REVIEW

CURRENT
OPINION Physiology of cerebrospinal fluid circulation
Jonathan Shapey a,b, A. Toma b, and S.R. Saeed b,c,d

Purpose of review
This article describes the physiology of cerebrospinal fluid (CSF). We review current evidence and new
concepts relating to CSF physiology with respect to CSF secretion, circulation and resorption and we
highlight key pathophysiological associations including the relationship between CSF and intracranial
pressure.
Recent findings
CSF secretion occurs primarily via the choroid plexus. Various transport mechanisms facilitate CSF
secretion but the role Aquaporins play in this process is a recent discovery and an area of ongoing
research. CSF circulation is a dynamic process but the importance of the perivascular ‘Glymphatic system’
and extraarachnoidal pathways of resorption are relatively new concepts.
Summary
CSF physiology is dependent on various interacting factors and is critical for normal brain development
and function.
Keywords
cerebrospinal fluid, cerebrospinal fluid circulation, cerebrospinal fluid resorption, cerebrospinal fluid secretion,
glymphatic system, intracranial pressure

INTRODUCTION CEREBROSPINAL FLUID SECRETION

Cerebrospinal fluid (CSF) plays an essential role in CSF secretion in adults varies between 400 and
brain protection and homeostasis. In addition to its 600 ml/day, the majority of which is produced by
protective hydromechanical function, it helps the choroid plexuses of the lateral ventricles and to a
maintain cerebral interstitial fluid (ISF) homeosta- lesser extent, the tela choroidea of the third and
sis and plays a role in the regulation of neuronal fourth ventricles. Extrachoroidal secretion of CSF
functioning [1]. Various studies have demonstrated plays a minimal role under physiological conditions
that normal CSF production, circulation and but is derived from extracellular fluid and cerebral
resorption are critical for normal brain develop- capillaries across the blood–brain barrier (Fig. 1).
ment and function [2,3]. Hydrocephalus is a spec-
trum of conditions caused by disturbances in
cerebrospinal fluid dynamics resulting from over- The choroid plexus
production, obstructed flow or limited resorption of Subarachnoid spaces appear after neural tube clo-
CSF [4,5]. The physiology of CSF production and sure by day 32 of gestation, by which time extrac-
circulation also underpins the management strate- horoidal CSF production has already begun to
gies employed in treating CSF leaks. This review
provides a synopsis of the current evidence relating
a
to CSF physiology. Wellcome/EPSRC Centre for Interventional and Surgical Sciences,
University College London, bDepartment of Neurosurgery, National Hos-
pital for Neurology and Neurosurgery, cThe Ear Institute, University
CEREBROSPINAL FLUID VOLUME College London and dThe Royal National Throat, Nose and Ear Hospital,
London, United Kingdom
The CSF volume is estimated to be about 150 ml in Correspondence to Jonathan Shapey, Wellcome/EPSRC Centre for
adults with approximately 25 ml contained in the Interventional and Surgical Sciences (WEISS), Charles Bell House,
cerebral ventricles, 50 ml in cranial subarachnoid 1st Floor, 43-45 Foley Street, London W1W 7TS, United Kingdom.
space and 75 ml in the spinal subarachnoid spaces E-mail: [Link]@[Link]
[6]. The ratio of CSF volume to brain volume Curr Opin Otolaryngol Head Neck Surg 2019, 27:326–333
increases in ageing and neurodegeneration [7,8]. DOI:10.1097/MOO.0000000000000576

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 Physiology of cerebrospinal fluid circulation Shapey et al.

to their usual location within the basolateral mem-

KEY POINTS brane.
 The bulk of CSF ion secretion occurs via the
transcellular route facilitated various transcellular
transport mechanisms including ATP-dependent Choroidal cerebrospinal fluid secretion
ion pumps. The first step of choroidal secretion involves the
passive filtration of plasma from choroidal capillar-
 Transepithelial CSF water movement follows the osmotic
gradient and is facilitated by aquaporins (AQP1) of the ies to the choroidal interstitial compartment along
apical basolateral and luminal membranes. a pressure gradient. Following this, the bulk of
ion transport from blood to the CSF occurs via
 CSF circulation is a dynamic process involving the the transcellular route facilitated by membrane
classical ventricular pathway and the perivascular
ion transporter proteins and cytoplasmic carbonic
‘Glymphatic system’.
anhydrase. Carbonic anhydrases catalyse the
 CSF resorption occurs at a variety of anatomical sites conversion of H2O and CO2 to Hþ and HCO3.
including the arachnoidal villi and via the Transcellular transport of Naþ and Cl (along with
extraarachnoid pathways. HCO3) are the most important ions transported by
 The rate of CSF production and resorption is finely the choroid plexus epithelium, generating the
balanced and directly related to ICP. osmotic gradient that drives H2O secretion [11].
ATP-dependent ion pumps of the apical membrane
expel Naþ, Cl, HCO3 and Kþ ions towards the
ventricular lumen and create the electrochemical
increase the volume of the embryo’s cephalic gradient that is exploited by a variety of other trans-
extremity [6]. The first hindbrain choroid plexus porters involved in CSF secretion. Transepithelial
does not appear within the fourth ventricle until water movement also occurs via the transcellular
day 41 of gestation and is then followed by the route, following the osmotic gradient generated by
synchronous development of the telencephalic ATP-dependent mechanisms and is facilitated by
choroid plexuses in the lateral ventricles and aquaporins (AQP1) of the apical basolateral and
finally the diencephalic choroid plexus of the third luminal membranes [11,12]. Aquaporins are
ventricle [3,9]. expressed in various secretory epithelia such as pan-
The choroid plexus consists of granular menin- creatic duct cells (AQP1 and AQP5) and salivary
geal protrusions into the ventricular lumen and an gland cells (AQP3 and AQP5) and the abundance
epithelial surface continuous with the ependyma. of AQP1 in choroid plexus epithelia contributes to
The choroid plexus has a relatively simple structure the luminal membrane’s high water permeability.
whereby cuboidal epithelial cells surround a stromal However, luminal membrane expression of AQP1
core of capillaries and connective tissue [9]. Choroi- and the high cellular water permeability do not, in
dal cells present microvilli at their apical pole and themselves, represent an absolute measure of the
are joined together by tight junctions to form the secretory capacity of the choroid plexus epithelium
blood–brain barrier that prevents paracellular free supporting the notion that various compensatory
passage of molecules from the systemic circulation mechanisms such as transcellular or paracellular
into the CSF. Beneath the epithelial basement mem- water pathways and other osmotic driving forces
brane of the choroid plexus, is a highly vascularized coexist [11].
network of fenestrated capillaries that are connected The composition of CSF differs from that of
by thin membranes permeable to small molecules plasma (Table 1). CSF is 99% water, compared with
that enable the rapid delivery of water to the epi- the 92% water of plasma [1]. Naþ, Cl and Mg2þ
thelial cells for CSF production [10]. concentrations are higher and Kþ and Ca2þ are lower
The epithelial cells of the choroid plexus acquire than those in plasma. In particular, there is a precise
their secretory, transport and barrier functions regulation of Kþ concentration within the CSF to
shortly after differentiation [10]. All epithelial cells ensure that any Kþ lost from the ventricular system
have a polarized asymmetrical distribution of mem- is replaced and further modulation of Kþ transcel-
brane proteins but a striking feature of the choroid lular transport is required to maintain a CSF Kþ
plexus is the apparent inverse polarization of its concentration of approximately 2.8 mM [11]. The
epithelial cells [11]. Unlike the typical configuration choroid plexuses also secrete vitamins B1, B12, C,
of epithelial cells, the ATP/K/ATPase and similar folate and b2-microglobulin, arginine vasopressin,
‘basolateral transporters’ are all expressed in the nitric oxide and growth factors that act on the
luminal membrane of the choroid plexus as opposed subventricular zone [6].

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Otology and neuro-otology

FIGURE 1. CSF circulation (previously published). CSF produced in the choroid plexus flows from the ventricular system to the
subarachnoid space of the brain and spinal cord. CSF contained in the subarachnoid space keeps the CNS buoyant and serves
as a fluid source for glymphatic influx. Egress sites of cranial CSF (orange arrows) fall into three functionally distinct categories,
namely, the perineural sheaths surrounding cranial and spinal nerves, dural lymphatic vessels and arachnoid granulations. The
contribution and importance of each egress pathway are still a matter of debate. A main perineural egress site in both rodents
and humans is along the olfactory nerve through the cribriform plate (1) towards lymphatic vessels of the nasal mucosa. From
here, the CSF is drained to the cervical lymph nodes. Other significant perineural efflux pathways in rodents are the trigeminal,
glossopharyngeal, vagal and spinal accessory nerves (2). Dural lymphatic vessels also carry CSF towards the cervical lymphatic
system (3). In rodents, these vessels exit the skull along the pterygopalatine artery, the veins that drain the sigmoid sinus and the
retroglenoid vein, and the foramina of the cranial nerves. In humans, meningeal lymphatic vessels have been visualized with MRI
and were located around the dural sinuses, middle meningeal artery and cribriform plate. Arachnoid granulations are protrusions
of the arachnoid membrane where CSF flows into the sagittal sinus, and constitute the only known egress site that drains directly
to the bloodstream. Traditionally, this site was thought to be the main cerebrospinal fluid egress site in humans, but evidence
suggests that, under physiological intracranial pressure, virtually no CSF leaves to the bloodstream. The main egress site of CSF in
the spinal cord is along the spinal nerves (4). CSF, Cerebrospinal fluid. Source: [18 ].
&

CSF production is finely regulated by the auto- blood pressure [11]. CSF production may be
nomic nervous system and neuropeptides such as decreased by the administration of loop diuretics
dopamine and atrial natriuretic peptide. The sym- and carbonic anhydrase inhibitors. Finally, any
pathetic nervous system reduces CSF secretion, increase in intraventricular pressure decreases the
whereas the cholinergic system increases secretion. pressure gradient across the blood–brain barrier,
Circadian variation in CSF secretion has also been reducing plasma filtration and CSF production.
observed [13]. Many of the key hormones that regu- However, it is important to note that this feedback
late systemic water and electrolyte homeostasis such loop is slow and is rapidly exceeded at the initiation
as aldosterone, angiotensin II and arginine vasopres- phase of hydrocephalus.
sin are present in the choroid plexus and ventricular
system. These hormones are believed to have a
dual role: they are locally involved in CSF produc- CEREBROSPINAL FLUID CIRCULATION
tion and the regulation of brain extracellular fluid CSF circulation is a dynamic phenomenon and cir-
but are also implicated in the central regulation of culates from sites of secretion to sites of resorption

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 Physiology of cerebrospinal fluid circulation Shapey et al.

Table 1. Composition of normal plasma and CSF of CSF through the aqueduct and the rest of the
(original) ventricular system. During diastole the brain’s vol-
ume decreases and CSF flows in reverse through the
Constituent (mM) Plasma CSF aqueduct and foramen magnum. Movement of CSF
Sodium (Na ) þ
138 138 into the brain via the Virchow–Brain spaces is also
Potassium (K ) þ
4.5 2.8
powered by arterial pulsations [21]. This suggests a
link between the reduced arterial pulsations often
Calcium (Ca2þ) 2.4 1.1
seen in some elderly patients and accumulation of
Chloride (Cl) 102 119 &
amyloid b in Alzheimer’s disease [18 ,19]. There is
Bicarbonate (HCO3) 24 22
also increasing evidence that the cribriform plate
Glucose 5.0 3.3 may be another key site for extracranial outflow
Total protein (g/l) 70 0.35 although in-vivo studies in humans are still needed
to confirm these findings [1,22,23].
CSF, Cerebrospinal fluid.

(Fig. 1). According to the classical teaching, intro- Imaging the cerebrospinal fluid circulation
duced by Cushing as the ‘third circulation’ in 1926 MRI is well suited to evaluate the CSF system because
[14,15], CSF flows out of the ventricular system, via of its ability to image directly in the mid-sagittal
the foramina of Lushka and Magendie in a unidirec- plane and because of the various pulse sequences
&
tional, rostrocaudal manner into the subarachanoid available [24 ]. CSF outflow results in a distinctive
space. CSF then continues to flow either down CSF flow void within the cerebral aqueduct on MR
&
around the spinal cord or up over the cerebral imaging (Fig. 3A) [24 ,25]. Hydrocephalus and
convexities, eventually being resorbed by the arach- its associated radiological features are also easily
noid granulations and arachnoidal villi either side of identifiable using MRI (Fig. 3C and D). However,
the superior sagittal sinus. This model was based on the administration of intrathecal contrast material
tracer studies using large molecules but now appears followed by thin-cut computed tomography (CT)
to be an oversimplification of CSF circulation. of the skull base (CT cisternogram) or entire spine
Recent studies have highlighted a secondary (CT myelogram) has been shown to be the definitive
route of CSF circulation along the perivascular study of choice to accurately define the location of a
Virchow–Robin spaces, resembling the lymphatic CSF leak [26,27]. A detailed discussion of how to
system in other parts of the body [16,17]. The brain’s investigate CSF leaks and encephaloceles may be
glial membrane (the glia limitans) is composed of found in the subsequent article by Lipshitz et al. [28].
continuous astrocytic endfeet and forms the outer
wall of the Virchow–Robin spaces. It has a high
concentration of aquaporin channels (AQP4) and CEREBROSPINAL FLUID RESORPTION
facilitates CSF transport from the Virchow–Robin CSF clearance into lymph and blood involves a
spaces into the interstitial space of the brain that is variety of anatomical sites and physiological mech-
then cleared along paravenous drainage pathways anisms. Previously, the predominant site of CSF
&
[18 ]. In-vivo imaging using small fluorescent trac- resorption was thought to be through the venous
ers in mice have also demonstrated how this micro- system via the arachnoid granulations and arach-
circulation is responsible for removing amyloid b noidal villi. Arachnoidal villi are finger-like evagi-
and other waste products from the central nervous nations of the subarachnoid space which project
system [16]. Given its lymphatic-like function, into the cerebral venous sinuses and act as one-
and involvement of astroglia, this CSF circulation way valves permitting CSF to pass into the sinuses
system has been term the ‘glymphatic system’ but preventing blood entering the subarachnoid
&
[16,18 ,19]. spaces [29]. The majority of arachnoidal resorption
CSF flow is pulsatile and is dependent upon occurs via the arachnoidal villi located either of the
pulsatile arterial perfusion that initiates three vector superior sagittal sinus although some resorption
forces: a centripetal ISF shockwave (ventricular CSF occurs via the arachnoidal villi of spinal nerve roots.
pulse wave), followed by centrifugal brain expan- However, over recent years, there has been a
sion and a subsequent subarachnoid CSF frontocci- gradual acceptance that a significant portion (if not
pital pulse wave (Fig. 2) [20]. During systole, blood the bulk) of CSF resorption actually occurs via extra-
&
flows into the brain causing it to expand inward, arachnoid pathways [1,16,24 ]. These pathways
compressing the ventricles, and outward, compress- include CSF passage through the brain parenchyma,
ing the cortical veins and subarachnoid space. The via lymphatics near the cribriform plate or through
brain’s inward expansion leads to pulsatile outflow the perineural sheath of the cranial nerves (Fig. 1)

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Otology and neuro-otology

FIGURE 2. Timeline-based pulsatile vector model of CSF/ISF dynamics under normal conditions (previously published). CSF,
Cerebrospinal fluid; ISF, interstitial fluid. Source: [20].

&
[6,22,24 ,30]. The cribriform plate has been identi- CSF resorption surfaces have been identified on the
fied as a key extracranial site in CSF outflow in meningeal sheaths of cranial nerve roots, particularly
nonhuman species with subsequent resorption via the optic, trigeminal, facial and vestibulocochlear
the nasal mucosa and cervical lymphatics [1,22,23]. nerves [6]. These accessory pathways are thought

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 Physiology of cerebrospinal fluid circulation Shapey et al.

FIGURE 3. MRI of CSF circulation and hydrocephalus (original). (a) T2-weighted image demonstrating flow through the
cerebral aquaduct in a patient with hydrocephalus (red arrow). (b) Balanced steady-state gradient echo image using a CISS
(Constructive Interference Steady State) sequence demonstrating a spontaneous third ventriculostomgy (red arrow). (c) and
(d) T2-weighted image of a patient with a pineal meningioma and hydrocephalus before (c) and after (d) an endoscopic
third ventriculostomy [ETV]. (e) and (f) T2-weighted image of a patient with a colloid cyst and associated hydrocephalus before
(e) and after (f) an ETV.

to be especially active in neonates because arachnoi- per minute. Brain catabolites build up when fluid
dal villi are not fully functional until 18 months of turnover rates fall by more than 50% and a reduc-
age. Similarly, in the elderly, the accessory pathways tion in the CSF clearance of amyloid b is now
are thought to return to prominence because of the thought to be related to the development of
fibrous changes observed in arachnoid granulations Alzheimer’s disease [8].
with advancing age [6].

INTRACRANIAL PRESSURE AND

CEREBROSPINAL FLUID HOMEOSTASIS CEREBROSPINAL FLUID
AND TURNOVER In normal adults in the left lateral position, CSF
CSF and interstitial brain fluid dynamically pressure is approximately 10–15 cmH2O and is
exchange water and solutes and this equilibrium stable when CSF formation and resorption are bal-
maintains an optimal microenvironment for anced. CSF pressure is dynamic and varies with
neurons. The rate of CSF turnover rate is approxi- posture as well as other factors including carotid
mately 4 times per 24 h. It is directly proportional pulsation, respiration, abdominal pressure, jugular
to CSF formation rate and inversely related to CSF venous pressure, state of arousal and physical activ-
volume [1]. In ageing, there is less efficient active ity. The Monro–Kellie doctrine states that because
transport with slower CSF turnover causing an the adult skull is a rigid structure, intracranial pres-
accumulation of potentially harmful metabolites sure (ICP) within the cranial cavity is dependent on
within the brain’s interstitium. Clearance of brain the constituents of the cavity. CSF constitutes 9% of
metabolites depends on a CSF renewal of 0.3–0.4% the intracranial contents by volume and is therefore

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Otology and neuro-otology

an important component of ICP. CSF pressure is Financial support and sponsorship

regulated at all levels of CSF hydrodynamics. Raised J.S. is supported by Wellcome Trust (203145Z/16/Z,
ICP exerts negative feedback on choroidal secretion WT106882) and EPSRC (NS/A000050/1) funding.
by reducing the pressure gradient across the blood–
brain barrier and by decreasing cerebral perfusion Conflicts of interest
pressure. In acute hydrocephalus, circulating levels There are no conflicts of interest.
of atrial natriuretic peptide and arginine vasopressin
are increased in the CSF and act to decrease
choroidal secretion of CSF. However, as mentioned REFERENCES AND RECOMMENDED
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