REVIEW

Review of Cerebrospinal Fluid Physiology and

Dynamics: A Call for Medical Education Reform
Travis J. Atchley, MD * BACKGROUND: The flow of cerebrospinal fluid (CSF) has been described as a unidi-
‡ rectional system with the choroid plexus serving as the primary secretor of CSF and the
Barbara Vukic, MD
Miroslav Vukic, MD, PhD§
Beverly C. Walters, MD *
*Department of Neurosurgery, University
of Alabama at Birmingham, Birmingham,
Alabama, USA; ‡School of Medicine, Uni-
versity of Zagreb, Zagreb, Croatia; §Depart-
ment of Neurosurgery, Sisters of Mercy
University Hospital, Zagreb, Croatia
Correspondence:
Travis J. Atchley, MD,
Department of Neurosurgery,
University of Alabama at Birmingham,
1060 Faculty Office, Tower 1720,
2nd Ave South,
Birmingham, AL 35294, USA.
Email: tatchley@uabmc.edu
Received, April 6, 2021.
Accepted, December 5, 2021.
Published Online, May 10, 2022.
© Congress of Neurological Surgeons
2022. All rights reserved.
arachnoid granulations as primary reabsorption site. This theory of neurosurgical fore-
fathers has been universally adopted and taught as dogma. Many neuroscientists have
found difficulty reconciling this theory with common pathologies, and recent studies have
found that this “classic” hypothesis may not represent the full picture.
OBJECTIVE: To review modern CSF dynamic theories and to call for medical education reform.
METHODS: We reviewed the literature from January 1990 to December 2020. We
searched the PubMed database using key terms “cerebrospinal fluid circulation,” “ce-
rebrospinal fluid dynamics,” “cerebrospinal fluid physiology,” “glymphatic system,” and
“glymphatic pathway.” We selected articles with a primary aim to discuss either CSF
dynamics and/or the glymphatic system.
RESULTS: The Bulat–Klarica–Orešković hypothesis purports that CSF is secreted and
reabsorbed throughout the craniospinal axis. CSF demonstrates similar physiology to that
of water elsewhere in the body. CSF “circulates” throughout the subarachnoid space in a
pulsatile to-and-fro fashion. Osmolarity plays a critical role in CSF dynamics. Aquaporin-4
and the glymphatic system contribute to CSF volume and flow by establishing osmolarity
gradients and facilitating CSF movement. Multiple studies demonstrate that the choroid
plexus does not play any significant role in CSF circulation.
CONCLUSION: We have highlighted major studies to illustrate modern principles of CSF
dynamics. Despite these, the medical education system has been slow to reform curricula
and update learning resources.
KEY WORDS: Cerebrospinal fluid, CSF flow, CSF dynamics, Hydrocephalus, Medical education

Neurosurgery 91:1–7, 2022 https://doi.org/10.1227/neu.0000000000002000

I
t has been more than 100 years since the
initial hypothesis of cerebrospinal fluid (CSF)
circulation was introduced. At the time, it was
supported by key neurosurgical figures Lewis
Weed, Walter Dandy, and Harvey Cushing and
became known as the “classic” or Weed–Dandy–
Cushing hypothesis.1-4 Given the support of
neurosurgical namesakes, this theory was spread
among the medical community at large and re-
mains a staple of medical education. However,
more recent experiments call to question the
fundamental principles of this “classic” theory
and suggest a much more dynamic CSF system.5-7
ABBREVIATIONS: HPc, hydrostatic pressures of
capillary; HPi, hydrostatic pressures of interstitium;
OPc, osmotic pressures of capillary; OPi, osmotic
pressures of interstitium; RLV, right lateral
ventricle; SAS, subarachnoid space.
Despite the growing literature and evidence to
support the new hypotheses, US medical edu-
cation and licensing examinations continue to
instruct and test rising physicians and practi-
tioners on the outdated model. Bulat, Klaric, and
Orešković have been at the forefront of under-
standing CSF physiology in the modern era.7 In
addition, the discovery of the glymphatic system
has important implications in understanding CSF
dynamics. This publication has 2 primary aims:
1. To summarize the major hypotheses of CSF
dynamics and present the growing evi-
dence and arguments in support of modern
hypotheses and
2. to call on the governing bodies of medical ed-
ucation to recognize the shortcomings of current
neuroscience education and hopefully revise
curricula and testing materials nationwide.

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ATCHLEY ET AL

Only with a thorough understanding of this modern paradigm

of CSF dynamics can we expect current and future neuroscientists
and clinicians to develop new potential therapies for the treatment
of hydrocephalus.

METHODS
We reviewed the extant literature from January 1990 to December
2020. We searched the PubMed database using key terms “cerebrospinal
fluid circulation,” “cerebrospinal fluid dynamics,” “cerebrospinal fluid
physiology,” “glymphatic system,” and “glymphatic pathway.” We se-
lected articles published in English and with a primary aim to discuss
either CSF dynamics and/or the glymphatic system.

Classic (Weed–Dandy–Cushing) Hypothesis

The classic hypothesis of CSF physiology is based on 3 principles: (1)
active formation and secretion of CSF, (2) passive absorption of CSF, and
(3) unidirectional flow of CSF from its place of secretion to place of FIGURE 1. Illustration of Dandy’s canine experiment (1919) during which a
absorption.8-10 In this hypothesis, the choroid plexus was believed to be choroid plexectomy was performed in the right lateral ventricle and both fo-
the major source (up to 80%) of CSF production and generator of bulk ramina of Monro were obstructed. Subsequently, the left lateral ventricle
flow of CSF circulation. The remaining 20% to 30% was believed to collapsed while the right enlarged. Reprinted with permission of Klarica et al
originate from extrachoroidal sites. Arachnoid granulations, sac-like (2017) in Neuroscience. Reprinted from Neuroscience, Vol 354, Orešković,
protrusions of the subarachnoid space (SAS) into the dural venous si- Radoš, and Klarica. Role of choroid plexus in cerebrospinal fluid hydrodynamics.
nuses, were believed to be the major sites of CSF absorption. Hydrostatic 69-87, Copyright 2017, with permission from IBRO, published by Elsevier.
gradients (driven by active choroid plexus secretion of CSF) result in
circulation of CSF from regions of high to low pressure. This leads to the
classic pathway of CSF circulation found in nearly every medical and
Paramount in the classic model is the choroid plexus as the source of CSF
neuroscience textbook. CSF originates from the choroid plexus in the
production and as the primary “generator” of CSF flow. In past ex-
lateral ventricles, traverses the foramina of Monro into the third ventricle,
periments, CSF macromolecules (proteins, dextrans, etc.) were used as
down the aqueduct (of Sylvius) into the fourth ventricle, and finally into
markers of CSF bulk flow. However, CSF is 99% water, and more recent
the craniospinal SAS through the foramina of Luschka and Magendie.8,10
experiments have turned to investigating the movement of water to better
The basis for this classic model was based much on the work of Dr Walter
understand the fluid dynamics of this system.17 Bulat et al18 ex-
Dandy in his famous canine studies in the early 20th century. In a single
perimented with both slow and rapid 3H-water infusions directly into the
canine subject with bilateral obstructed foramina of Monro, unilateral
lateral ventricle, which demonstrated significantly elevated 3H-water
choroid plexectomy resulted in collapse of the ipsilateral lateral ventricle with
concentrations in the sinus confluence compared with cisternal CSF.
dilatation of the contralateral ventricle as illustrated in Figure 1.1,11 This was
This suggested that 3H-water is absorbed directly from the ventricles into
the major source of “proof” that the choroid plexus served as the source of
periventricular capillaries which drain into the sinus confluence, rather
CSF secretion. However, this study has fallen under criticism given its sample
than bulk flow through the CSF “outflow” tracts into the SAS and into
size of only one patient and lack of reproducibility in both animal and human
arachnoid granulations. The results of this experiment by Bulat et al18
subjects.12,13 More recently, Milhorat14 found no difference in ventricular
(2008) are shown in Figure 2. Laboratory experiments and computer-
size or CSF composition in hydrocephalic rhesus monkeys with and without
based models have repeatedly shown a rapid turnover of water between
choroid plexectomy (both unilateral and bilateral).
the CSF and plasma.5,19,20 These experiments and models demonstrated
The classic hypothesis relies on the choroid plexus acting as the
a lack of active CSF/water formation (ie, by the choroid plexus) and a lack
“pump” of CSF, generating a pressure gradient favoring flow from the
of passive absorption in other sites (arachnoid granulations). In 2013,
ventricles into the SAS. This theory was again supported by Dandy’s
Igarashi et al21 demonstrated that choroid plexus–specific water channels
canine studies from which human generalizations were made.1 This
(AQP-1) did not significantly contribute to the CSF water volume in
“transmantle” gradient has been discounted both in normal animals and
AQP-1 knockout mice. However, the more ubiquitous AQP-4 channels
those with hydrocephalus.15,16 Although the early findings of Dandy and
located in the pericapillary spaces were the main sites of water entry into
his contemporaries were instrumental to the field of neurological surgery,
the ventricular system, and this was confirmed in AQP-4 knockout
recent investigations with more refined methods and equipment have
mice.21 These findings strongly argue against the role of the choroid
furthered our understanding of CSF physiology and have demonstrated
plexus as a biological pump or the main source of CSF formation.
new concepts of CSF physiology.
Furthermore, if as these studies demonstrate, there are no sites of active or
passive CSF secretion/absorption, this removes the driving force for a
Modern Hypotheses unidirectional flow as proposed by the classic hypothesis. Yamada and
A modern CSF hypothesis proposed by Bulat, Klarica, and Orešković Kelly20 using specialized MRI techniques and advanced tracing software
questions the major tenets of the classic model presented above. demonstrated the pulsatility of CSF throughout the craniospinal axis,

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 REVIEW OF CSF DYNAMICS

FIGURE 2. Concentration of 3H-water in cisternal cerebrospinal fluid, confluence and arterial plasma during infusion of
3
H-water in saline into lateral ventricle at lower (A and B), and 5× higher concentrations (C and D). Reprinted with
permission of Bulat et al, 200818 in Brain Research Reviews, by CC BY 3.0 license (https://www.collantropol.hr/antrop;
https://creativecommons.org/licenses/by/3.0/). CSF, cerebrospinal fluid.

and, more importantly, they showed a lack of unidirectional flow as
previously hypothesized. Secretion and absorption of CSF throughout the
entire craniospinal SAS (Figure 3) have been recorded in multiple in-
dependent studies.7,18,20,22 Even as early as the 1970s, Naidich et al23
and Drayer et al24 demonstrated that large volumes of CSF uptake
occurred in the periventricular white matter.
Studies with radioactively labeled water in multiple animal models and
humans have repeatedly shown that radioactive water enters into all CSF and
CNS compartments swiftly and evenly.18,21,25 This holds true both before
and after plexectomy.19 In a pathophysiologic state, such as a hyperosmolar
right lateral ventricle (RLV), Klarica et al25 showed a larger and more rapid
influx of plasma 3H2O into the pathologic RLV (8 minutes to equilibrium)
than in the iso-osmolar CSF spaces (20 minutes to equilibrium). This canine
study again emphasizes that there is no single active site of CSF secretion;
rather, local regions of hyperosmolarity within the CNS can result in more
robust water arrival into the CNS.25,26 Ultimately, CSF volume is controlled
by the relationship between hydrostatic and oncotic forces within the blood
vessels and within the CSF spaces (Figures 3 and 4). CSF “pulsates” in a to-
and-fro pattern within the craniospinal axis. Osmolarity may be the major
driving force for water entry/exit into the SAS and ventricular system. Water
flows in or out of the SAS and ventricular system always to maintain iso-
osmolarity.5,25,27 In a study of 8 cats, a hyperosmolar solution was slowly
infused into the feline RLV over 7 days with maintained patency of CSF
pathways. Although there was enlargement of the left lateral ventricles
compared with normal controls, the RLV were asymmetrically larger in all
study cats likely owing to a local and persistent increase in osmolarity.25 In
this and other clinical scenarios of hyperosmolar CSF such as SAH, infection,
or tumors, water is “pulled” into the CSF spaces and leads to a dilatation of
the ventricular system. The chronicity of this shift may or may not result in
elevated intracranial pressure and clinical hydrocephalus.21 The action of
gravity and the distribution of large blood vessels at the cranial base and
within gyri also alter the hydrodynamics of CSF. These result in additional
directional forces in addition to the vessel-induced pulsations.7
In light of these describe experiments and findings, the Bulat–Klarica–
Orešković hypothesis proposes that osmotic and hydrostatic forces are
the main determinants of CSF movement. The cerebral capillaries are the
dominant “producers” of CSF rather than the choroid plexus. At the
astrocyte capillary interfaces throughout the SAS, there is permanent and
constant fluid and solute exchange and ultimately CSF turnover. Os-
molarity is likely the major driving force for water entry/exit into the CSF.
CSF does not “flow” through the CNS but rather “pulsates” in a to-and-
fro craniospinal direction.5,27
The Bulat–Klarica–Orešković hypothesis proposes a new paradigm of
CSF dynamics, and after its recent description, the glymphatic system

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ATCHLEY ET AL
FIGURE 3. A, Overview of bulk flow of CSF throughout SAS. B, Capillary-
SAS interface. C, Astrocyte capillary interface. D, Net CSF/water entry and exit
determined by hydrostatic pressures of capillary and interstitium and osmotic
pressures of capillary and interstitium. Reprinted with permission of Orešković
et al, 2017 in Pediatric Neurosurgery7 with permission from S. Karger AG,
Basel. CSF, cerebrospinal fluid; HPc, hydrostatic pressures of capillary; HPi,
hydrostatic pressures of interstitium; OPc, osmotic pressures of capillary; OPi,
osmotic pressures of interstitium; SAS, subarachnoid space.
provides an avenue for CSF egress. In brief, this is a fluid clearance system
facilitated by AQP-4 which clears solutes and waste from neuropil. CSF is
driven into the perivascular space of terminal arterioles and taken into the
brain parenchyma by astrocyte foot processes with dense expression of
AQP-4. The CSF then mixes with interstitial fluid and is directed toward
venous perivascular and perineuronal spaces. This directional flow is
thought in part to be mediated by local differences in osmolarity. Thus,
periarteriolar water is driven toward relatively hyperosmolar perivenular
regions facilitated by the glymphatic system. CSF can then exit along cranial
and spinal nerves, arachnoid granulations, and meningeal lymphatic
channels.28,29 Although the primary purpose of the glymphatic system is
solute and waste elimination from the CNS, its presence demonstrates a
diffuse system for CSF entry into and exit from the CNS which com-
plements the Bulat–Klarica–Orešković hypothesis.28,30 In addition, Bui-
shas et al31 developed a computational model that incorporates the osmotic
principles of CSF dynamics and the glymphatic system in an attempt to
predict the effects of CSF osmolarity on CSF egress and hydrocephalus.
This model, while needing validation, may reconcile the effects of blood,
CSF, and extracellular osmolarity on water flux in the CNS and may
provide a link between osmolarity disturbances and neuropathology.30
Arguments Against New Models
Despite the basic science supporting the Bulat–Klarica–Orešković
hypothesis and the clinical evidence arguing against the Weed–Dandy–
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Cushing hypothesis, there remains skepticism over adopting more
modern theories. Critics cite 2 major arguments against these hypotheses:
1. If CSF osmolarity is a major contributor in hydrocephalus, why are
CSF samples across populations (both healthy and hydrocephalic) iso-
osmolar?
2. If there is no predetermined craniospinal circulation route and the
choroid plexi are not the generators of CSF flow, how do lesions along
the ventricular pathway result in asymmetric/obstructive hydrocephalus?
Recent experimental evidence has repeatedly demonstrated that the
SAS is “freely passable” to water throughout the craniospinal axis. Similar
to other fluid compartments, a rapid change in CSF osmolality would be
met with an equally robust shift in water content either into or out of the
SAS to maintain iso-osmolarity.5,20,26 Igarashi et al21 found that even
after acute application of hyperosomolar solution into a lateral ventricle,
CSF became iso-osmolar rapidly, although there was an acute rise in
intracranial pressure associated with a large water shift into the SAS and
ventricular system. This “compensated hydrocephalus” supports the
notion that CSF osmolarity (and the physiologic need to maintain iso-
osmolar equilibrium), not the choroid plexus, and is a major contributor
in CSF dynamics.21
Obstructive hydrocephalus as a consequence of blockade or stenosis
along the ventricular pathway has been almost dogma in medical education
and the field of neuroscience. However, this asymmetric hydrocephalus can
still be explained in the Bulat–Klarica–Orešković hypothesis.7 In the
presence of a fully passable SAS, CSF to-and-fro pulsations coincide with
systole and diastole and tend toward a craniospinal direction for most body
positions. However, in an obstruction of CSF pathways, these pulsations
are likely not fully transmitted to the lumbar cistern, the region of greatest
compensation. If CSF cannot efficiently shift into the compensatory
lumbar sack, derangements of the normal systole–diastole pulsatlity ensue.
Without adequate compensation, this may result in failure of normal
cerebral perfusion locally because of increased pulsatility surpassing regional
blood flow. This initiates local ischemia and inflammation with resultant
ventricular dilatation because of increased CSF osmolarity. This inflam-
matory cascade occurs only “proximal” to the obstruction because the rest
of the CSF spaces remain in continuity with normal craniospinal com-
pensatory mechanisms.7 In cases without ventricular outflow obstruction,
such as aneurysmal subarachnoid hemorrhage, basilar cistern blood
products may alter CSF osmolarity leading to increased water volume
within the cranial axis and impairing compensatory CSF shifts into the
lumbar cistern, diffuse ventriculomegaly may ensure.7
Despite replicated studies supporting the Bulat–Klarica–Orešković
hypothesis, the medical education system and many neuroscientists at large
have been hesitant to adopt these new experimental data. Perhaps it is a
resistance to change or a desire to overly simplify a complex topic; re-
gardless, we must reconsider the Weed–Dandy–Cushing as the sole model
given the volume of recent evidence. Even if the modern theory is not tested
or formally taught in medical education for a few years, educators can do
their part by informing students of these modern theories or by providing a
disclaimer from the outset. It is one thing to present scientific data as fact
when contradictory data are absent; however, we must caution against
continued distribution of disputed theories and promote the adoption of
new models supported by ample evidence.
Clinical Implications of Adopting New Model
The major implications in understanding and adopting this new
model lie in therapeutic intervention. Ventricular shunting, the most
neurosurgery-online.com
 REVIEW OF CSF DYNAMICS

FIGURE 4. A, Illustration of SAS and endothelium interface. B, Pressure gradient of capillary bed within parenchyma. C, Organization of pericytes and basement membrane
comprising the blood–brain barrier. D, Hydrostatic and osmotic forces resulting in to-and-fro cerebrospinal fluid pulsation. Reprinted from Brain Research Reviews, Vol 64/
edition number 2, Orešković and Klarica, The formation of cerebrospinal fluid: nearly a 100 years of interpretations and misinterpretations. 241-262, Copyright 2010, with
permission from Elsevier. HPc, hydrostatic pressures of capillary; HPi, hydrostatic pressures of interstitium; OPc, osmotic pressures of capillary; OPi, osmotic pressures of
interstitium.

common intervention for hydrocephalus, addresses only the outcome
not the etiology of hydrocephalus. Far from perfect, shunting is as-
sociated with an array of morbidity from infection, malfunction, and
the need for multiple systems.7 A thorough and universal under-
standing of CSF dynamics in relationship to osmolarity and pulsatility
may allow novel interventions and therapies to come to the forefront.
In addition, recognizing this new paradigm will likely improve new
experimental investigations into the molecular and cellular basis for
hydrocephalus and may help bring neuroscientists one step closer to
both treating and hopefully preventing hydrocephalus. Igarashi et al32
have already found potential molecular targets, such as AQP-4, that
may provide the basis for future therapeutic interventions. The
discovery of the glymphatic system also has implications for CSF
physiology and pathogenesis and aligns within the Bulat–Klarica–
Orešković hypothesis. Tan et al29 and Bae et al33 both found that
aberrations in the glymphatic system have been associated with
idiopathic normal pressure hydrocephalus and other neurodegener-
ative conditions such as Alzheimer disease. Available imaging of the
glymphatic system may also aid in the diagnosis of idiopathic normal
pressure hydrocephalus when the clinical picture is equivocal.29 Al-
though much is still unknown about CSF dynamics, the future in-
vestigations and treatment of hydrocephalus depend on a modern
understanding and appreciation for the roles hydrodynamics and
osmolarity in CSF pathophysiology.
CONCLUSION/CALL FOR REFORM
Many neuroscientists, including Orešković and Klarica, have
demonstrated that the classic Weed–Dandy–Cushing model of
CSF physiology cannot account for the vast observations in the
experimental and clinical study of hydrocephalus. We have

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ATCHLEY ET AL
attempted to summarize the literature and address some of the
major controversies regarding CSF hydrodynamics:
1. Is the choroid plexus the major site of CSF formation? No.
Water freely enters and exits the CSF spaces through AQP-4
and is driven largely by hydrostatic and oncotic gradients.
2. Does CSF circulate in a unidirectional fashion? No. Water
enters the CSF spaces throughout the craniospinal axis.
Motion of CSF is driven by systole–diastole pulsations,
gravity, and body posture.
3. Why do obstructions along the traditional CSF pathways
result in asymmetric ventricular dilatation? Obstructions de-
crease the transmission of CSF pulsations into the SAS and
cisterns (ie, the regions of greatest compensation). Without
this even distribution of pulsatility, ischemia proximal to the
blockade may occur. This results in local inflammation and
rises in CSF osmolarity which then contributes to the in-
creased volume of water in the affected CSF spaces.
The experiments of Orešković and Klarica show that there is no
unidirectional CSF circulation and that CSF physiology is de-
pendent on hydrodynamics, osmolarity, and systole–diastole
pulsations.7,27 In addition, the glymphatic system helps support
the idea of diffuse water and solute flux within the CNS and aligns
itself well within the Bulat–Klarica–Orešković model.28,30 In a
review of CSF dynamics, Brinker et al34 support the principles of
bidirectional CSF flow within the SAS and underscore the im-
portant of water egress and osmolarity in CSF dynamics. Al-
though we do not discount the importance of the work performed
by neurosurgical icons, we recognize the importance to accept new
facts and theories when presented with prevailing, peer-reviewed
evidence. Weed, Dandy, and Cushing have transformed our
understanding of the nervous system and laid the foundation for
subsequent neurosurgical investigation. We will forever appreciate
the essential work of these forefathers, but it is time to adopt more
modern hypotheses and practices in light of new evidence.
In addition, we must call on our education system to present
these more up-to-date fundamental principles. It is imperative
that we teach future neuroscientists and clinicians theories
founded on both experimental and clinical evidence, rather than
purport the classic model given its relative simplicity. Revising
medical curricula is not easy and is of course not necessary with
every single scientific advancement. However, presenting out-
dated science as fact and failing to acknowledge the existence of
other theories/hypotheses remain detrimental to early physician-
scientists. It is our hope that this historical review of CSF
physiology and a brief overview of the Bulat–Klarica–Orešković
hypothesis will provide a foundation on which to revise medical
education. It is our plea that educators, board examiners, and
clinicians alike recognize the strong evidence in support of the
modern CSF dynamics hypothesis and advocate for its universal
inclusion in medical education. This may be achieved by updating
future editions of introductory neuroscience texts, revising
medical board review resources, advocating for the modernization
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© Congress of Neurological Surgeons 2022. Unauthorized reproduction of this article is prohibited.
of medical school lecture material, and promoting neurosurgical
experience as part of clinical neurology clerkships where possible.
Funding
This study did not receive any funding or financial support. funding
Disclosures
The authors have no personal, financial, or institutional interest in any of the
drugs, materials, or devices described in this article.
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