Reassessing cerebrospinal fluid (CSF) hydrodynamics: A literature … · 2019. 11. 17. ·...

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Journal of Bodywork & Movement Therapies (2013) xx, 1e11

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LITERATURE REVIEW

Reassessing cerebrospinal fluid (CSF) hydrodynamics:A literature review presenting a novel hypothesis forCSF physiology

Bruno Chikly, MD, DO a,*, Jorgen Quaghebeur, MSc, DO b

a 28607 N. 152nd Street, Scottsdale, AZ 85262, USAbDepartment of Research, Flanders International College of Osteopathy (FICO), Santvoortbeeklaan 23, B 2100 Antwerp,Belgium

Received 3 November 2012; received in revised form 27 December 2012; accepted 30 January 2013

KEYWORDSArachnoid;Cerebrospinal fluid;Cerebrospinal fluidhydrodynamics;Cerebrospinal fluidphysiology;Choroid plexus;Classical hypothesisof cerebrospinal fluidphysiology;Osteopathy;Osteopathy in thecranial field

Abbreviations: AV, arachnoid villi; AVus(ses); CSF, cerebrospinal fluid; IF, in* Corresponding author.E-mail address: [email protected] (B.

Please cite this article in press as: Cpresenting a novel hypothesis for Cj.jbmt.2013.02.002

1360-8592/$ - see front matter ª 201http://dx.doi.org/10.1016/j.jbmt.201

Summary The traditional model of cerebrospinal fluid (CSF) hydrodynamics is being increas-ingly challenged in view of recent scientific evidences. The established model presumes thatCSF is primarily produced in the choroid plexuses (CP), then flows from the ventricles to thesubarachnoid spaces, and is mainly reabsorbed into arachnoid villi (AV). This model is see-mingly based on faulty research and misinterpretations. This literature review presents numer-ous evidence for a new hypothesis of CSF physiology, namely, CSF is produced and reabsorbedthroughout the entire CSF-Interstitial fluid (IF) functional unit. IF and CSF are mainly formedand reabsorbed across the walls of CNS blood capillaries. CP, AV and lymphatics become minorsites for CSF hydrodynamics. The lymphatics may play a more significant role in CSF absorptionwhen CSF-IF pressure increases. The consequences of this complete reformulation of CSF hy-drodynamics may influence applications in research, publications, including osteopathic man-ual treatments.ª 2013 Elsevier Ltd. All rights reserved.

Introduction hydrodynamics. In the traditional hypothesis it is commonly

This article describes some of the new conceptsand hypotheses concerning cerebrospinal fluid (CSF)

G, arachnoid villi granulations; CMterstitial fluid; SAS, subarachnoid

Chikly).

hikly, B., Quaghebeur, J., ReasseSF physiology, Journal of Bodyw

3 Elsevier Ltd. All rights reserved3.02.002

accepted that the CSF is mainly secreted from the choroidplexuses (CP) of the brain ventricles, then flows inside theventricular cavities to reach the subarachnoid spaces, and

, cisterna magna; CNS, central nervous system; CP, choroid plex-space.

ssing cerebrospinal fluid (CSF) hydrodynamics: A literature reviework & Movement Therapies (2013), http://dx.doi.org/10.1016/

.

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http://dx.doi.org/10.1016/j.jbmt.2013.02.002

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2 B. Chikly, J. Quaghebeur

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then is mainly reabsorbed into venous sinuses acrossarachnoid villi. A large number of publications from ex-periments showed there is little convincing “in vivo” evi-dence to support the classical model. (Bulat and Klarica,2011; Bulat et al., 2008; Jurjevi�c et al., 2011; Klaricaet al., 2009, 2006, 2005; Marakovi�c et al., 2011,2010; Mi�seet al., 1996; Ore�skovi�c and Bulat, 1993; Ore�skovi�c andKlarica, 2010, 2011; Ore�skovi�c et al., 2000, 2001, 2002,2003, 2008; Ore�skovi�c et al., 2005; Ore�skovi�c et al., 1991;Striki�c et al., 1994; Vladi�c et al., 2009, 2000; Zmajevi�cet al., 2002) This traditional model is being increasinglychallenged, in view of recent scientific evidence.

Cerebrospinal fluid secretion: traditional andnon-traditional hypotheses

Choroid plexuses and ventricular ependyma

The classical modelResearch on cerebrospinal fluid started almost a centuryago. (Cushing, 1914; Dandy and Blackfan, 1914; Weed,1914a) The classical model describes a continuous produc-tion of CSF from the plasma of the CP vasculature. Thisview was established by the experiments of Dandy in 1919who performed unilateral choroid plexectomy in a dog andcompleted bilateral obstruction of the foramen of Monro.(Dandy, 1918, 1919, 1945) The blockage produced a dilationin the ventricle still containing a choroid plexus but not inthe one without. Therefore he concluded that the CSF is

Figure 1 The traditional model of cere

Please cite this article in press as: Chikly, B., Quaghebeur, J., Reassepresenting a novel hypothesis for CSF physiology, Journal of Bodywj.jbmt.2013.02.002

formed from the choroid plexuses. Further, the dilatationof the ventricle implied that CSF absorption does not occurinside the brain ventricle and the “circulation of CSF” isobstructed if the two foramina of Monro are blocked. Theseinterpretations formed the basis of the traditional hy-pothesis. It is important to note that this experiment wasperformed on a single dog and it was never reproduced.(Hassin, 1924; Hassin et al., 1937; Milhorat, 1969) Asa consequence of Dandy’s experiment, surgical choroidplexectomy for hydrocephalus was promoted. (Dandy,1918, 1919, 1945).

Choroid plexuses (CP) are villous structures covered bya single layer of epithelial cells. Scientists worldwide agreewith the traditional hypothesis that CSF is produced mainlyby the choroid plexuses. There are 2 steps in this process:

A. First, a passive filtration of plasma occurs acrossfenestrated choroidal capillary endothelium to thebasolateral surface of the CP epithelial cells. Thisphase is facilitated by hydrostatic pressure. (Pollayet al., 1983).

B. Then, an active secretion occurs across a single layerof CP epithelium that is released from the apical sideinto the ventricular cavity. (Brown et al., 2004;Davson et al., 1987) In this model, hydrostatic oroncotic pressures should not significantly influenceactive CSF formation. Some authors also describe theventricular ependyma itself as another source of CSFproduction. (Brown et al., 2004; Johanson et al.,2008; O’Connell, 1970; Pollay and Curl, 1967;Welch, 1967).

brospinal fluid (CSF) hydrodynamics.


Reassessing cerebrospinal fluid (CSF) hydrodynamics: A literature review 3

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Data conflicting with the classical model

Dandy’s choroid plexectomy for hydrocephalus has beenabandoned since results are unsatisfactory. Ore�skovi�c andKlarica reexamined the CSF formation rate, including theventriculocisternal perfusion established by Heisey et al.,a method still regarded as the most precise one. (Heiseyet al., 1962; Ore�skovi�c and Klarica, 2010) They showed thatthe classical ventriculocisternal perfusion method is neitherprecise nor dependable for measuring CSF formation rate.(Marakovi�c et al., 2011) Contradictory to conventionalknowledge Milhorat removed the choroid plexuses from bothlateral ventricles in a human subject and in monkeys andfound no significant changes in the volume of CSF secretionnor in CSF composition. (Hammock and Milhorat, 1973;Milhorat, 1969, 1975, 1976; Milhorat et al., 1976) Even aftera total choroid plexectomy the CSF is secreted at the rate ofapproximately 1 L per day. (Tamburrini et al., 2006).

Ore�skovi�c, Klarica, et al. reproduced many experimentsaddressing CSF physiology taking great care not to replicateprevious experimental errors. The results hold in questionour traditional models of CSF. They inserted a cannula withstopcock, (modified from Flexner and Winters) for the oc-clusion and drainage in cats aqueduct of Sylvius (Flexner,1933; Flexner and Winters, 1932; Klarica et al., 2009) andobserved a fluctuation of aqueduct of Sylvius CSF. (Klaricaet al., 2009; Ore�skovi�c et al., 2001, 2002, 2003, 2005) For120e190 min following aqueductal occlusion they moni-tored the ventricular size and CSF pressure in cats’ ven-tricles and cisterna magnae.

In this experiment an increased ventricular volume andpressure, and the presence of a clear transmantle pressureshould be observed, according to the classical model. Thetransmantle pressure is the difference between the pres-sure inside the brain ventricles (i.e. lateral ventricles oraqueduct of Sylvius) and the pressure in the subarachnoidspaces (i.e. cisterna magna). (Figs. 2e6).

Figure 2 The scheme of the experimental model of Ore�skovi�c anfollowing aqueductal occlusion. Adapted from Ore�skovi�c, D., Klaa hundred years of interpretations and misinterpretations. Brain R


However the CSF pressure in the lateral ventricles andcisterna magna of each cat did not differ during 120 min ofthis experiment. X-ray ventriculography before and 2 hafter aqueductal occlusion did not confirm ventriculardilatation. In other words they observed no increase inpressure or dilation of the ventricles with ventriculography,and no transmantle pressure ever developed. (Klaricaet al., 2009) These experiments suggested that the CP arenot the main location of CSF production.

Capillary endotheliumOther experimentation found that the CP are responsiblefor 60 to 85 percent of the total production of CSF.(Davson, 1984; Davson et al., 1987; McComb, 1983) Somestudies have shown that about 15 to 30 percent of CSF isproduced from an extrachoroidal origin. (Brown et al.,2004; Cserr, 1989; Davson et al., 1987; Pollay and Curl,1967) Hakim et al. and Di Chiro suggested that CSF canbe formed and reabsorbed everywhere within the CNS. (DiChiro, 1964, 1966; Hakim et al., 1976) The weight of the CPin the lateral, third and fourth ventricles is only two tothree grams. Crone and Raichle established that the sur-face of the brain capillaries is extremely large, 250 cm2/gof tissue, which is about 5000 times larger than the surfaceof the CP. (Crone, 1963; Raichle, 1983) Some experimentalmodels concluded that the CNS capillary endothelium maybe an important source of CSF production. (Brightman,1968; Rall, 1968; Welch, 1975a; Weller et al., 1992)Research demonstrated that the elevation of intracranialhydrostatic pressure considerably lowers the production ofCSF, and vice versa. (Calhoun et al., 1967; Flexner andWinters, 1932; Frier et al., 1972; Hochwald and Sahar,1971; Martins et al., 1977; Milhorat and Hammock, 1983;Ore�skovi�c and Bulat, 1993; Ore�skovi�c et al., 2000; Weissand Wertman, 1978) Other experiments showed that theelevation of CSF osmolarity considerably increases theproduction of CSF, and vice versa. (Marakovi�c et al., 2010)

d Klarica to recover CSF from the aqueduct of Sylvius in cats,rica M., 2010. The formation of cerebrospinal fluid: Nearlyes. Rev. 64 (2), 241e262. (Fig. 7 page 11).


Figure 3 Astrocytic endfeet: they cover approximately 99% of all cerebral capillaries.


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In brain edema, clinicians observe that the injection intothe bloodstream of an hyperosmolar solution (i.e. man-nitol) decreases bulk water flow from brain tissue. (Donatoet al., 1994; Klarica et al., 2005) These experiments are allcontrary to the classical hypothesis from which we expectCSF formation being dependant on active CSF secretion inthe CP and passive absorption in the arachnoid villi. Ac-cording to the experiments of Bulat, Klarica and Ore�skovi�c,the interstitial fluid (IF), the fluid in the cerebral

Figure 4 Cross section of a CNS capillary


parenchyma, and CSF, the fluid in the subarachnoid spaces,constitute a functional unit. The volumes of these fluidcompartments are mainly regulated by modifications inosmotic and hydrostatic pressure in the capillaries on oneside and the IF-CSF unit on the other. They further suggestthat the production and reabsorption of CSF mostly takesplace within the CNS capillaries. (Bulat and Klarica, 2011;Klarica et al., 2009; Marakovi�c et al., 2010; Ore�skovi�c andKlarica, 2010, 2011).

and its perivascular astrocytic endfeet.


Figure 5 The Glymphatic system (Gliovascular Clearance System) in the CNS: Draining from arteriole to venule. Adapted fromIliff, J.J., Wang M., Liao Y., Plogg B.A., Peng W., Gundersen G.A., Benveniste H., Vates G.E., Deane R., Goldman S.A., NagelhusE.A., Nedergaard M., 2012. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance ofinterstitial solutes, including Amyloid b. Sci. Transl. Med. 4 (147), 147ra111. (Fig. 5, page 7).


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The fact that the endothelium of CNS capillaries containNaþeHþ antiporters (for transport of substances acrosscellular membrane) and the high NaþeKþ-ATPase activityof this endothelium also suggest that brain microvesselsplay an essential part in CNS fluid volume regulation.(Kalaria et al., 1998).

Cerebrospinal fluid transport

The general classical agreement is that the CSF is secretedinto the brain ventricles and flows unidirectionally through

Figure 6 Arachnoid granulations: CSF


the ventricular axis (see Fig. 1). Transchoroidal secretion ofwater, ions and macromolecules drive CSF down the ven-triculoecisternal axis. (Johanson, 1999) Traditionally,secreted CSF flows down the ventricular cavities to the 4thventricle and then out through hindbrain foramina into thecisterna magna and other basal regions of the subarachnoidspace.

Ore�skovi�c, Klarica, et al. used a cannula that permits theflow of CSF unless a stopcock is turned off to occlude theflow. This way an acute occlusion of the aqueduct of Sylviusin cats was performed. (Klarica et al., 2009; Ore�skovi�cet al., 2001, 2002, 2003, 2005) They monitored CSF flow

reabsorption, the traditional model.



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in the cats’ aqueduct of Sylvius, but did not retrieve anyCSF via the cannula in the aqueduct of Sylvius in more than3 h! They observed CSF continually pulsating but no liquidwas drained during these experiments! These data added totheir suspicion of a faulty classical model and made themask whether CSF really circulated. (Ore�skovi�c et al., 2001)The same phenomenon (no outflow of CSF) was noticed incontrol cats at physiological CSF pressure without aque-ductal obstruction. (Ore�skovi�c et al., 2001) At the sametime, when they injected artificial/mock CSF at differentrates during a 20-min. period into the lateral ventricles,they found that at 13 ml/min infusion, an important trans-mantle pressure was recorded. Transmantle pressure is thepressure recorded between ventricle and SAS. However,after the infusion of artificial CSF was ended, CSF pressuresreturned toward physiological values and transmantlepressure returned to normal. This suggests that the ab-sorption of CSF took place in the isolated ventricles.(Klarica et al., 2009) Clinically, patients with communi-cating and non-communicating hydrocephalus do notexhibit transmantle pressure gradients either. (Stephensenet al., 2002a, b).

Bulat, Ore�skovi�c, Klarica, et al. did other experimentswhere they slowly infused cats’ lateral ventricles with 3H-water (Tritium). Since approximately 98.5 percent of CSFand IF bulk volume is water, the movement of water willdetermine most of CSF-IF physiologic activity. They realizedthat CSF does not flow along CSF spaces but is very rapidlyreabsorbed into neighboring brain capillaries. During slowinfusion (1.77 ml/min) of 3H-water into cats’ lateral ven-tricles under normal CSF pressure, CSF concentrations inthe cisterna magna and arterial plasma were identical.(Bulat, 1993; Bulat et al., 2008).

Fenstermacher et al. showed that 3H-water passesacross brain ependyma into caudate nucleus only a fewmm, being rapidly eliminated into CNS capillaries (half lifeof 1.5 min). (Fenstermacher and Kaye, 1988) Retro-spectively, in the experiment creating an acute occlusion ofa cat’s aqueduct of Sylvius, the fact that pressure is notmodified in isolated ventricles supports the hypothesis thatCSF is quickly reabsorbed transventricularly into periven-tricular capillaries. In contrast, distribution of substanceswith larger molecular weight into subarachnoid spaces hasa completely different outcome. When a marked macro-molecule such as 3H-inulin was injected into the CSF withinthe subarachnoid space, it was very slowly eliminated intothe bloodstream and distributed multidirectionally becauseof its long elimination time from subarachnoidal spaces.Renkin and Crone observed the distribution of 3H-inulinfrom the CM to the cisterna basalis and lumbar cistern, overa 24-h period. (Crone, 1963; Renkin and Crone, 1996).

These kinds of macromolecules have been used in thepast to study CSF physiology, which brought numerousmisconceptions about CSF circulation and reabsorption. Inthese earlier experiments, the injection of macromoleculesinto the ventricular spaces to define circulation of CSF gavethe wrong impression that CSF is transported from lateralventricles to 3rd and 4th ventricles and then into the cis-terna magna and all the subarachnoid spaces. (Smith et al.,1982; Striki�c et al., 1994; Vladi�c et al., 2000, 2009) Incontrast, injection of 3H-water in any part of the CSF sys-tem, can result in multidirectional water distribution


including a “retrograde” path into the lateral ventricles(Bulat and Klarica, 2011).

These results have been confirmed by Iliff et al., whodemonstrated that tracers injected in ventricular spaces orsubarachnoid CSF of mice entered the parenchyma of thebrain depending on their molecular size, (Iliff et al., 2012)and get transported in a space between the brain capillariesand astrocyte’s feet the ‘glymphatic system’ (gliovascularclearance system). The CSF circulation appears across allblood vessels in and outside the brain within the CNS.

Cerebrospinal fluid absorption: traditional andnon-traditional hypotheses

Choroid plexus absorption

The Choroid Plexi may absorb about 1/10th of their ownsecretion. (Brightman, 1968; Cserr, 1971; Dodge andFishman, 1970; Foley, 1921; Schwalbe, 1869; Welch, 1975b;Wright, 1972) For that reason, the function of these struc-tures has been compared to the proximal renal tubule.

Arachnoid villi: the venous side

In the 18th century Pacchioni described extrusions of thecranial arachnoid membrane that project into the venoussinuses of the dura mater called arachnoid villi. Arachnoidvilli are microscopic while arachnoid granulations can beseen with the naked eye. In 1914, Weed showed in a crucialexperiment that the arachnoid villi and granulations (AVG)are the major source of CSF absorption. (Weed, 1914a) Thishypothesis has become firmly established and most in-vestigators still believe reabsorption of CSF is a passiveprocess located mainly in the AVG. (Brodbelt and Stoodley,2007; Weed, 1935) The exact means by which CSF trans-ports through the AVG remains controversial, but numerousmechanisms have been suggested. The hypothesis of anopen tubular system communicating directly or indirectlywith the AVG has been refuted by Shabo and Maxwell,describing them as the results of histological preparationartefacts. (Shabo and Maxwell, 1968) Other describedmechanisms include transport via vacuoles, transcellularchannels, endothelial cell gaps, and arachnoid cellularphagocytosis or pinocytosis. Recent research seems to showthat the AVG, under physiologic conditions are not the locusof most CSF reabsorption, but accessory pathways at best,even though under conditions of elevated CSF pressure AVGmay participate modestly in CSF reabsorption. (Boultonet al., 1999) There are a few reasons against the ideathat the AVG is a major source of CSF absorption. First of allvenous sinuses do not exist in rats until 20 days after birth.The AVG do not appear to exist before birth in sheep as wellas in humans. They begin to develop around the time ofbirth and increase in number with age. (Gomez et al., 1983;Johnston et al., 2004; Koh et al., 2005; Osaka et al., 1980)Furthermore, it is imperative that a mechanism exists toclear CSF in gestation. Extracranial lymphatic vessels playan important role in CSF transport before birth and mayrepresent a better pathway for CSF clearance in theneonate.



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The lymphatic side: “perineural pathways”

To this day no lymphatics have been found in the brainparenchyma, but lymphatic vessels have been noted in thedura mater, the pia mater, the pituitary capsule, the orbit,the nasal mucosa, and the middle ear. (Mascagni, 1787)Some type of lymphatic-like drainage is necessary toevacuate the small amount of proteins of the central ner-vous system, which becomes particularly important in casesof edema, hemorrhage or infection. (Brinker et al., 1990;Xing et al., 1994) The traditional hypothesis was updated byreviewing a large collection of evidence presenting thelymphatics as the primary site of CSF reabsorption ina previous publication. (Chikly, 1998; Koh et al., 2005) Byinjecting Berlin Blue dye into a dog’s subarachnoid space in1869, Schwalbe made the first observation that the lym-phatic pathways were the major means to absorb CSF.(Schwalbe, 1869) Later, in 1872, Quincke theorized that theCSF can leave the subarachnoid space through small areassurrounding the nerve roots. (Quincke, 1872) In 1875, Keyand Retzius were the first to demonstrate the circulationthrough the arachnoid granulations into lymphatic vesselsin the nasal mucosa, the frontal sinus and along cranialnerves using dye-colored gelatin. (Key and Retzius, 1875)More recently this CSF lymphatic absorption hypothesis hasbeen reexamined. (Johnston, 2003, 2005; Johnston et al.,2004; Koh et al., 2006) Boulton et al. demonstrated forexample that 48 percent of the protein tracer injected inthe lateral ventricles of sheep is transported into extrac-ranial lymphatics. (Boulton et al., 1997, 1998) Brinker et al.also showed that at least 50 percent of CSF is reabsorbedthrough the lymphatics rather than arachnoid villi. (Brinkeret al., 1994) Increase in CSF intraventricular pressure willaugment the amount of CSF drained by the lymphaticsrather than the arachnoid villi. (Hasuo et al., 1983; Jacksonet al., 1979; Johnston and Elias, 1987; McComb et al., 1982;Sahar, 1972; Xing et al., 1994).

Drainage through nasal lymphaticsThe historical experiment of Schwalbe using Berlin bluedye, as well as the work of Weed, showed some quantity ofthe marker passing along the olfactory bulb, olfactorynerve pathways to the nasal mucosa, the nasal lymphaticsand then to the cervical lymphatics. (Kida et al., 1993;Schwalbe, 1869; Weed, 1914b) Numerous experiments withdifferent species confirmed the existence of the samepathway. (Bradbury and Cole, 1980; Bradbury and Westrop,1983, 1984; Casley-Smith, 1988; Cserr et al., 1992; Dandy,1929; Ehrlich et al., 1986; Jackson et al., 1979; Johnston,2003, 2005; Johnston et al., 2004; Leeds et al., 1989;Lowhagen et al., 1994; McComb, 1983; McComb andHyman, 1990; Nagra et al., 2006; Shen et al., 1985;Weed, 1914b; Yamazuni, 1989) At relatively low intra-cranial pressures, carbon particles and labeled proteinsfollow the olfactory tracts and pass through the cribriformplate (lamina cribrosa) to the nasal mucosa, the retro-pharyngeal lymph nodes and to the nodes at the base of theneck. This pathway has been confirmed in humans,(Caversaccio et al., 1996; Johnston et al., 2004; Lowhagenet al., 1994; Weller et al., 1992) and nonhuman primates.(Botel et al., 1994; Brinker et al., 1997; Cserr, 1984; Foldiand Casley-Smith, 1983) To demonstrate the importance


of lymphatic drainage of CSF, Papaiconomou, et al. sealedthe cribriform plate extracranially, which significantlyimpaired CSF transport. (Papaiconomou et al., 2002).

Drainage through other perineural pathwaysLymphatic drainage has been found in most cranial andspinal nerve pathways including optic nerve pathways(Berens Von Rautenfeld et al., 1994; Bradbury and Westrop,1984; De La Motte, 1978; McComb, 1983; McComb et al.,1982; Shen et al., 1985); auditory nerve pathways(Arnold, 1983); trigeminal nerves, facial nerves and othercranial nerves (Arnold et al., 1972); as well as lumbar spinalnerves (Brierly and Field, 1948; Hut, 1983).

Direct dural pathwayUnder high pathological pressure, the CSF can also escapefrom the arachnoid barrier and be reabsorbed by the lym-phatics of the duramater. (Butler, 1984) In addition,McCombet al. infused cats and rabbits with marked CSF under highpressure. He found the tracer in the olfactory bulbs, opticnerves, and deep cervical lymph nodes, but when it wasinfused at normal CSF pressure, the tracer was not shown inthese structures. This suggests that the lymphatic pathway isa secondary path that can become more important underhigh CSF pressure. (McComb et al., 1982, 1984).

Transependymal exchange

According to the classical model the secretion of CSF ismainly an active process in the choroid plexi. There isa filtration across the endothelial capillary wall a secretionthrough the choroidal epithelium. Since the second phaseof CSF formation is an active process, the CSF formationrate should not be CSF pressure-dependant, it should not besignificantly altered by moderate changes in intracranialpressure.

This is contradictory to various studies showing that CSFsecretion decreases as CSF pressure increases and vice-versa. (Calhoun et al., 1967; Frier et al., 1972; Martinset al., 1977; Ore�skovi�c et al., 1991, 2000; Weiss andWertman, 1978).

Ore�skovi�c et al. showed that at physiological pressure,CSF formation and absorption are in balance within theisolated brain ventricles. (Ore�skovi�c et al., 1991) This im-plies that the CSF is not only transported to the subarach-noid spaces to be reabsorbed mainly into the venoussinuses, but that it is also significantly absorbed inside theventricles themselves. (Brightman, 1968; Bulat and Klarica,2011; Bulat et al., 2008; Cserr, 1971; Dodge and Fishman,1970; Foley, 1921; Hassin, 1924; Hopkins et al., 1977;Naidich et al., 1976; Ore�skovi�c et al., 1991; Wright, 1972).

We previously noted that Bulat, Ore�skovi�c, Klarica, et al.observed that CSF does not flow along CSF spaces but israpidly reabsorbed transventricularly into periventricularbrain capillaries. Under normal CSF pressure, 3H-water isreabsorbed into periventricular capillaries and is notdelivered to subarachnoid spaces, suggesting that CSF bulkwater is absorbed into brain ventricles. (Bulat, 1993; Bulatand Klarica, 2005; Bulat et al., 2008) Iliif also saw the CSF inthe SAS getting reabsorbed by cerebral capillaries (para-vascular spaces). (Iliff et al., 2012).



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There is no net CSF formation under normal conditions.It seems that CSF is produced and is reabsorbed everywherein the CSF spaces. The volume of CSF depends on the hy-drostatic gradients and osmotic forces present between theblood (capillaries) on one side and the interstitial fluid ofbrain parenchyma and the CSF on the other.

Conclusion

From more recent research, there is relatively little con-vincing, in vivo evidence to support the traditional model ofthe production, circulation, and reabsorption of CSF. Thetraditional model is seemingly based on faulty research andmisinterpretations of that research, and this hypothesis isnow increasingly being challenged.

Evidence for the new model presented here is strong andis being more widely adopted by investigators around theworld.

The CSF is a filtrate and secretion, produced in activeand passive processes.

Interstitial fluid (IF) surrounding the subarachnoid spaceand CSF form a unit of function that is produced by hy-drostatic and oncotic exchange across the endothelial wallsof arterial capillaries in the CNS.

Essentially, the volume of CSF depends on the hydro-static pressure and osmotic force within the CNS betweenthe capillaries on one side and the IF and CSF unit on theother. The future will tell us the exact percentage of cho-roid plexi/cerebral capillary CSF secretion and lymphatic/venous/CP/capillary endothelium CSF reabsorption. Itseems these percentage are now shifting in favor of cere-bral capillary endothelium.

The consequences of this reformulation of CSF hydro-dynamics will affect research and publications in physiol-ogy, medicine and surgery, especially related to thetreatment of hydrocephalus and other neurological disor-der. This model may also be of interest in the practice ofosteopathy in the cranial field.

Disclosure statement

No competing financial interests exist.

Author’s contribution

Both authors contributed equally to this work.

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