 3 H-inulin, is absorbed from brain ventricles into periventricular capillaries, which eventually drain in the venous sinuses[ ].
Figures 2 and 3 illustrate that aquaporins, associated with astrocytes in the glial and ependymal cell layers, may control brain water movement around the Virchow Robin space and across the brain compartments. Diagram of the CSF "Circulation". This diagram summarizes fluid and cellular movements across the different barriers of the brain compartments blood, interstitial fluid, Virchow Robin space, cerebrospinal fluid space comprising the cerebral ventricles, basal cisterns and cortical subarachnoid space.
Aquaporins and other transporters control the fluid exchange at the glial, endothelial, and choroid plexus barrier. At the glial, endothelial, and pial barrier bi-directional flow may generate either a net in- or outflux, providing fluid exchange rates, which surpass the net CSF production rate by far. The choroid plexus is the only direct connection between the blood and the CSF compartment. Major portions of brain water are drained into the cervical lymphatics from the VRS including its capillary section via intramural arterial pathways asterisks and from the CSF space via perineural subarachnoid space of cranial nerves.
The capillary and venular endothelium may contribute to brain water absorption. Fluid movements at the barriers are driven by osmotic and hydrostatic gradients or by active transporter processes. Fluid movements into and out of the VRS depend on respiratory and cardiac pressure pulsations. Phase-contrast magnetic resonance imaging MRI can provide quantitative blood flow velocity information in humans[ ]. It was applied to the study of CSF flow along the aqueduct, a small canal connecting the third and fourth cerebral ventricles[ , ].
Advanced phase-contrast MRI, the cine phase-contrast technique yields quantitative flow information by synchronizing the acquisition of the images to the cardiac cycle[ ]. Eventually, these MRI techniques may be applied to assess the heartbeat related stroke volume of CSF, from which the CSF net flow along the aqueduct may be calculated[ ]. Applying these techniques, the normal aqueduct flow has been measured many times in adults with flow rates ranging from 0.
Based upon these data, the average normal flow in healthy adults was suggested to be 0. Findings showing a reversed caudocranial flow of CSF along the aqueduct are even more puzzling. A reversed flow of 0. Furthermore, a reversed flow was reported in adult patients suffering from normal pressure hydrocephalus: mean stroke volume in the control group was In NPH patients, similar observations were reported by others[ ].
Technical limitations of the MRI flow measurements must be considered before interpreting these MRI data that are not congruent with the traditional understanding of CSF physiology. Thus it was pointed out that the evaluation of the flow void is subjective and highly dependent on the acquisition parameters used, as well as on the technical characteristics of the MR imaging systems e. Unfortunately, there is no class A evidence reported, which would clarify these conflicting data.
Appropriate clinical studies would be important. Also, MRI techniques may be used to study interstitial water movement: diffusion-weighted MRI provides a quantitative parameter, i. There are numerous limitations of the early experiments that form our classical understanding of CSF physiology. Recent progress in neuroanatomy, molecular and cellular biology, and neuroimaging challenge the traditional model.
The pillars of the classical model, i. CSF production at the choroid plexus, directed bulk flow and absorption across the arachnoid villi are currently being questioned. More recent experimental and clinical data have caused a growing number of researchers to reach the consensus that ISF and CSF are mainly formed and reabsorbed across the walls of CNS blood capillaries, which implies that there is no need for a directed CSF circulation from CP to the arachnoid villi.
Eventually, a number of "unequivocal" findings, often more than years old and still governing the customary understanding of CSF physiology, must be revised[ 7 , 9 , 10 , 88 , 95 , 98 , , , ]. However, the novel concepts are also challenged mainly by the lack of validated supporting data. For example, Klarica et al. Subsequent experiments demonstrated that the CSF pressure is not increased during the first hours after the occlusion of aqueduct of Sylvius[ ].
Since they furthermore showed that following its intraventricular injection radioactive water is almost completely absorbed in the ventricles and does not reach the basal cisterns[ ], they concluded that the choroid plexus is not the major site of CSF production and that no directed CSF circulation according to the classical understanding exists.
Instead they proposed a model that assumes CSF production and absorption occurs at the level of the capillaries[ 10 ]. Considering the existence of CSF flow along the aqueduct as shown by MRI flow studies, others recognized that a model assuming CSF flow exclusively at the capillary bed is deficient[ 7 ].
Furthermore the view of Klarica et al. In fact, the proposed model does not consider the complex regulation of water movement between the brain compartments as discussed above. Finally, as in the original experiments of Dandy, the experiments of Klarica et al. There are similar concerns with the most recent publications of Nedergaard and her group. In a series of experiments, fluorescent tracers of different molecular weight were injected into the cisterna magna of mice[ 95 ].
The experiments showed a rapid increase of fluorescence within the Virchow Robin space around the arterioles. Fluorescent tracer was subsequently found within the brain interstitium and later around the venules. Histological examination 30 minutes after cisternal fluorescent tracer injection revealed that larger molecular tracer FITC-d, kD was confined to the VRS, while smaller molecular weight tracer TR-d3, 3 kD was concentrated in the VRS and also entered the interstitium.
Investigating AQP4-deficient mice with the same experimental techniques, the authors found significantly less fluorescence within both, the VRS around the arteries and in the brain interstitium[ 95 ].
Considering the temporospatial occurrence of fluorescence, the authors deduced the existence of a directed flow of CSF from the subarachnoid space along the arteries and arterioles into the VRS, from here into the brain interstitium, and finally from the brain into the VRS around the venous vessels. Since the authors showed in AQP4 deficient mice that, following its interstitial injection, the clearance of soluble amyloid beta was significantly reduced, they concluded to have discovered an unknown system for the clearing of interstitial protein waste[ 88 , ].
Assuming the PVS to serve as lymphatics of the brain a notion which was conceptualized already in by Foldi[ ] and considering the involvement of astrocytes and their aquaporins the authors coined the term "glymphatics" to describe the system[ 95 ]. This notion is supported by previous findings of Rennels et al.
However, as already discussed above, especially the work of the groups of Cserr[ 94 ] and Weller[ 45 , 70 ] support the view that the periarterial flow provides a drainage OUT of the parenchyma. Such experiments have depicted the movement of tracers within the VRS to be sluggish and the direction of flow varying in an unpredictable manner[ 71 ].
Currently, it is difficult to come to final conclusions about the direction of perivascular CSF flow. This is a complex research topic with difficult, technically challenging experiments not easily replicated among the different groups. This appears to be a limitation of the scanning technique in terms of temporal resolution.
It seems important to provide data with higher frequency imaging to clarify the direction of perivascular flow[ 71 ]. Considering these criticisms and the point that the glymphatic concept represents a fundamental revision of the current understanding of CSF physiology, we feel that the concept needs to be substantiated by comprehensive ultrastructural investigations.
Also studies in other species are warranted. This conclusion was derived from in vivo two-photon laser scanning microscopy, fluorescent microscopy and measurements of the ISF volume comparing awake, asleep and anaesthesized animals. However, again, this is a very complex study design possibly prone to experimental errors: investigating animals with multiple brain catheters and fixated in a stereotactic or microscopic holder, one may assume that awake animals are under massive stress and may fell asleep just because of exhaustion.
Although microdialysis was used to measure norepinephrine levels as a gauge for stress levels and norepinephrine did not increase in the experiments, important stress parameters may differ between the experimental groups, i.
The fact that none of these parameters was recorded during the experiments is a major drawback, since each of the parameters may alter cerebral blood flow, cerebral blood volume, intracranial pressure and even the perivascular pump[ 79 ]. A CSF leak is when the CSF escapes through a tear or hole in the dura, the outermost layer of the meninges, which surround the brain. The dura can be injured or punctured during a head injury or a surgical procedure involving the sinuses, brain or spine.
It may also be damaged by a lumbar puncture , including a spinal tap, spinal anesthesia or myelogram. Spontaneous CSF leaks can occur due to increased intracranial pressure pressure in the head. This can happen to patients with hydrocephalus , a buildup of CSF in the skull. Spontaneous leaks may also occur without an identifiable cause. A CSF leak is a very serious condition, and patients who have tears in their dura with persistent CSF leaks need repair as soon as possible to reduce headache pain and the chance of meningitis.
Surgery for endoscopic nasal CSF leak closure, which is performed entirely through the nostrils, does not require cutting through the skin. The CSF leak is repaired using your own tissue from the nose or with a biomaterial graft. Length of stay in the hospital depends on the size of the leak — most patients are in the hospital for a few days after surgery. Some patients may require a lumbar drain that is removed before going home. Ear CSF leak closure requires cutting the skin behind the ear and removing portions of mastoid honeycomb-like, bony tissue to access the source of the CSF leak around the ear.
Using your own tissue or a biomaterial graft, the surgeon repairs the leak and seals the surgical opening. The anesthetic will sting or burn when first injected. There will be a hard pressure sensation when the needle is inserted. Often, there is some brief pain when the needle goes through the tissue surrounding the spinal cord.
This pain should stop in a few seconds. In most cases, the procedure takes about 30 minutes. The actual pressure measurements and CSF collection only take a few minutes. This test is done to measure pressures within the CSF and to collect a sample of the fluid for further testing. CSF analysis can be used to diagnose certain neurologic disorders.
These may include infections such as meningitis and brain or spinal cord damage. A spinal tap may also be done to establish the diagnosis of normal pressure hydrocephalus or bleeding into the spinal fluid from an aneurysm. Normal value ranges may vary slightly among different laboratories.
Talk to your provider about the meaning of your specific test results. The examples above show the common measurements for results for these tests. Some laboratories use different measurements or may test different specimens. If the CSF looks cloudy, it could mean there is an infection or a buildup of white blood cells or protein. If the CSF looks bloody or red, it may be a sign of bleeding or spinal cord obstruction. If it is brown, orange, or yellow, it may be a sign of increased CSF protein or previous bleeding more than 3 days ago.
There may be blood in the sample that came from the spinal tap itself. This makes it harder to interpret the test results. Brain herniation may occur if this test is done on a person with a mass in the brain such as a tumor or abscess. This can result in brain damage or death. This test is not done if an exam or test reveals signs of a brain mass. Damage to the nerves in the spinal cord may occur, particularly if the person moves during the test. Cisternal puncture or ventricular puncture carries additional risks of brain or spinal cord damage and bleeding within the brain.
Spinal tap; Ventricular puncture; Lumbar puncture; Cisternal puncture; Cerebrospinal fluid culture. Approach to the patient with neurologic disease. Goldman-Cecil Medicine. Philadelphia, PA: Elsevier; chap Euerle BD. Spinal puncture and cerebrospinal fluid examination.
Rosenberg GA. Brain edema and disorders of cerebrospinal fluid circulation.
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