N E U R O L O G Y, P S Y C H I A T R Y A N D B R A I N R E S E A R C H 1 7 ( 2 0 1 1 ) 5 1 –6 6

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/npbr

The peripheral cerebrospinal fluid outflow pathway –

physiology and pathophysiology of CSF recirculation: A review
and hypothesis

K. Bechter *

Clinic for Psychiatry and Psychotherapy II, Ulm University, Germany

A R T I C L E I N F O A B S T R A C T

Article history: An anatomical connection from subarachnoid spaces along nerves into peripheral tissues
Received 13 May 2011 represents an important route for CNS antigens release, termed here peripheral cerebrospi-
Accepted 27 June 2011 nal fluid outflow pathway (PCOP), is assumed analogous to mammals in humans: CSF
Available online 9 August 2011 leaves the subarachnoid spaces along nerves and joins respective interstitial tissue fluids,
then the lymph then blood; in detail, flowing from the subfrontal subarachnoid spaces
Keywords: through the cribriform plate near olfactory nerves to nasal submucosa to the cervical
Cerebrospinal fluid lymph system, along cranial nerves and spinal nerves into respective peripheral tissues.
Neuroinflammation Microanatomic details and relative shares of outflow volumes at various parts of the PCOP
Depression as compared to CSF reabsorption volumes into the venous system remain to be deter-
Schizophrenia mined.
Pain Beyond, CSF functions as a third signaling system involving all CNS structures preferably
surfaces, including spinal cord and nerve roots. But CSF may interact also with all cranial
and peripheral nerves via the PCOP, and related peripheral tissues connected by nerves, e.g.
subcutaneous tissues, muscles or neuronal ganglia, and even, a special case, the eye. PCOP
associated pathomechanisms might arise with any abnormal pathogenic CSF contents
including solutes and cells in various diseases, relevant especially in acute neuroinflamma-
tion, possibly in systemic inflammation, likely in chronic neuroinflammation and possibly
in low level neuroinflammation. The latter may include subgroups of psychiatric disorders.
PCOP associated pathomechanisms might explain for example the surprising muscle
involvement in depression and schizophrenia, or diffuse pain or dysautonomia. PCOP asso-
ciated pathomechanisms should generally relate to PCOP anatomy and the CSF outflow
physiology respectively pathophysiology.
Ó 2011 Elsevier GmbH. All rights reserved.

1. Introduction
In mammals, CNS antigens are transported by CSF from sub-
arachnoid spaces through the cribriform plate into nasal sub-
mucosa reaching then the cervical lymph system, and along
all other cranial nerves and all spinal nerves into the periph-
ery, where CSF gathers with interstitial tissue fluid into the
respective lymphatic system where specific immune re-
sponses are generated.1–4 This extralymphatic pathway was
demonstrated also in primates.5 An analogous peripheral

* Address: Ulm University, Clinic for Psychiatry and Psychotherapy II, Ludwig-Heilmeyer-Str. 2, D-89312 Günzburg, Germany. Tel.: +49
8221 96 2540/96 00; fax: +49 8221 96 2736.
E-mail address: Karl.Bechter@bkh-guenzburg.de.
Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; PCOP, peripheral cerebrospinal outflow pathway
0941-9500/$ - see front matter Ó 2011 Elsevier GmbH. All rights reserved.
doi:10.1016/j.npbr.2011.06.003
52 N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
CSF outflow pathway (=PCOP), as termed here, can be as-
sumed to exist in humans because of an analogy of the ana-
tomical structures. A pathogenetic interaction of CSF with
nerves during outflow along the PCOP was only recently
hypothesized,6 derived from careful clinical observations dur-
ing cerebrospinal fluid filtration in patients with therapy-
resistent depression.7,8 CSF filtration was an effective new
treatment in autoimmune inflammatory neurological disor-
der Guillain–Barré-syndrome,9 nerves dysfunction being
associated with pathologic CSF contents.10–13 A body of evi-
dence now shows the involvement of inflammatory patho-
mechanisms in a subgroup of severe psychiatric disorders,14
subsumed under the mild encephalitis hypothesis.15 Recent
studies strongly support such view: CSF investigation with
modern methods established in clinical neurology showed
evidence of low level neuroinflammation in more than 40%
of cases of severe depression or schizophrenia,16 further sup-
ported by abnormal CSF cell patterns which resembled pat-
terns found in inflammatory neurological disorders.17
Considering symptom patterns in CNS inflammatory disor-
ders including comorbidities and overlapping symptoms in
a more general framework one may think of pathomecha-
nisms simply related to abnormal CSF contents as the com-
mon denominator. In such scenario the CSF recirculation
pathways might play an elusive role to understand symptom
emergence related to the anatomical and physiological char-
acteristics of the PCOP. Such idea of CSF associated commu-
nalities in disease pathogenesis is followed in this paper.
2. An overview on CSF recirculation –
concepts, uncertainties, gaps of knowledge
Various fields deal with aspects of CSF production, flow, circu-
lation, outflow and reuptake or reabsorption. Detailed ana-
tomical and physiological aspects have been reviewed
recently.18–20 Nevertheless, a number of uncertainties, gaps
of knowledge, and even controversial views remained. Those
are considered here, followed by an outline of hypothetic
PCOP specific pathomechanisms. The latter appeared plausi-
ble to occur when considering a relatively extended exchange
area and exposure time in between CSF and nerves at the
PCOP, and when assuming that CSF contents during PCOP
passage somehow may contact nerves, and/or when assum-
ing that also CSF cells followed the PCOP (activated immune
cells may produce toxic or disturbing molecules during PCOP
passage, able to mediate powerful local effects there). How-
ever, the exact microanatomy of PCOP-CSF-passage is not
definitely known. CSF outflow between perineurium and epi-
neurium was shown but it remained unclear whether CSF
flows through specialized small channules,21 or not. When
nerves were shielded from CSF during outflow (by channules),
possible sites of CSF-nerve-interaction might be peripheral
areas near channules ends or near nerves ends. When CSF
cells physiologically followed the PCOP, an aspect not clear
but plausible in my eyes, even if partially shielded such acti-
vated trafficking immune cells might induce varying local
pathogenic effects on nerves. Recently the CSF cell trafficking
during the CSF outflow path trough the cribriform plate (here
termed Part A PCOP, see below) was questioned,18 or assumed
1 7 (2 0 11 ) 5 1–66
to occur.22 In general, CSF contents should preferably interact
with the surface of the CNS adjacent to the ventricles and
subarachnoid spaces, also including spinal cord and nerve
roots. The PCOP from anatomy can be considered as an exten-
sion of the subarachnoid spaces along nerves ending at
respective peripheral tissues connected by the nerves. These
preformed anatomical structures represent the PCOP, the
CSF recirculation pathways along the PCOP being character-
ized by a very complex anatomy, the respective flow and out-
flow physiology being only partially defined yet.18,19 This
chapter focuses on neglected and unknown aspects of CSF
recirculation relevant for the PCOP hypothesis raised (see
Figs. 1 and 2). For better understanding a definition of the var-
ious types of CSF flow and fluid exchange between CSF spaces
and tissues and compartments is given (Table 1). CSF net flow
within the subarachnoid spaces is strictly to be differentiated
from rapid flow, the former of minute quantity and only par-
tially measurable yet, the latter of large quantity representing
a rapid and powerful oscillatory or pulsatile CSF movement
associated with each cardiac cycle.23–27 More details about
why respective terms (see Table) were chosen maybe found
in the text.
(1) CSF is mainly secreted from the choroid plexus epithe-
lia on a leaky basal membrane (localized within the
four cerebral ventricles), together with the tanycytes
of the circumventricular organs described as the
blood-CSF-barrier.28 CSF protein contents reflect blood
protein concentrations, but lowered depending from
molecular sizes.29 The choroid plexus secret various
signaling molecules into the CSF,30 represent sites of
cell trafficking from blood into CSF, sense systemic
inflammation and regulate CNS inflammation.31,32 CSF
spaces and especially CSF immune cells appear to play
a unique but previously underestimated role in CNS
immunoregulation in health and disease.33
(2) Gross rapid CSF movements occur with each cardiac
cycle during systole and diastole. But these movements
represent pulsatile fluctuations forth and back in
between ventricles and around the subarachnoid
spaces. Especially the flow through the anatomical
communication of the three foramina of the fourth
ventricle is easily visualized in vivo as a jet like outflow
and inflow.24 The flow velocity differs between systole
and diastole. Flow volumes out of the ventricles is
nearly identical to the volume flowing back, only differ-
ing for the minute volume produced in between this
short time period. In a recent single case study the
net volume produced was fitting well with previous
clinical estimates.27 Net CSF flow along the neuraxis
ventral and dorsal to the spinal cord can also be visual-
ized and quantified in vivo.27,34 The focus of pulsatile
oscillations arises at the craniocervical border24,27
(and Supplementary Material). The mechanistic power
of these rapid CSF movements around the brain and
possible direct clinical consequences is illustrated by
an inborn anomaly, that is arachnoid cysts: those cysts
may acquire a valve-like mechanism, then at some
time point or another may grow rapidly and displace
 N E U R O L O G Y, P S Y C H I A T R Y A N D B R A I N R E S E A R C H 1 7 ( 2 0 1 1 ) 5 1 –6 6 53

Anatomical Site Flow CSF Composition

plexus chorioidei CSF production primary plasma filtrate

(inside cerebral ventricles) + selected blood cells
(mainly lymphocytes)
trafficking through large
venules of choroid plexus
(and meninges)

adjuncts from blood,

brain, spinal cord,
through aqueduct and foramina and meninges:
interstitial fluids with cells

into subarachnoid spaces diffusion from blood

around brain and myelon vessels dependent on
CSF flow velocity: with
slowing CSF flow the diffusion

of proteins and
CSF reabsorption into blood
ions from veins into CSF
at veins and sinuses mainly
through arachnoid granulations increases
around brain and near nerve
roots, to some extent distributed
all over the meninges

CSF outflow into periphery

near olfactory nerves and along
all other brain nerves (incl. optical
nerve into eye) and all spinal
nerves into related tissues
lymph back to blood
connected by respective nerves

Fig. 1 – Schematic representation of CSF production, flow and variance of composition adapted according to previous
publications (see text).

brain parenchyma and may cause severe or even life-
threatening neurological symptoms, or may remain
clinically silent although continuous intracyst turbu-
lences were demonstrated.35 In some persons, over
time local brain dysfunction and psychiatric disorders
may evolve.36
(3) CSF reabsorption takes place into meningeal veins and
sinuses mainly at specialized structures around the
scull and near nerve roots, the arachnoid granula-
tions,18–20 characterized now in vivo as unidirectional
outflow34 here termed reabsorption. Relative shares of
CSF reabsorption vs. CSF outflow (according to the ter-
minology used here) were discussed repeatedly, but
the jury is yet out. I with some others think, that in con-
trast to previous views, CSF reabsorption at arachnoid
granulations may serve mainly as a security mecha-
nism in case of increased intracranial pressure,
whereas normally such reabsorption may be lim-
ited.37,38 Overall, the outflow along the PCOP may
approach similar quantities like reabsorption.34
(4) CSF outflow through the cribriform plate into the nasal
submucosa, and along cranial nerves and spinal nerves
into the periphery represents an important part of CSF
recirculation.18–21 However, the relative outflow vol-
umes along cranial and peripheral nerves as compared
to reabsorption remained poorly defined (see above).
Present estimates may be biased by preferred experi-
mental approaches (compare38), and the lack of studies
performed in animals during physiological motor activ-
ity (studies were done in paretic anesthesized or fixed
animals) and the CSF outflow at lower body parts was
never quantified. From general considerations one
may expect, that especially at lower body parts and
along large nerves, the physiological CSF outflow vol-
umes may be major. Beyond, outflow volumes may
depend from other factors, e.g. motor activity and
posture.
(5) The PCOP anatomically included all CSF outflow path-
ways, that is through the cribriform plate near olfactory
nerves (Part A) and along cranial nerves III–XII (Part B)
54 N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H 1 7 (2 0 11 ) 5 1–66

Rapid streams &

fluctuations
Outflow
6
Reabsorption
Net Flow

3
5

Fig. 2 – The cartoon demonstrates a complete view of the CSF recirculation pathways including the peripheral CSF outflow
pathway (PCOP) and the related structures connected by nerves, as examples the subcutaneous tissues with free nerves ends,
the neuromuscular junctions, and nerve–nerve connections e.g. to the sympathetic trunk. The microanatomy of the PCOP
and of that to related tissues is however not defined. Various types of CSF movements and exchange of CSF contents between
compartments are depicted. The rapid streams are in general pulsatile with each cardiac cycle, going forth and back with
systole–diastole, main volumes flowing in between the ventricles and the subarachnoid spaces nearby but well involving the
whole subarachnoid spaces. Slow net flow within the subarachnoid spaces was shown, flowing in distal direction
(=downwards) around the spinal cord, and from the craniocervical border upwards around the brain, here possibly
preferentially, though not yet well measured, to the subfrontal area where CSF leaves to the nasal submucosa. Regarding the
PCOP outflow it remains open whether CSF is reabsorbed, in part probably at sites near nerve roots into arachnoid
granulations, or whether the major part may flow out along the nerves into the periphery, an assumption here preferred. The
PCOP part A appears best investigated, because the pathway through the cribriform plate into nasal submucosa and from
there to cervical lymph nodes was preferred in experimental approaches. CSF outflow along the optical nerve into the eye and
its respective particular lymphatic system has also well been studied. The PCOP outflow along the cranial and the spinal
nerves has been less thoroughly investigated but may clinically be especially important, a speculation here. The relative
volumes of CSF outflow at the various sites of the PCOP remain unclear. (1) Ventricles with choroid plexus, (2) cribriform plate,
(3) skin, (4) muscle, (5) sympathetic trunk, and (6) arachnoid granulations.

and along spinal nerves (Part C). The optical nerve (II) is tissues). So the PCOP represented anatomical pre-
considered separately. PCOP-related structures are here formed spaces stretching from the exit of nerves out
considered all tissues connected by the respective of the subarachnoid spaces (where the dura respec-
nerves (including all efferent and afferent innervated tively leptomeninx ends to continue as perineurium)
 N E U R O L O G Y, P S Y C H I A T R Y A N D B R A I N R E S E A R C H 1 7 ( 2 0 1 1 ) 5 1 –6 6 55

Table 1 – Types of CSF flow mechanisms and definition of terms used.

Rapid CSF flow (streams, oscillations, fluctuations): rapid complex pulsatile CSF movements arising with each cardiac cycle
associated intracranial blood volume redistribution. The ventricular CSF ejection volume (see Supplementary Video Material)
represents one important driving force for this CSF redistribution within the subarachnoid spaces. Flow direction reverses in
between systolic versus diastolic phase. These redistribution forces to a considerable part drive CSF reabsorption and
outflow. The graph (Fig. 2) simplifies rapid CSF flow from technical reasons, a most exact description to be found in Gupta
et al. 200927 and other papers (see text and references)
Secretion or absorption: production of CSF by choroid plexus plus diffusion of blood contents plus flow of a part of brain
interstitial fluid, all together directed into the subarachnoid spaces
Reabsorption or reuptake: outflow of CSF out of the subarachnoid spaces through biological membranes. Specialized
structures for rapid reabsorption are the arachnoid granulations. Reuptake takes also place at certain brain sites5
Note: exchange at the anatomical barriers rep. biological membranes to some extent is bidirectional (compare20)
Outflow: slow outflow of CSF out of the subarachnoid spaces along anatomically defined but not yet fully characterized
structures near olfactory nerves into nasal submucosa and along all other brain nerves and peripheral nerves into respective
peripheral tissues. The exact anatomy of the windup is to be shown
Net flow: slow overall directed movement of CSF inside the subarachnoid spaces representing an anatomical-physiological
manifestation of the balance between CSF secretion versus reabsorption plus outflow.29 Net flow along the spinal cord is
directed downwards under normal conditions, around the brain to the arachnoid granulations and (possibly preferentially) to
subfrontal subarachnoid spaces (inferred from the overall scenario of outflow at part A (see text))
Net outflow: the sum of CSF leaving the subarachnoid spaces via reabsorption, reuptake and outflow balancing the volumes
of overall CSF secretion
Migration of CSF cells: CSF cells migrate at many sites, but especially at choroid plexus into the CSF spaces,31,32 but where
CSF cells regularly leave remains only partially known
Blood-CSF-Barrier disturbance: A clinical term to interpret Qalbumin increases (=CSF albumin increases), shown to depend
mainly from CSF net flow velocity, however not representing a direct measure of the Blood–CSF-barrier function at the
choroid plexus instead resulting from varied and often combined pathologies16

as far as to the wind up of nerve fibers in neurally sup-

ported tissues. The microanatomical sites of CSF out-
flow may be small channules, shown in several
studies for the pathway trough the cribriform plate,
possibly also for the parts B and C. Generally, CSF out-
flow seems to take place between perineurium and epi-
neurium (compare20,21,38).
In sum, the PCOP can be considered widely distributed
throughout the body, implying considerable differences
regarding lengths and local anatomical aspects. Ana-
tomical differences suggest physiological differences
to be present, including differing outflow volumes at
different PCOP sites. Therefore, the PCOP is described
in tripartite here: (part A) CSF outflow along or aside
olfactory nerves21 from the subfrontal subarachnoid
spaces passing trough the cribriform plate into nasal
submucosa, apparently a major site of physiological
CSF outflow seemingly ending up directly in cervical
lymphatics. CSF outflow takes also place along the opti-
cal nerve, between perineurum and epineurum into the
eye there joining its particular lymphatics.39 (Part B)
CSF outflow along cranial nerves III-XII passing the
scull base together with the nerves, which seems to
end up in connected structures or tissues e. g. the inner
ear, or near free nerves ends. Outflow volumes may dif-
fer in between single cranial nerves due to anatomical
and size differences. (Part C) CSF outflow along spinal
nerves passing through intervertebral foramina reach-
ing respective nerves ends or connected tissues. Out-
flow volumes may vary dependent from nerve sizes
and from circumstantial factors especially at part C,
e.g. gravity forces like posture, and from dynamic forces
related to motor activity. These latter aspects are how-
ever speculative and need to be investigated.
(6) Certain CSF contents apparently distribute also into
perivascular spaces (Virchow-Robin spaces), appearing
there within few minutes and at preferential sites
within brain parenchyma.40 But these perivascular
spaces seem separated from the subarachnoid spaces
by the pia mater,41,42 an apparent border for most CSF
contents, details to be studied.
(7) Some bidirectional exchange in between blood–CSF and
CNS parenchyma–CSF (here termed secretion or
absorption vs. reabsorption; see Table) can apparently
take place.20
(8) Interstitial brain fluid drains along perivascular spaces,
which are separated from CSF outflow pathways, both
ending up at cervical lymph nodes.18 Another share of
brain interstitial fluid drains directly into CSF.
(9) The sites where PCOP outflow ends appear only vaguely
described yet. Free nerves ends or the ends of the hyp-
othetic small channules along nerves may represent
such endpoints, where CSF distributes into interstitial
fluids.1 Beyond, several anatomically dead ends seem
to exist, that is nerve-nerve-connections, e.g. at neuro-
nal ganglia or at the sympathetic trunk and at neuro-
muscular junctions. A further dead end apparently
represents the central canal of the spinal cord, at least
in adult humans. This canal is not relevant for CSF
recirculation, as falsely described in some recent publi-
cations (see below). One may assume, that at these ana-
tomical dead ends of the subarachnoid spaces CSF
reabsorption may take place, or another explanation
may be found.
(10) It remains to be demonstrated, whether and where CSF
cells regularly leave the subarachnoid spaces. The sizes
of all parts of the PCOP presumably would allow cell
56 N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
trafficking with CSF outflow,18,19 and now it is assumed
that at least through the cribriform plate CSF cells leave
the subarachnoid spaces.22,43 Facing the paucity of cells
present within the CSF and the few studies carefully
addressing this issue, the view presented here that all
CSF contents may physiologically follow the PCOP
along all its parts, maybe justified, and was in part sup-
ported by recent case observations.44
(11) The driving forces behind both, CSF reabsorption and
CSF outflow, might be various. A major force probably
should represent the pulsatile waves and CSF oscilla-
tions occurring within the subarachnoid spaces with
each cardiac cycle (compare34). Other important driving
forces for net flow may represent gravity forces and
motor activity. Positioning at least impacts subarach-
noid fluid pressure.45 The CSF production rate and its
modulating factors, for example drinking volume, are
apparently also important for net flow, the production
rate overall balancing both outflow and reabsorption
apparently.19,20,42
(12) Beyond the well described gross rapid pulsatile CSF
movements within the subarachnoid spaces, one may
infer from plausibility considerations and from inter-
pretations of laboratory findings that a slow net flow
of CSF within the subarachnoid spaces takes place, into
two respectively three directions (see Table): a) slow
CSF stream downwards along the neuraxis around the
spinal cord, which was concluded to exist based on
the measures of blood derived protein concentrations
varying with CSF flow velocity under physiological
and pathological conditions.29,46 This slow net flow
was from quantitative imaging data referred to as neg-
ligible at the level of the spinal cord,27 but was overall
nicely matching the interpretation of collected clinical
data where this net flow was an important confounder
of CSF data interpretation.29 But this volume appears
nevertheless relevant for outflow. b) From plausibility
inference, one can assume another similar slow net
flow within the subarachnoid spaces from ventricles
to areas around the scull directed in a distributed man-
ner to the arachnoid granulations, which was recently
even measured by imaging.34 c) Another slow flow has
to be assumed directed to the subfrontal area, where
CSF outflow through the cribriform plate takes place.
(13) Physiological functions of the CSF outflow at the PCOP
may, beyond the well described CNS antigen release
(see introduction), include other functions attributed
to the CSF such as is homeostasis and detoxification.33,34
(14) The concept of the volume transmission mode of
CSF47,48 is here adopted and specified for the PCOP site
analogously. CSF associated pathomechanisms prevail-
ing in various diseases maybe able to involve the whole
subarachnoid spaces in parallel, depending from its
physiological and anatomical conditions, and may as
proposed here in very detail (see below), similarly
involve the PCOP site. The latter assumption appears
however only justified when a considerable outflow vol-
ume prevailed at the PCOP, being able to mediate rele-
vant pathologies by abnormal CSF contents. An old
clinical experience described by Felgenhauer was that
1 7 (2 0 11 ) 5 1–66
the lumbar CSF was poorly sensitive for the brain cor-
tex.49 This clinical knowledge would match with the
view proposed here, that two different main directions
of slow CSF net flow within the subarachnoid spaces
prevail, the one downwards the neuraxis, the other
one directed to the upper brain areas, to arachnoid
granulations around the scull and to the subfrontal
area (see above): because CSF net flow of the upper sub-
arachnoid spaces does not relevant drain to the lumbar
site, despite the mixing power of the rapid CSF oscilla-
tions, the lumbar CSF may be not ‘diagnostic’ for the
brain cortex.
(15) CSF production rates were calculated.20 An estimate of
PCOP-CSF outflow volumes under physiological condi-
tions in humans is speculative though feasible: a rou-
tine neurosurgical treatment of CSF fistulas is now to
establish CSF outflow via lumbar catheter: 5–15 ml
CSF per hour are recollected in such patients into an
extracorporal lumbar drainage system and removed,
by this procedure achieving low CSF pressure at the cra-
nial level, to facilitate spontaneous healing of fistula or
detoxification in subarachnoid bleeding.50,51 Extrapolat-
ing from these experiences, and in line with recent
measurements,52 and when assuming that reabsorp-
tion volumes near nerve roots into arachnoid granula-
tions may be low, the total physiological PCOP-CSF
outflow volume (parts A + B + C) may reach up to
20 ml per hour in adults. This outflow estimate may
be too high (though plausible when assuming low phys-
iological reabsorption volumes), but yet half that out-
flow volume per hour may have enough power to
induce relevant pathologies at the PCOP via the volume
transmission mode, a concept extended here to the
PCOP.
3. On the physiology of CSF flow,
reabsorption, outflow
Open aspects of CSF recirculation are now discussed in more
detail.
3.1. Views about CSF recirculation
According to traded clinician’s view CSF flows from the spinal
subarachnoid spaces down- and upwards around the spinal
cord, preferring the ventral versus dorsal site, for up or
down.53 Though, this appears generally true for the rapid
CSF streams and fluctuations arising during each cardiac cy-
cle this movement represents merely CSF oscillations.24,27 It
is important to notice, that these rapid CSF movements repre-
sent not an unidirectional or continuous flow, instead an
oscillatory mechanism of rapid CSF redistribution between
ventricles and throughout the subarachnoid spaces around
the brain and around the spinal cord with a flow maximum
near the craniocervical border. The anatomical situation
around the spinal cord resembles a stick (spinal cord) located
in a tube (subarachnoid spaces). A continuous stream could
occur only when the tube was U-shaped or two tubes con-
nected with each other, but both views are anatomically not
 N E U R O L O G Y, P S Y C H I A T R Y A N D B R A I N R E S E A R C H
the case. Instead complex rapid CSF oscillation24,25,27 mean-
dering around the spinal cord,25 take place. But also CSF net
flow was established, down the spinal cord based on clinical
and in part experimental observations29,54,55 and by imag-
ing.27 But even in recent publications, CSF flow was depicted
generally flowing through the central canal of the spinal cord,
then back through the spinal subarachnoid spaces to sub-
arachnoid spaces around the brain.32 Such flow characteris-
tics would match with general rules of flow. However, there
is no distal anatomical aperture of the spinal cord’s central
canal to the subarachnoid spaces in normal adults (though
an aperture is present during development and in some
mammals19), nor would the canal match the size needed for
respective flow volumes – another assumption, that CSF flow
downwards around the spinal cord may end up somewhere at
the meninges, then CSF being there reabsorbed into venous
blood, e.g. near the nerve roots, is possible and usually
stressed, also by Linke (though by him with doubts). Arach-
noid granulations near nerve roots exist in humans (com-
pare19). The relative volumes reabsorbed there under
physiological conditions are however unknown.
In conclusion: rapid CSF fluctuations or streams or oscilla-
tions represent powerful pulsatile CSF movements leading to
rapid CSF redistribution in between ventricles and subarach-
noid spaces and also throughout the subarachnoid spaces.
But these streams represent not a continuous unidirectional
flow of CSF. Nevertheless, these streams contribute to rapid
mix-up of CSF contents and represent one of the driving
forces for CSF slow flow. Inferred from the findings within
the subarachnoid spaces of a slow change of blood derived
protein contents, blood derived proteins increasing with slow
CSF net flows, and from recent rare imaging study, a slow net
flow balancing the CSF production rate, which takes place in
the ventricles, is to be assumed. This slow CSF net flow within
the subarachnoid spaces seems directed mainly into two
directions, that is one downward along the neuraxis, another
upwards to the subarachnoid spaces surrounding the brain
and especially to the cribriform plate, an area where a major
CSF outflow has been described (such remains however to be
demonstrated in humans). Overall, CSF production rate has to
balance CSF reabsorption plus PCOP outflow volumes. The
relative shares of physiological reabsorption vs. physiological
PCOP outflow remain to be determined. PCOP outflow may be
varying from local factors including posture, motor activity
and local anatomy (like size of respective nerves and bodily
architecture).
3.2. About CSF outflow at the PCOP
Yet early studies in the 19th century by H. Quincke56 showed
that cinnabar, when injected into the lumbar subarachnoid
spaces of dogs, was widely distributed following a route along
spinal nerves, in part even ending up at thoracic autonomic
ganglia. Quincke speculated that corpuscular bodies, when
present within inflammatory CSF, might be able to elicit nerve
dysfunction or damage. His findings were broadly substanti-
ated during the 20th century, though several questions on
CSF flow and recirculation remained open up to now. A view
not far from that presented here (Fig. 1) was found in RM
Schmidt’s CSF textbook, PG Linke stressing the following54:
1 7 ( 2 0 1 1 ) 5 1 –6 6 57
The role of Pacchioni’s (arachnoid) granulations for the drain-
age of CSF was controversial and the possibility that CSF reab-
sorption represented a type of security mechanism in the
case of increased intracranial pressure was preferred. The re-
sults of many coloring experiments were difficult to interpret,
varying concentrations and chemical specificities of com-
pounds made it difficult to delineate the characteristics of
CSF flow. Chemical substances were often taken up rapidly
into the blood before appearing in the lymphatic system,
the latter showing a characteristic time delay. Undoubtedly,
the sheets of cranial nerves had a role for CSF outflow, dyes
arriving at the nasal submucosa and at cranial nerves ends,
e.g. in the epichorioidal and the perilymphatic room of the in-
ner ear. The same was true for spinal nerves, in animals and
in humans: e.g. contrast compounds jodipin, lipiodol, pant-
opaque, thorotrast and others, followed the nerve sheets (in-
side the perineurium) and these colored spaces were
considered the extension of the subarachnoid spaces. The
findings did hardly allow a good quantitative estimate but
were nevertheless close to recent estimates. Experiments by
Weed LH et al. (continued from 1923), allowed according to
Linke the conclusion that under physiological pressure condi-
tions CSF was flowing from the subarachnoid spaces to the
venous system and along all brain and spinal nerves into
the lymphatic system.
3.3. CSF outflow versus CSF reabsorption in humans and
in mammals
In humans, according to recent extensive experiences, about
20 ml of CSF is produced per hour, the production rate fluctu-
ating by time and being generally higher in males than in fe-
males.52,53 CSF originates mainly as a ventricular plexus
filtrate,28,57 from meningeal vasculature further blood con-
tents may add (Fig. 2). For long, the clinician’s view was that
CSF was reabsorbed into blood at subarachnoid venous capil-
laries especially arachnoid granulations.58 However, in mam-
mals CSF outflow through the cribriform plate was
demonstrated also long ago.59 It now appears, that in mam-
mals including primates CSF outflow from subarachnoid
spaces through the cribriform plate near olfactory nerves
reaches nasal submucosa, then the cervical lymphatic system
and along other cranial nerves the cervical and submaxillary
lymph nodes and along spinal nerves the peripheral tissues’
lymphatic system.1–3,5,60 The relative shares of CSF outflow
vs. CSF reabsorption seem however not fully clear. In rats
and sheep, CSF was reabsorbed into blood at arachnoid gran-
ulations, but was also flowing through distributed ‘extralym-
phatic pathways’ to interstitial tissue fluids. Quantitatively,
both pathways seemed to contribute equally to the clearance
of CSF tracer from the cranial vault.38 Furthermore, brain
interstitial fluid drained into the cervical lymph system and
in part into the CSF.42,61 Partially, CSF drained even back into
the blood via small venules42 and this passage seemed to in-
clude cells.31 However, experimental blockade of the cribri-
form plate in sheep underlined the importance of
extralymphatic pathway outflow in regulating CSF pres-
sure,62–64 so this outflow seemed previously underestimated
whereas reabsorption overestimated. Therefore, outflow
could instead even represent the primary physiological
58 N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
mechanism of CSF recirculation whereas CSF reabsorption
into the cranial venous system may represent a secondary
mechanism, recruited to complement lymphatic transport
when global absorption capacity was stressed or compro-
mised.65,66 Regarding the microanatomy of outflow pathways
several questions are open. Various tracers introduced into
CSF spaces spread into spaces between the perineurium
and epineurium in rats,67 possibly through longitudinal
channules within the endoneural space.60 But details re-
mained unclear and need further studies.
Another question is whether the extralymphatic pathway
system in several mammals fits fully with the situation in hu-
mans. The anatomy of the peripheral nervous system is anal-
ogous in humans and mammals68 therefore also CSF outflow
in humans should be analogous. Similarities in CNS diseases
between animals and humans strengthen such assumption:
e.g. myelin antigen reactive T cells were more frequently de-
tected in cervical lymph nodes in patients with multiple scle-
rosis than in normal controls, corresponding to the findings
in experimental allergic encephalomyelitis.69 Another clinical
finding may support such view: a collection of fluid around
the median nerve is an established MRI sign for carpal tunnel
syndrome.70 The underlining pathomechanism remained
open, but may be interpreted as follows: The physiological
CSF outflow along the median nerve may be blocked by swol-
len tissues under the ligamentum transversum, however after
incision by the classical surgery procedure the stop mecha-
nism for CSF collection may be resolved. (The collection fluid
before surgery was not on both sites of the ligamentum in-
stead only proximal to).
Another question is cell trafficking along the PCOP. Lym-
phatic outflow of cells and destruction of blood cells specifi-
cally in cervical lymph nodes was shown after injection into
the subarachnoid spaces.71,72 Drainage of CSF cells into the
lymphatic system of the neck was demonstrated in hu-
mans.73 Therefore it may not be farfetched to think that cell
trafficking along the PCOP at all its parts may occur. Cell traf-
ficking through the cribriform plate is now assumed by others
to likely represent a major route for migration of inflamma-
tory cells from CNS to regional lymph nodes (see above). Con-
sidering the anatomical sizes, one may well assume that
along the PCOP parts B and C similar physiological cell traf-
ficking may occur, an assumption strongly supported by
own recent case observations44: A patient suffering from re-
peated leukemic relapses within the intrathecal spaces, not
paralleled by relapse in blood, developed disseminated
metastasis at unusual sites along large lower body nerves
and related subcutaneous tissues. This distribution pattern
of leukemic cells perfectly matched the PCOP distribution
pattern described here.
Summing up, in mammals including humans, physiologi-
cal CSF outflow through the cribriform plate near olfactory
nerves, and also to the optical nerve and its particular lym-
phatic system (part A), and along the other cranial nerves
III–XII (part B), and along all spinal nerves (part C), can be as-
sumed and is together here referred to as PCOP. Many ques-
tions remain open to be studied in more detail such as:
What is the microanatomy of PCOP? Which relative volumes
of CSF may follow the various PCOP parts? Which share of
CSF is reabsorbed? Where exactly does CSF mix up with inter-
1 7 (2 0 11 ) 5 1–66
stitial fluids, e. g. near free nerves’ ends or all along nerves
somewhere? Does CSF reabsorption happen at nerve-nerve
and nerve-muscle connections? What relative influence on
PCOP efflux may gravity forces and motor activity have? Do
CSF cells physiologically follow the whole PCOP?
4. The PCOP in neuroinflammation including
low level neuroinflammation, and a possible
pathogenetic role of CSF in general inflammation,
in major psychoses, neurodegeneration and
neuropathy
Pathomechanisms associated with pathogenic CSF contents
should involve by anatomy primarily the tissues adjacent to
the CSF spaces, that is ventricles and subarachnoid spaces,
there especially the brain cortex and surface of spinal cord
and nerves as far as lying within the subarachnoid spaces,
but in addition may involve the PCOP. The PCOP can be con-
sidered an extension of the subarachnoid spaces.
The new idea presented here in detail, is that of possible
pathogenetic interactions between CSF and nerves at the
PCOP site and possibly even of CSF with PCOP related tissues
predilecting sites where cranial or spinal nerves end, respec-
tively the CSF outflow winds up.
Most severe CSF abnormalities are observed in acute
meningoencephalitis. A myalgic-meningo-radicular syn-
drome in acute meningoencephalitis is classical (compare58).
However, when focusing on pathogenetic details, the strong
myalgic component of the clinical syndrome may be incom-
pletely understood. Hypothesizing a possible involvement of
PCOP related tissues, here the muscles, by a direct interaction
with CSF may complete the pathogenetic scenario. In this
view, myopathy (=myalgia) may arise from direct interaction
of muscles with inflammatory CSF contents, e.g. CSF cells
trafficking. This view is highly speculative, but seems to me
possible at least not well investigated yet.
From this, another idea evolves: in chronic or low level
neuroinflammation a similar involvement of the PCOP may
occur and could be relevant in symptom pathogenesis. The
further discussion here is focused on such possible PCOP
associated pathogenesis of partial aspects or comorbid symp-
toms in major psychoses, neurodegeneration and neuropa-
thy, diseases in which chronic immune activation was
described as a common scenario74–77 and for psychiatric dis-
orders summarized in a multifactorial pathogenetic model of
low level neuroinflammation relevant in a subgroup of severe
psychiatric disorders especially syndromes of affective and
schizophrenic disorders, the mild encephalitis (ME) hypothe-
sis.15 (In principle, in all CNS-inflammatory disorders the
PCOP may be involved, see below).
The PCOP hypothesis presented here would complement
the ME hypothesis. A prerequisite was that CSF abnormalities
were present in such subgroup. Just now with modern CSF
analytic methods, we found CSF abnormalities in 41% of pa-
tients with affective and schizophrenic spectrum disorders,
directly indicating or well compatible with the interpretation
of low level neuroinflammation.16 In addition, some cases
presented CSF cell patterns which were similar to patterns
found in patients with acute or chronic CNS inflammatory
neurological disorders.17 Many studies including neuroimag-
 N E U R O L O G Y, P S Y C H I A T R Y A N D B R A I N R E S E A R C H
ing showed neurodegeneration and increasingly evidence for
inflammation in major psychoses.78–83 White matter altera-
tions in schizophrenia resembled demyelinating diseases.84
In post-mortem studies evidence for microglial activation,85
or glial cells abnormality or excitotoxicity and neuroinflam-
mation was found.86,87
In autoimmunity three factors generally play an interac-
tive role: genes, environment and the immune system,88,89 a
scenario matching with the ME hypothesis. The role of envi-
ronmental factors in the etiology of psychoses are at least
in part infectious agents.15 But it may be difficult to detect
‘hidden’ infection using current methodology in clinical pa-
tients.90 For example, Borna disease virus is one candidate
capable to induce psychiatric and/or neurological disorders
by complex pathomechanisms,91 but the jury remains yet
open.15,92–94 Previously unsuspected agents in psychosis risk
now include parvovirus B-19,95,96 toxoplasma,96–98 retrovi-
rus,99 CMV and mumps virus,100 and herpes simplex
virus,101,102 and others.103 Many viruses prefer the CNS and
persist latently within the CNS over many years,104 seemingly
without pathology. However, recent results underline the
possibility that persistent or latent viruses may induce brain
dysfunction via reactivations or by yet unknown pathomech-
anisms. For example, psychiatric morbidity is frequent in
HIV-infection even in cases not fulfilling criteria of HIV-
encephalitis.105 The role of viruses integrated in the human
genome, recently detected for Borna Disease Virus se-
quences,106 is yet unclear.107 From history, the difficulty to
elucidate a possible causality of infections for neuropsychiat-
ric disorders, like general paresis and poliomyelitis, is docu-
mented.108 The low pathogenicity (=number of diseased per
number of infected) of most infections, an evolutionary
advantage for the virus, poses a major problem for research
because many non-specific only partially relevant factors
may contribute to disease pathogenesis in the single case.
First studies with antiviral, anti-inflammatory, immune-
modulatory and immune-suppressive treatments in patients
with major psychoses were performed with encouraging
results.7,8,109,110
The PCOP hypothesis raised here may specifically explain
a number of comorbid findings and symptoms in major psy-
choses. Well established findings are distributed brain dys-
function in schizophrenia (similar in depression) including
cerebellar dysfunction and slight neurodegeneration (com-
pare111–120) are not fully understood pathogenetically. Rather
fuzzy confirmed findings were small distributed muscle le-
sions in schizophrenia and in depression, the lesion pattern
resembling that of muscle lesions found in meningoencepha-
litis.121 Another surprising finding was reduced retinal func-
tion in severe depression.122 Assuming that low level
inflammation distributed by the carrier CSF, involving all
structures of the subarachnoid spaces (including the ventri-
cles), but in addition and nearly in parallel also the PCOP
including such pathways like the CSF outflow into the eye
and through the cribriform plate and into the muscles via
nerve-muscle-connections, could elegantly explain such dis-
tributed and often combined symptoms and findings by one
explanatory principle: abnormal CSF contents representing
and distributing low level neuroinflammation. Such assump-
tion does not preclude instead include possible intraparen-
1 7 ( 2 0 1 1 ) 5 1 –6 6 59
chymal low level neuroinflammation, though CSF may not
act directly, i.e. anatomically distributing CSF related inflam-
matory toxicity but from a common immune driven patho-
genesis, which may prevail in parallel at various sites. On
the other hand the link could be closer since recent studies
not only show that CSF signaling not only prefers cortex areas
but may reach deep into brain parenchyma in adult
primates.123
Such overall scenario fits also findings in chronic multi-
ple sclerosis. Indeed, CSF from MS patients induces acute
conduction blocks in the isolated optic nerve or at periph-
eral nerves.10,124 CSF from patients with major psychosis is
not well investigated in this respect, but several reports of
CSF toxicity in psychiatric disorders are available. Neuro-
toxicity and neuroinflammation are closely linked but in
some way may vary regarding the type of neuroinflamma-
tory response. Though lacking key features of inflamma-
tion, such was defined as ‘neuroinflammation’, the
clinical or histological outcome being dependent from neu-
roprotective factors and other molecular details relevant
for neurodegeneration.125
Olfactory dysfunction is surprisingly frequent in several
neuropsychiatric disorders in which chronic low level neuro-
inflammation or neurodegeneration appears involved, includ-
ing multiple sclerosis, Alzheimer’s disease, Parkinson’s
disease, in all of which common autoimmune mechanisms
are thought to underlie neurodegeneration.126 Brain imaging
in functional and structural analysis (diffusion tender imag-
ing) showed rather similar abnormalities of white matter
tracts and of gray matter in bipolar depression and in schizo-
phrenia, which have considerable similarities to that ob-
served in neurological conditions associated with
inflammation, degeneration, and demyelination. Olfactory
dysfunction is also frequent in viral CNS infections, e.g. BDV
infection,92 but also in major psychosis both, the affective
and schizophrenic disorders. The findings in schizophrenia
are here discussed in more detail: genetic and environmental
factors contribute to olfactory dysfunction in schizophre-
nia,127,128 similar to cognitive dysfunctions,129 and a role of
cytokines for cognitive dysfunction was plausible.130 Cyto-
kines were shown increased within CSF in neuroinflamma-
tion in many studies.77 May these cognitive dysfunctions in
part arise from interaction of CSF with the brain cortex?
Other often neglected but surprisingly frequent symp-
toms in major psychosis are a range of sensory disturbances
including pain, together described as coenesthesias, repre-
senting bodily hallucinations in advanced stages.131 Comor-
bid pain was described in 60–80% of patients with
depression,132,133 but the pathomechanisms, often thought
to be of central and neuronal origin, remained poorly deter-
mined. Trying to explain these surprisingly complex symp-
tom patterns by unifying principle, not alone from
neuronal mechanisms, may be justified. An attractive com-
mon anatomical link of pathology could represent in my
view the CSF, by anatomy involving preferably surface struc-
tures of the CNS within the subarachnoid spaces, and in par-
allel as hypothesized even the PCOP. One should consider
both, loss and gain of function and over the long term neu-
rodegeneration in parallel as possible pathologies in such
CSF associated pathomechanisms and dysfunctions. Pain in
60 N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
severe depressed patients improved rapidly under cerebro-
spinal fluid filtration.6 It appears, and for example also in
multiple sclerosis, that the central origin of pain was often
overestimated, whereas peripheral involvement underesti-
mated.134 CSF can easily get toxic properties and associates
with pain and other symptoms but also with neurodegener-
ation.135–137 A special case regarding anatomy represents the
olfactory system, grossly surrounded by CSF, but represent-
ing also a predilection site of intraparenchymal pathology
in viral menigoencephalitis. Furthermore, there is in general
increasing evidence, that viral infection leading to brain
dysfunction is more prevalent than appreciated.138 Other
neuropsychological symptoms compatible with CSF associ-
ated pathomechanisms seem neurological soft signs,139 or
dysautonomia140–143 in psychoses, also found in neuroborre-
liosis,144 or dysfunctional vision demonstrated during
depression.145
Another area of unexplained pathogenetic aspects is neu-
ropathy. For example, neuropathy often accompanies CNS
infections, like HIV-infection or neuroborreliosis. In HIV re-
lated distal symmetrical polyneuropathy an inflammation of
dorsal root ganglia was prevalent in advanced disease, but
the authors stated ‘there are likely to be other, as of, yet unde-
termined, factors that contribute to the development of ‘clin-
ical manifestations’.146 Another example, HTLV-1 associated
myelopathy (HAM/TSP) is well-investigated68: 43% of HAM/
TSP patients presented in parallel neuropathy. Interleukin 6
was found increased within CSF in such patients. Also selec-
tive cytotoxic T lymphocytes were demonstrated in CSF from
a HAM/TSP patient.147 Histopathology showed demyeliniza-
tion, remyelinization, axonal atrophy, degeneration and peri-
neural fibrosis but without inflammatory infiltrates and
without immune globulin accumulation. To explain the ex-
tended pathology, it was suggested that unknown soluble
CSF factors were damaging nerve roots,68 but the site of
pathology was not fully clear. Could both nerve roots within
the subarachoid spaces and peripheral nerves via the PCOP
be hit by toxic CSF? – Neurotoxicity of CSF was demonstrated
also in various motor neuron diseases.148,149 However, CSF
toxins could not fully explain the findings and symptoms: if
nerve roots only were involved, the striking regional differ-
ences of pathology were hard to explain. Considering a con-
tributive toxic CSF-nerve-interaction at the PCOP site could
complete the picture. Especially when CSF toxicity and nerve
pathology was induced by local CSF cells trafficking along the
PCOP (see above), such associated toxicity might vary over
time and could be influenced by circumstantial factors, like
motor activity.
In sum, toxic CSF or abnormal CSF signaling could in gen-
eral elicit dysfunction and pathology with a preference for
CNS structures adjacent to the CSF spaces throughout the
subarachnoid spaces with its complex anatomical-physiolog-
ical pattern of CSF distribution and flow, but including also
nerve roots, and possibly in parallel nerves at the PCOP site
and even PCOP related structures. A number of clinical signs
and symptoms when appearing in a combined manner would
correspond with such anatomical widely distributed patho-
physiological scenario and be relevant in various types of
neuroinflammation with primary or secondary neuropsychi-
atric symptoms.
1 7 (2 0 11 ) 5 1–66
5. PCOP associated pathology/
pathophysiology in six patterns – a hypothesis
Based on findings and observations outlined above, six path-
ophysiological patterns possibly associated with the PCOP
CSF outflow are proposed here, which may arise in various
disorders associated with abnormal CSF contents and may
contribute to emergence of the clinical picture. General con-
tributive factors in inflammatory disorders include host
genes, infectious agents and other triggers, agent derived
factors, inflammatory biochemistry, and immunopathology
or autoimmunity seemingly often triggered by infec-
tions.88,150,151 The CSF is an important carrier of CNS im-
mune surveillance by immune cells including soluble
factors as specific signaling molecules.152 Describing possible
interactions between abnormal CSF contents at the PCOP
and related structures may add rather new aspects to better
understand several surprising or unexplained comorbid
symptoms in disease. These hypothesized patterns are not
mutually exclusive but may overlap or pass from one into
another over time:
Pattern (a): Regular PCOP involvement in acute CNS
inflammatory disorders and acute systemic inflammatory
disorders with CNS involvement.
Many and often all structures inside the entire CSF spaces,
especially the subarachnoid spaces, including brain, spinal
cord, and nerve roots, may be involved in the case of acute
inflammatory CSF pathologies. But similar pathologies may
in parallel involve the PCOP and related peripheral tissues.
As an example for the latter, abnormal CSF contents may in-
crease pain sensitivity at meningeal nerves (associated with
the subarachnoid spaces) but also peripheral free nerves ends
via PCOP, thus eliciting diffuse overly distributed pain symp-
toms. In more chronic or advanced stages of neurodegenera-
tion myopathy, neuropathy and peripheral nerve dysfunction
may develop from local PCOP associated pathologies. How-
ever, with severe acute inflammation the PCOP outflow vol-
ume may decline, because the pathway may be blocked by
tissue edema and this may contribute to an increasing intra-
thecal pressure, as observed in advanced stages of acute
meningoencephalitis.
Pattern (b): Possible PCOP involvement due to a bystander
effect in acute systemic inflammatory disorders.
Activated T cells (not restricted to CNS specific cells)
more effectively migrate from blood into the CSF than
non-activated.153,154 This implies that in diseases with
(strongly) increased numbers of activated immune cells,
the immune cell recirculation (from blood through CSF and
back) may increase generally, then possibly mediating PCOP
associated symptoms which may be similar to that in a)
though minor.
Pattern (c): Regular PCOP involvement in chronic inflam-
matory neurological disorders.
From pathomechanisms similar as in (a), but differing by
chronic inflammatory type biochemistry (compare74), analo-
gous chronic PCOP specific pathologies might arise.
Pattern (d): PCOP involvement in low level
neuroinflammation.
Low level neuroinflammation was often mentioned in
recent literature, but an accepted definition is lacking.
 N E U R O L O G Y, P S Y C H I A T R Y A N D B R A I N R E S E A R C H
Respective pathomechanisms overlap with chronic
neuroinflammation though mechanisms seem in part
different, e.g. like that caused by neurotoxicity not fulfilling
established criteria of inflammation.125 PCOP associated
pathologies may occur as comorbid minor symptoms in all
diseases accompanied or characterized by low level neuroin-
flammation. Examples of comorbidities of pattern (d) may
represent autoimmune and rheumatic disorders, neurode-
generative disorders and the ME subgroup of major psycho-
ses. Candidate symptoms may be diffuse pain, olfactory
dysfunction, eye (retinal and optical nerves) dysfunction,
the so-called neurological soft signs in major psychoses,
and any other symptoms matching with the PCOP scenario,
and may be paralleled by pattern f symptoms. Note: a paral-
lelism of symptoms arising from CSF pathologies induced at
central parts of the CNS, especially of structures neighboring
the CSF spaces, and of PCOP associated (peripheral) symp-
toms and pathologies is generally expected. PCOP associated
symptoms may vary over time with factors influencing local
CSF outflow volumes to vary (a speculation based on preli-
minary clinical observations).
Pattern (e): PCOP involvement by time-variant
neuroinflammation.
In relapsing-remitting or smoldering low level neuroin-
flammation the pathogenic CSF biochemistry may over time
add up to toxicity at certain PCOP sites, e.g. due to local CSF
immune cell accumulation or from a threshold effect at long
nerves. Such mechanisms may also be relevant for local
pathologies in inflammatory neuropathies.
Pattern (f): Involvement of PCOP related tissues in patterns
(a–e).
Additional pathology in parallel to the mechanisms (a–e)
may arise in PCOP related tissues anatomically connected
by nerves, under those especially muscles and subcutaneous
tissues and autonomic ganglia. Such view is highly specula-
tive because the microanatomic ending of the PCOP part B
and C is not clear yet, though the idea is compatible with
the observed distribution of CSF dyes in a number of studies.
An example perfectly matching the idea of pattern (f) would
represent the muscle lesions found in subgroups of depres-
sion and schizophrenia, resembling the patterns found in
meningoencephalitis (see above). Subgroups of fatigue syn-
drome and fibromyalgia represent further candidates (com-
pare the open questions155–157).
6. Testing the PCOP hypothesis
The PCOP in all its parts (as termed here A, B, C) likely rep-
resents a physiological CSF outflow pathway in humans,
confirmed in a number of animal studies. The relative out-
flow volumes as compared to reabsorption appear to be un-
clear, but may near to equal. Experimental approaches
preferred studying the part A, studies on parts B and C are
sparse. A distinct pathophysiology associated with abnormal
CSF contents along the PCOP remains to be shown. Facing
considerable gaps of knowledge, e.g. the unknown micro-
anatomy of the CSF outflow at parts B and C, also the path-
ophysiological hypothesis of the PCOP focusing on party B
and C has to stay rather preliminary. Nevertheless, there is
increasing evidence that the pathophysiological role of CSF
1 7 ( 2 0 1 1 ) 5 1 –6 6 61
was generally underestimated,20,33,34,152 so the PCOP hypoth-
esis presented may be early but not far-fetched. An impor-
tant role of CSF cells yet in the beginning of CNS
inflammation,158,159 and also of local activation of immune
cells within the CSF spaces in interaction with systemic
cells152 and in the peripheral nervous system,160 was only re-
cently learned. Cell trafficking through the cribriform plate is
now considered a physiological phenomenon (see above),
but may take place similarly at PCOP’s Part B and C. During
trafficking along the PCOP, nerves may be shielded, when
trafficking occurs through small channules. Nevertheless,
when CSF solutes and CSF cells were able to secreting pow-
erful molecules these may interact with nerves at the PCOP.
But whether CSF cells may traffic along the PCOP is open.
Nevertheless, dendritic cells were demonstrated within
CSF,161 migrating in neuroinflammatory disorders from CSF
(but not from brain parenchyma) to cervical lymph nodes,162
thus suggesting that these cells may traffic along the PCOP,
matching with our recent finding.44
Recently a second functional thymus in the neck of mice
was detected,163 an important new finding.164 Keeping in mind
that brain antigens drained with brain interstitial fluid to cer-
vical lymph nodes18 and with CSF outflow to nasal submucosa
to cervical lymph nodes, one may yet underestimate the role
of cervical nodes in CNS immunity. T cells activated there
have an increased ability to migrate to the CNS.165 Immune
cells, when migrated to the CNS, can interact with CNS cells
and possibly over years produce immune globulines and other
possibly toxic or neurodegenerative mediators,166–168 though
counterbalanced by protective factors.169 Altered pathogenic
CSF contents may persist for long.74 Therefore the anatomical
connection between CNS and the periphery in interaction
with the carrier CSF may be relevant in chronic disease
pathogenesis, the PCOP represented the anatomical link.
Reduced CSF recirculation is hypothesized to play a role in
various CNS diseases,34 but may involve the PCOP and its
structures also. The physiological function of CSF recirculation
is in part detoxification, declining with age from reduced CSF
production but also during CNS inflammation, beyond is prob-
ably influenced by motor activity, posture, a.s.o., altogether
influencing CSF recirculation and detoxification (compare34).
Testing the PCOP hypothesis appears challenging: the CSF
pathways are widely distributed involving many structures
and distributed pathogenic CSF may therefore elicit complex
dysfunctions. Furthermore, abnormal CSF contents in ques-
tion range from monomolecular abnormal signaling to severe
complex inflammatory signatures. Studying the symptom
patterns in such pathologies involving structures of the whole
CSF spaces including various pathomechanisms is really dif-
ficult, because at various sites of CNS and the peripheral ner-
vous system rather similar symptoms may arise in parallel.
The experimental difficulties to study such pathologies are
evident also from previous experimental approaches56:
Quincke’s studies around 1872 are of special interest because
performed under natural behavioral conditions not on anes-
thesized or immobilized animals, the motor activity likely
influencing CSF recirculation dynamics. Quincke clearly de-
scribes dyes to arrive at the PCOP.
How should one study the PCOP? Single nerves could
be separated and blocked, or solutes infused into the
62 N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
subarachnoid spaces or in between nerve sheets. Cell traffick-
ing may be studied by fluorescent labeling, in vivo micros-
copy, and/or by experimentally increasing intrathecal cell
numbers, a. s. o. Surprisingly, the regular fate of CSF cells,
whether and where CSF cells leave the CSF spaces, are widely
unknown nor quantified up to now. However, answers to
these questions could be extraordinarily important, because
activated immune cells may mediate significant probably of-
ten local, pathogenetic effects.
Another speculation might be followed: the peripheral ner-
vous system tends to amplify local immune responses.170
Might CSF signaling at the PCOP be involved, including via di-
rect interactions of CSF with the sympathetic trunk or with
lymph node nerves? Neuronal signaling has a surprisingly
strong influence on immune responses within local lymph
nodes.171 The dysautonomia observed in inflammatory disor-
ders but also in schizophrenia and depression140–143 is an inter-
esting but poorly explained phenomenon. Might it relate to CSF
signaling? From an evolutionary point of view, CSF associated
mechanisms related to the PCOP could represent another regu-
latory arm though redundant. Redundancy is often observed in
nature when mechanisms need to be tightly controlled.
In conclusion, answers to the questions raised here may
provide new and better understanding of the interactions in
between nervous and immune system in a range of neuroin-
flammatory diseases and in neuropsychiatric diseases associ-
ated with neuroinflammation or neurodegeneration.
Acknowledgments
For helpful discussions I thank Robert Chang, Philadelphia;
Hansotto Reiber, Goettingen; Sibylle Herzog, Giessen; Hayret-
tin Tumani, Ulm; Thomas Becker and Horst-G. Maxeiner
Günzburg/Ulm, Michael Schmitt Rostock. I am especially
grateful to Bernd Schmitz Günzburg/Ulm for providing the
online multimedia material on rapid CSF flow and Clemens
Bechter for drawing the cartoon, my secretaries Ingrid Lech-
ner and Sabine Holeczek for assistance with writing. Funding
by the Stanley Foundation, Bethesda (CSF filtration) and the
Margarete Ammon Stiftung, München (biochemical and cellu-
lar CSF analyses, clinical studies) was indirectly helpful in
generating this hypothesis.
Appendix A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.npbr.2011.06.003.
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