The aim of this article is to provide a different perspective to choroid plexus (CP)
physiology and pathophysiology from that presented in the recently published review
by Spector et al (1). This review with an extensive insight into the relevant literature
data had an intention to interpret CP functions focusing on adult humans. The CP is
claimed to be the key “organelle” for interpretation and understanding of the classic
cerebrospinal fluid (CSF) physiology hypothesis. Namely, it is believed that CSF is
actively formed mainly by the CP inside brain ventricles, after which it circulates
from the ventricles through the entire CSF system to be passively absorbed into the
venous sinuses and/or via paraneural sheaths of nerves into the lymph (2-5). Since
CSF secretion by the CP is an active process, it seems logical that CSF secretion
is the main generator of CSF circulation if (physiological) volume of CSF is to be
maintained within the CSF system. In other words, CSF secretion and absorption inside
the CSF space should be balanced, because the amount of secreted CSF must be the same
as the amount of passively absorbed CSF. Any other relationship would result in an
imbalance of CSF volume, and in time, a pathological process (4). The CP is, in fact,
presented as a biological pump by which CSF is produced in an active process, since
the CSF formation rate (secretion) should not be significantly altered by moderate
changes in the ventricular pressure (3,5).
In this article we would like to present a different perspective from the mainstream
view described by Spector et al (1). Throughout the years, as we have been presenting
our views, we have never stated that the CP does not produce CSF and that it is not
the place of dynamic exchange in CSF (as misinterpreted in the mentioned article),
but instead we have criticized the concept of the CP as a CSF pump and the main source
of CSF formation.
It is necessary to stress that the basic understanding of the CP relation to CSF formation
is still incomplete and speculative, and that the key experiments were very often
conducted in ex vivo and in vitro conditions, which could significantly differ from
those in living organisms (4). Furthermore, the experiments on CP usually traced the
substance after it had been released from the blood into the CSF, but did not simultaneously
trace its movement from CSF into the blood (both directions). Thus, it was difficult
to conclude what was the net income of the substance from the blood into CSF. Anyhow,
as shown in the above mentioned review (1), numerous experiments in various animal
species undoubtedly demonstrated that the CP was the place where many substances from
the blood enter the CSF.
Subsequently, our group proposed a new hypothesis of CSF physiology stating that CSF
production and absorption (CSF exchange) were constant and present everywhere in the
CSF system and partially in the CP, mainly as a consequence of water filtration between
the capillaries and interstitial fluid (4,6-8). Because of this different approach
to CSF physiology, a considerable part of the recently published review (1) is devoted
to the criticism of our experimental results and ideas. Since the main intention of
Spector et al (1) was to present physiology of CP relevant to the adult humans, in
this essay we intended to show the obtained results mostly on humans, which in addition
overlap to those in the experimental animals.
Entry of water into the CSF system
Although examination of substances passing through CP is important, one must not forget
that those substances account to (less than) 1% of total CSF volume, whereas the remaining
99% accounts to water (4). For this reason, in terms of CSF formation volume, the
main question is how water enters the CSF system.
However, experiments that studied means of water entry from the blood to CSF failed
to recognize the CP as the site of entry. Recently, water flux from blood into the
CSF of the third ventricle has been examined by an MRI technique (JJVCPE imaging).
A series of highly sophisticated experiments were performed in control and AQP-1 or
AQP-4 loss of function mice (9). It was clearly demonstrated that water influx into
CSF was regulated by AQP-4 (outside the CP), known to be responsible for water homeostasis
of the pericapillary space, and not by AQP-1 found in the CP, ie, there was no significant
contribution of CSF by CP because there was no difference between AQP-1 knockout mice
and control animals. Spector et al (1) made two objections to those experiments: first,
that the relevance of the results in mice remains unknown in humans, and second, since
such small amount of CSF is formed in a short time frame of experiments (66 min),
the CP participation in CSF formation is invisible in the total CSF volume. However,
both objections can be explained by early human studies of Bering (10). The effect
of bilateral choroid plexectomy on appearance of water in CSF system has been studied
in human patients. In spite of radical surgical removal of both ventricular CPs, no
alteration in the water exchange (D2O appearance) could be detected before and after
choroid plexectomy. The curves of D2O could almost be superimposed on each other (10).
The author concludes: “... if the CP were responsible for a major fraction of the
water exchange, the postoperative appearance of D2O should have been much slower than
preoperatively. This is proof positive that CP have at most only a small part in the
water exchange of the CSF of the cerebral ventricles.” (10). It is important to stress
that duration of these experiments was 180 minutes and that, according to the classic
hypothesis, one would expect at least 36 mL of newly formed CSF, ie, an amount of
CSF which should be observed in collected results. Hence, even in longer studies in
humans, the results were analogous to those obtained in animals, ie, no significant
contribution of the CP to water influx was observed.
Very similar results were also obtained in dogs, where overlapping 3H2O curves within
the lateral brain ventricles and cisterna magna suggested the same mechanism of water
entry from the bloodstream into these compartments in terms of dynamics and volume
(11). But if the CP is the place of CSF formation, these two curves should differ
substantially, with the highest ventricular values at the CP location. Furthermore,
very recently new research results have showed oxygen enhancement in ventricular and
subarachnoidal (sulcal) CSF (12). These results, obtained on 15 healthy volunteers
using spin eco MRI sequence, support the idea that cerebral vessels are involved in
CSF production, and reveal that the CSF signal rapidly increases after oxygen administration
in both sulcal and ventricular CSF, with significantly more predominant increase in
sulcal CSF. These findings also correspond with the results obtained in humans by
Bering (10), according to which the appearance of D2O was faster in the cisterna magna
than in brain ventricles. This fact, together with the faster appearance of oxygen
in the sulci, led to an obvious conclusion: appearance of substances (D2O and oxygen)
cannot be a consequence of CSF flow from the cerebral ventricles. According to all
this, it should be concluded that CPs in humans only partially contribute to the CSF/water
volume.
Furthermore, it is well known that CSF communicates freely with the brain extracellular
fluid (4). There is no universal CSF in terms of fluid composition, since it depends
on the site from which it was sampled (2,13). In other words, the biochemical composition
of CSF differs depending on the CSF compartment, meaning that exchange of other substances,
and not only water, between CSF and surrounding tissue takes place everywhere inside
the CSF system. In this case, it is obvious that CP cannot be an exclusive and dominant
site of CSF exchange.
Choroid plexus and hydrocephalus
No one has done so much for the promotion of the idea that the CP is the site of CSF
formation as professor Dandy (14), connecting it closely to etiopathogenesis of hydrocephalus.
Based on an experiment on a dog (14), he concluded that CP was the exclusive site
of CSF formation, that the formation was an active process, and that the blockage
between the CP and the site of CSF absorption led to hydrocephalus development in
front of the blockage. Such interpretation of hydrocephalus etiology persists to this
day, even though it can hardly be applied to numerous clinical observations (8). Consistently
to his experiments, Dandy introduced choroid plexectomy as a surgical principle of
hydrocephalus treatment. If CP really was the site of CSF formation, choroid plexectomy
should stop CSF accumulation and eventually cure hydrocephalus. For many years this
was the most popular form of treatment for infantile hydrocephalus in the United States.
However, it became clear that bilateral extirpation or cauterization of the choroid
plexuses invariably failed to benefit the patients. Because of universally poor results,
choroid plexectomy was abandoned by neurosurgeons, and has no place in the current
treatment of hydrocephalus. Disadvantages of Dandy’s crucial experiment (14) have
been thoroughly analyzed and presented (4), but the failure of choroid plexectomy
to cure hydrocephalus is evidence enough that the CPs are not the main source of active
CSF formation.
With the development of endoscopic methods in the mid 1990s, new attempts were made
to cure hydrocephalus with different surgical procedures on the CP (4,15,16). Although
the results were somewhat better than those obtained by the classic surgical approach,
the same problems still persisted. The ventricular size was not significantly reduced
by CP coagulation, and only 35% of the patients achieved long-term control without
cerebrospinal fluid shunts (15). Another study (17) showed that shunting was required
in 48% of the cases, which was done from 1 week to 13 months after the CP coagulation.
And even when the CP was removed, the development of hydrocephalus still occurred.
A recent report showed that it was necessary to perform dual shunting in a male infant
with idiopathic CSF overproduction in spite of bilateral ventricular endoscopic CP
coagulation, because CSF production was still 700-800 mL/d (16). All this shows that
the role of CP in the pathophysiology of hydrocephalus is still unclear and that our
knowledge about this process is insufficient. It also clearly confirms the mentioned
claims about the CSF formation related to the CP.
CSF circulation
For some reason, Spector et al (1) described our experimental results on the absence
of the CSF flow (circulation) as unexpected. They can hardly be regarded as unexpected
since even Bering wrote in 1974 (13): ”The common concept that CSF flows slowly but
steadily from the cerebral ventricles into the subarachnoid space up over the cerebral
hemispheres to the arachnoid villi is not the case, and it leads to misinterpretation
of experimental data and clinical interpretation.” Furthermore, our findings on the
absence of CSF circulation are anything but unexpected, since our group has continuously
been publishing articles on CSF “circulation” since 1991 (4). However, our article
that Spector et al mention (18) is less relevant to the subject of “circulation” than
our articles that they did not mention (4,6-8,19-21). Moreover, Spector et al noted
that CSF circulation was shown by an MRI technique, yet omitted to mention the cases
in which MRI scans showed the opposite (4). Thus, recently developed Time-Spatial
Inversion Pulse (Time-SLIP) method allows direct visualization of the CSF flow using
MRI. In this method, the CSF itself serves as an endogenous tracer when radiofrequency
pulses are applied (22). Results obtained in humans suggest that there is no unidirectional
CSF circulation, and that CSF does not flow from the brain ventricles to the arachnoid
villi. Instead, only pulsatile to-and-fro movement of CSF in circadian rhythm is observed.
Controversy regarding the CP
It is unquestionable that CSF is formed within the ventricular cavities of some lower
vertebrates without CPs (4,23,24). It is also well known that it is formed within
the neural tube of fetal pigs (25) and humans (23) even before the choroid plexuses
anlage appears (26). Therefore, during the entire lifetime in some species, or only
during embryonic/fetal development in others, CSF is normally produced although CPs
(as the main place of CSF secretion) do not exist. A very similar case has recently
been reported in a patient with hydranencephaly and macrocephaly (27). A thirty-year
old female presented with an extremely large intracranial space and hydrocephalus
mainly filled with CSF (CSF occupied approximately 95% of the cranial cavity) and
with only small areas of sustained parenchyma. Since the patient had no CPs inside
the supratentorial space and no obstruction between the dural sinuses and CSF, the
development of hydrocephalus and macrocephaly could not be explained by the classic
hypothesis. Equally difficult to explain were the constant everyday presence and turnover
of such a large amount of CSF, as well as maintenance of CSF homeostasis for over
30 years in the absence of CPs.
Furthermore, in spite of the presence of the CPs in isolated brain ventricles in some
sharks, there was no open communication between internal and external CSF and no tendency
for ventricular dilatation in physiological conditions under stable and constant presence
of CSF in subarachnoid space (4,23,24). A similar case has recently been published,
which reported on a female patient (28) who presented with a large pineal cyst obstructing
the aqueduct of Sylvius, with complete absence of CSF movement through the aqueduct
and without development of hydrocephalus over at least 5-year observation period.
Additionally, she had no history of clinical symptoms such as headache, nausea, vomiting,
ataxia, dementia, etc. In light of the presumption that CPs represent CSF pumps, the
absence of hydrocephalus is practically unexplained. Also in this patient it is difficult
to explain CSF homeostasis with a constant CSF turnover behind the obstruction site.
Namely, there is a considerably larger volume of CSF behind the obstruction than in
ventricles (10:1), which should be sustained only by one CP located in IV ventricle.
Spector et al have misinterpreted the article of Lorenzo and Sondgrass (29) by concluding
that perfusion experiments in cats provided unequivocal evidence that CSF was formed
in ventricles exclusively, but not inside the subarachnoid space. We have thoroughly
discussed and explained that perfusion experiments were not a reliable method for
calculation of CSF formation (30). Regardless of that, since both ventriculo-cisternal
(cistern magna; CM) and ventriculo-subarachnoid (cortex) perfusion occupy a significant
part of the subarachnoid space, based on the comparison of both perfusion results
it cannot be concluded that CSF is formed exclusively inside the ventricles. CSF inside
the CM does not originate solely from the ventricles, but also from basal cisterns
and the spinal space. For this reason, the surface of CSF system included in both
perfusion methods is not so different, and 14% higher rate of CSF formation (although
not statistically significant) observed during ventriculo-cortical perfusion (29)
also fails to speak in favor of ventricular CSF formation hypothesis.
Although the above-mentioned results and controversies do not fit into the classic
hypothesis, they can be explained by the new hypothesis of CSF physiology, which offers
a different perspective on CSF physiology and pathophysiology (4,8,11,31,32).
The fact that after plexectomy the patient continues living with normal CSF turnover
(4,15,33,34) indicates that the CP is not of vital significance for a living organism.
It is a highly vascularized structure immerged into the brain ventricles' CSF, with
an expressed active metabolic nature (1,4,35). Based on all of the mentioned above,
one could presume that (in terms of evolution) getting the blood vessels in close
contact with the CSF volume inside of brain ventricles could accomplish a significant
and fast matter exchange between the blood and CSF, and vice versa, with a purpose
of maintaining the biochemical balance of CSF as an important physiological medium
for the normal CNS functioning.
Conclusions
The controversy regarding the role of brain plexuses is not yet at the point to be
resolved. The cumulating evidence and application of new technologies, such as MRI,
have already made their contributions, and we should further strive to improve our
concepts and create the right therapies for patients. Our contribution to this discussion
is rather straightforward – the role of CP in the physiology and pathophysiology of
CSF shown in the textbooks, atlases, and review articles is highly overemphasized
and needs to be revised.