Audenaert, Kurt

De Deyn, Peter Paul

De Groot, Veva

Killer, Hanspeter Esriel

Van Dam, Debby

Wostyn, Peter

English

PubMed

University of Groningen Research Database

  
 University of Groningen
Dilated Virchow-Robin spaces in primary open-angle glaucoma
Wostyn, Peter; De Groot, Veva; Van Dam, Debby; Audenaert, Kurt; Killer, Hanspeter Esriel;
De Deyn, Peter Paul
Published in:
Acta radiologica open
DOI:
10.1177/2058460116653630
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2016
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Wostyn, P., De Groot, V., Van Dam, D., Audenaert, K., Killer, H. E., & De Deyn, P. P. (2016). Dilated
Virchow-Robin spaces in primary open-angle glaucoma: a biomarker of glymphatic waste clearance
dysfunction? Acta radiologica open, 5(8). https://doi.org/10.1177/2058460116653630
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum.
Download date: 21-05-2019
Case Report
Dilated Virchow-Robin spaces in primary
open-angle glaucoma: a biomarker of
glymphatic waste clearance dysfunction?
Peter Wostyn1, Veva De Groot2, Debby Van Dam3,4,
Kurt Audenaert5, Hanspeter Esriel Killer6
and Peter Paul De Deyn3,4,7
We read with great interest the article entitled ‘‘Ocular
blood ﬂow and cerebrospinal ﬂuid pressure in glau-
coma’’ by Promelle et al. (1). The authors review the
most recent research on alterations in ocular blood ﬂow
and/or cerebrospinal ﬂuid (CSF) ﬂow in glaucoma.
They state that blood–CSF ﬂow interactions may be
involved in glaucoma, and also note that ‘‘the CSF’s
behavior is supposedly linked to blood pulsatility.’’ We
fully agree with this notion, as we believe that the vas-
cular system could play a role in the pathogenesis of
glaucoma through a mechanical interplay with the CSF
circulation.
The subarachnoid space (SAS) of the optic nerve
(ON) is contiguous with the SAS of the brain in a
normal population. Growing evidence in the literature
provides strong support for the concept that CSF pres-
sure and composition in the SAS surrounding the ON
may have fundamental signiﬁcance in the pathogenesis
of glaucoma (2,3). As an extension of the brain, the ON
displays remarkable similarities to the brain in terms of
anatomy and functionality (4). Knowledge obtained
from brain research could therefore lead to new insights
into the ON and vice versa. Recently, the ‘‘glymphatic
system’’ of the brain has been discovered in rodents by
Iliﬀ et al. (5). The authors argued that this system was
critical to the eﬃcient clearance of interstitial solutes,
including amyloid-b, from the brain (5). Their ﬁndings
suggested a brain-wide paravascular pathway in which
CSF ﬂows from the SAS along the arteries and arteri-
oles into the paravascular Virchow-Robin spaces
(VRSs) to exchange with interstitial ﬂuid (ISF), and
ISF is cleared from the brain into the VRSs surround-
ing the exiting veins. As ISF exits the brain through the
paravenous route, it travels to the lymphatic vessels
in the neck, and eventually returns its contents to the
systemic circulation.
Paravascular CSF recirculation and ISF solute clear-
ance is dependent upon water transport via astroglial
aquaporin-4 water channels, which are localized to
perivascular astrocytic endfeet ensheathing the cerebral
vasculature (5). Importantly, there is also evidence
demonstrating that there is a mechanical interplay
between the intracranial vascular system and the glym-
phatic system. Indeed, a recent study demonstrated that
cerebral arterial pulsatility is a key driver of paravas-
cular CSF inﬂux and subsequent CSF-ISF exchange in
the brain (6). Loss of elasticity in aging cerebral arteries
with progressive atherosclerosis, or cessation of pulsa-
tions, might contribute to failure of the clearance of
interstitial waste, including amyloid-b, from the brain,
and might play a role in the pathogenesis of
Alzheimer’s disease (6).
The above ﬁndings indicate that the VRSs have an
important role in the homeostasis of cerebral ﬂuids in
the central nervous system (7), and suggest a possible
correlation between VRS enlargement and a disturbance
of CSF dynamics. Indeed, if CSF outﬂow is reduced as a
consequence of either CSF ﬂow obstruction or cerebral
artery pulsatility ineﬃciency, or cerebrospinal venous
insuﬃciency and lymphatic disorders, local perivascular
CSF recirculation may be impaired and, consequently,
1Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium
2Department of Ophthalmology, Antwerp University Hospital, Antwerp,
Belgium
3Laboratory of Neurochemistry and Behavior, Institute Born-Bunge,
University of Antwerp, Department of Biomedical Sciences, Antwerp,
Belgium
4Department of Neurology and Alzheimer Research Center, University
of Groningen and University Medical Center Groningen, Groningen,
The Netherlands
5Department of Psychiatry, Ghent University Hospital, Ghent, Belgium
6Department of Ophthalmology, Kantonsspital Aarau, Aarau, Switzerland
7Department of Neurology and Memory Clinic, Middelheim General
Hospital (ZNA), Antwerp, Belgium
Corresponding author:
Peter Wostyn, Department of Psychiatry, PC Sint-Amandus,
Reigerlostraat 10, 8730 Beernem, Belgium.
Email: wostyn.peter@skynet.be
Acta Radiologica Open
5(8) 1–2
! The Foundation Acta Radiologica
2016
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/2058460116653630
arr.sagepub.com
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.
creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the
original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).
the VRSs may dilate due to ﬂuid retention (7).
Interestingly, dilated VRSs are a known histological fea-
ture of cerebral small vessel disease and can be demon-
strated on magnetic resonance imaging (8).
Since the ON is a direct extension of the brain, the
question is whether there is also evidence for the exist-
ence of a paravascular transport system in the ON. The
observation of such an anatomically distinct clearing
system in the ON could also provide new insights into
the pathogenesis of glaucoma. Indeed, if conﬁrmed,
one might expect that a dysfunctional glymphatic
system could ultimately result in reduced neurotoxin
clearance in the ON and lead to glaucomatous neuro-
degeneration (4).
Many studies have demonstrated vascular-related
risk factors for glaucoma. Atherosclerotic cerebrovas-
cular disease is a risk factor for glaucomatous optic
neuropathy, and both systemic hypertension and sys-
temic arterial stiﬀness have been reported to be asso-
ciated with primary open-angle glaucoma (POAG)
(9,10). Given that impairment of the arterial pulsa-
tion-driven ‘‘perivascular pump’’ may lead to CSF
ﬂux disturbance, and given that distension of the
VRSs may be related to the ﬂuid retention in and
along the paravascular circulation (7), we postulate
that dilated VRSs could occur in POAG in association
with arterial stiﬀening or loss of arterial pulsatility.
Interestingly, in accordance with this view, a very
recent study showed signiﬁcantly higher deep white
matter lesion load and increased numbers of dilated
VRSs in association with POAG suggesting the pres-
ence of signiﬁcant cerebral small vessel disease (8). If
dilation of VRSs may result from a disturbed interplay
between the vascular and glymphatic system, then
preventing arterial stiﬀness may protect against glau-
coma, at least in part, by promoting solute clearance
via the CSF.
Declaration of conflicting interests
The author(s) declared no potential conﬂicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no ﬁnancial support for the research,
authorship, and/or publication of this article.
References
1. Promelle V, Daouk J, Bouzerar R, et al. Ocular blood
flow and cerebrospinal fluid pressure in glaucoma. Acta
Radiol Open 2016;5:2058460115624275.
2. Berdahl JP, Allingham RR. Intracranial pressure and
glaucoma. Curr Opin Ophthalmol 2010;21:106–111.
3. Killer HE, Miller NR, Flammer J, et al. Cerebrospinal
fluid exchange in the optic nerve in normal-tension glau-
coma. Br J Ophthalmol 2012;96:544–548.
4. Wostyn P, Van Dam D, Audenaert K, et al. A new glau-
coma hypothesis: a role of glymphatic system dysfunc-
tion. Fluids Barriers CNS 2015;12:16.
5. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway
facilitates CSF flow through the brain parenchyma and
the clearance of interstitial solutes, including amyloid b.
Sci Transl Med 2012;4:147ra111.
6. Iliff JJ, Wang M, Zeppenfeld DM, et al. Cerebral arterial
pulsation drives paravascular CSF-interstitial fluid
exchange in the murine brain. J Neurosci 2013;33:
18190–18199.
7. Gallina P, Scollato A, Conti R, et al. Ab Clearance,
‘‘hub’’ of multiple deficiencies leading to Alzheimer dis-
ease. Front Aging Neurosci 2015;7:200.
8. Mercieca K, Cain J, Hansen T, et al. Primary open angle
glaucoma is associated with MR biomarkers of cerebral
small vessel disease. Sci Rep 2016;6:22160.
9. Nakazawa T. Ocular blood flow and influencing factors
for glaucoma. Asia Pac J Ophthalmol (Phila) 2016;5:
38–44.
10. Shim SH, Kim CY, Kim JM, et al. The role of systemic
arterial stiffness in open-angle glaucoma with diabetes
mellitus. Biomed Res Int 2015;2015:425835.
2 Acta Radiologica Open 5(8)


Dilated Virchow-Robin spaces in primary open-angle glaucoma:a biomarker of glymphatic waste clearance dysfunction?

ARTS repository - University of Groningen

   University of GroningenDilated Virchow-Robin spaces in primary open-angle glaucomaWostyn, Peter; De Groot, Veva; Van Dam, Debby; Audenaert, Kurt; Killer, Hanspeter Esriel;De Deyn, Peter PaulPublished in:Acta radiologica openDOI:10.1177/2058460116653630IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2016Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Wostyn, P., De Groot, V., Van Dam, D., Audenaert, K., Killer, H. E., & De Deyn, P. P. (2016). DilatedVirchow-Robin spaces in primary open-angle glaucoma: a biomarker of glymphatic waste clearancedysfunction? Acta radiologica open, 5(8). https://doi.org/10.1177/2058460116653630CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 21-06-2022Case ReportDilated Virchow-Robin spaces in primaryopen-angle glaucoma: a biomarker ofglymphatic waste clearance dysfunction?Peter Wostyn1, Veva De Groot2, Debby Van Dam3,4,Kurt Audenaert5, Hanspeter Esriel Killer6and Peter Paul De Deyn3,4,7We read with great interest the article entitled ‘‘Ocularblood flow and cerebrospinal fluid pressure in glau-coma’’ by Promelle et al. (1). The authors review themost recent research on alterations in ocular blood flowand/or cerebrospinal fluid (CSF) flow in glaucoma.They state that blood–CSF flow interactions may beinvolved in glaucoma, and also note that ‘‘the CSF’sbehavior is supposedly linked to blood pulsatility.’’ Wefully agree with this notion, as we believe that the vas-cular system could play a role in the pathogenesis ofglaucoma through a mechanical interplay with the CSFcirculation.The subarachnoid space (SAS) of the optic nerve(ON) is contiguous with the SAS of the brain in anormal population. Growing evidence in the literatureprovides strong support for the concept that CSF pres-sure and composition in the SAS surrounding the ONmay have fundamental significance in the pathogenesisof glaucoma (2,3). As an extension of the brain, the ONdisplays remarkable similarities to the brain in terms ofanatomy and functionality (4). Knowledge obtainedfrom brain research could therefore lead to new insightsinto the ON and vice versa. Recently, the ‘‘glymphaticsystem’’ of the brain has been discovered in rodents byIliff et al. (5). The authors argued that this system wascritical to the efficient clearance of interstitial solutes,including amyloid-b, from the brain (5). Their findingssuggested a brain-wide paravascular pathway in whichCSF flows from the SAS along the arteries and arteri-oles into the paravascular Virchow-Robin spaces(VRSs) to exchange with interstitial fluid (ISF), andISF is cleared from the brain into the VRSs surround-ing the exiting veins. As ISF exits the brain through theparavenous route, it travels to the lymphatic vesselsin the neck, and eventually returns its contents to thesystemic circulation.Paravascular CSF recirculation and ISF solute clear-ance is dependent upon water transport via astroglialaquaporin-4 water channels, which are localized toperivascular astrocytic endfeet ensheathing the cerebralvasculature (5). Importantly, there is also evidencedemonstrating that there is a mechanical interplaybetween the intracranial vascular system and the glym-phatic system. Indeed, a recent study demonstrated thatcerebral arterial pulsatility is a key driver of paravas-cular CSF influx and subsequent CSF-ISF exchange inthe brain (6). Loss of elasticity in aging cerebral arterieswith progressive atherosclerosis, or cessation of pulsa-tions, might contribute to failure of the clearance ofinterstitial waste, including amyloid-b, from the brain,and might play a role in the pathogenesis ofAlzheimer’s disease (6).The above findings indicate that the VRSs have animportant role in the homeostasis of cerebral fluids inthe central nervous system (7), and suggest a possiblecorrelation between VRS enlargement and a disturbanceof CSF dynamics. Indeed, if CSF outflow is reduced as aconsequence of either CSF flow obstruction or cerebralartery pulsatility inefficiency, or cerebrospinal venousinsufficiency and lymphatic disorders, local perivascularCSF recirculation may be impaired and, consequently,1Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium2Department of Ophthalmology, Antwerp University Hospital, Antwerp,Belgium3Laboratory of Neurochemistry and Behavior, Institute Born-Bunge,University of Antwerp, Department of Biomedical Sciences, Antwerp,Belgium4Department of Neurology and Alzheimer Research Center, Universityof Groningen and University Medical Center Groningen, Groningen,The Netherlands5Department of Psychiatry, Ghent University Hospital, Ghent, Belgium6Department of Ophthalmology, Kantonsspital Aarau, Aarau, Switzerland7Department of Neurology and Memory Clinic, Middelheim GeneralHospital (ZNA), Antwerp, BelgiumCorresponding author:Peter Wostyn, Department of Psychiatry, PC Sint-Amandus,Reigerlostraat 10, 8730 Beernem, Belgium.Email: wostyn.peter@skynet.beActa Radiologica Open5(8) 1–2! The Foundation Acta Radiologica2016Reprints and permissions:sagepub.co.uk/journalsPermissions.navDOI: 10.1177/2058460116653630arr.sagepub.comCreative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided theoriginal work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).the VRSs may dilate due to fluid retention (7).Interestingly, dilated VRSs are a known histological fea-ture of cerebral small vessel disease and can be demon-strated on magnetic resonance imaging (8).Since the ON is a direct extension of the brain, thequestion is whether there is also evidence for the exist-ence of a paravascular transport system in the ON. Theobservation of such an anatomically distinct clearingsystem in the ON could also provide new insights intothe pathogenesis of glaucoma. Indeed, if confirmed,one might expect that a dysfunctional glymphaticsystem could ultimately result in reduced neurotoxinclearance in the ON and lead to glaucomatous neuro-degeneration (4).Many studies have demonstrated vascular-relatedrisk factors for glaucoma. Atherosclerotic cerebrovas-cular disease is a risk factor for glaucomatous opticneuropathy, and both systemic hypertension and sys-temic arterial stiffness have been reported to be asso-ciated with primary open-angle glaucoma (POAG)(9,10). Given that impairment of the arterial pulsa-tion-driven ‘‘perivascular pump’’ may lead to CSFflux disturbance, and given that distension of theVRSs may be related to the fluid retention in andalong the paravascular circulation (7), we postulatethat dilated VRSs could occur in POAG in associationwith arterial stiffening or loss of arterial pulsatility.Interestingly, in accordance with this view, a veryrecent study showed significantly higher deep whitematter lesion load and increased numbers of dilatedVRSs in association with POAG suggesting the pres-ence of significant cerebral small vessel disease (8). Ifdilation of VRSs may result from a disturbed interplaybetween the vascular and glymphatic system, thenpreventing arterial stiffness may protect against glau-coma, at least in part, by promoting solute clearancevia the CSF.Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest withrespect to the research, authorship, and/or publication of thisarticle.FundingThe author(s) received no financial support for the research,authorship, and/or publication of this article.References1. Promelle V, Daouk J, Bouzerar R, et al. Ocular bloodflow and cerebrospinal fluid pressure in glaucoma. ActaRadiol Open 2016;5:2058460115624275.2. Berdahl JP, Allingham RR. Intracranial pressure andglaucoma. Curr Opin Ophthalmol 2010;21:106–111.3. Killer HE, Miller NR, Flammer J, et al. Cerebrospinalfluid exchange in the optic nerve in normal-tension glau-coma. Br J Ophthalmol 2012;96:544–548.4. Wostyn P, Van Dam D, Audenaert K, et al. A new glau-coma hypothesis: a role of glymphatic system dysfunc-tion. Fluids Barriers CNS 2015;12:16.5. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathwayfacilitates CSF flow through the brain parenchyma andthe clearance of interstitial solutes, including amyloid b.Sci Transl Med 2012;4:147ra111.6. Iliff JJ, Wang M, Zeppenfeld DM, et al. Cerebral arterialpulsation drives paravascular CSF-interstitial fluidexchange in the murine brain. J Neurosci 2013;33:18190–18199.7. Gallina P, Scollato A, Conti R, et al. Ab Clearance,‘‘hub’’ of multiple deficiencies leading to Alzheimer dis-ease. Front Aging Neurosci 2015;7:200.8. Mercieca K, Cain J, Hansen T, et al. Primary open angleglaucoma is associated with MR biomarkers of cerebralsmall vessel disease. Sci Rep 2016;6:22160.9. Nakazawa T. Ocular blood flow and influencing factorsfor glaucoma. Asia Pac J Ophthalmol (Phila) 2016;5:38–44.10. Shim SH, Kim CY, Kim JM, et al. The role of systemicarterial stiffness in open-angle glaucoma with diabetesmellitus. Biomed Res Int 2015;2015:425835.2 Acta Radiologica Open 5(8)

University of Groningen

   University of GroningenDilated Virchow-Robin spaces in primary open-angle glaucomaWostyn, Peter; De Groot, Veva; Van Dam, Debby; Audenaert, Kurt; Killer, Hanspeter Esriel;De Deyn, Peter PaulPublished in:Acta radiologica openDOI:10.1177/2058460116653630IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2016Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Wostyn, P., De Groot, V., Van Dam, D., Audenaert, K., Killer, H. E., & De Deyn, P. P. (2016). DilatedVirchow-Robin spaces in primary open-angle glaucoma: a biomarker of glymphatic waste clearancedysfunction? Acta radiologica open, 5(8). https://doi.org/10.1177/2058460116653630CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 28-04-2023Case ReportDilated Virchow-Robin spaces in primaryopen-angle glaucoma: a biomarker ofglymphatic waste clearance dysfunction?Peter Wostyn1, Veva De Groot2, Debby Van Dam3,4,Kurt Audenaert5, Hanspeter Esriel Killer6and Peter Paul De Deyn3,4,7We read with great interest the article entitled ‘‘Ocularblood flow and cerebrospinal fluid pressure in glau-coma’’ by Promelle et al. (1). The authors review themost recent research on alterations in ocular blood flowand/or cerebrospinal fluid (CSF) flow in glaucoma.They state that blood–CSF flow interactions may beinvolved in glaucoma, and also note that ‘‘the CSF’sbehavior is supposedly linked to blood pulsatility.’’ Wefully agree with this notion, as we believe that the vas-cular system could play a role in the pathogenesis ofglaucoma through a mechanical interplay with the CSFcirculation.The subarachnoid space (SAS) of the optic nerve(ON) is contiguous with the SAS of the brain in anormal population. Growing evidence in the literatureprovides strong support for the concept that CSF pres-sure and composition in the SAS surrounding the ONmay have fundamental significance in the pathogenesisof glaucoma (2,3). As an extension of the brain, the ONdisplays remarkable similarities to the brain in terms ofanatomy and functionality (4). Knowledge obtainedfrom brain research could therefore lead to new insightsinto the ON and vice versa. Recently, the ‘‘glymphaticsystem’’ of the brain has been discovered in rodents byIliff et al. (5). The authors argued that this system wascritical to the efficient clearance of interstitial solutes,including amyloid-b, from the brain (5). Their findingssuggested a brain-wide paravascular pathway in whichCSF flows from the SAS along the arteries and arteri-oles into the paravascular Virchow-Robin spaces(VRSs) to exchange with interstitial fluid (ISF), andISF is cleared from the brain into the VRSs surround-ing the exiting veins. As ISF exits the brain through theparavenous route, it travels to the lymphatic vesselsin the neck, and eventually returns its contents to thesystemic circulation.Paravascular CSF recirculation and ISF solute clear-ance is dependent upon water transport via astroglialaquaporin-4 water channels, which are localized toperivascular astrocytic endfeet ensheathing the cerebralvasculature (5). Importantly, there is also evidencedemonstrating that there is a mechanical interplaybetween the intracranial vascular system and the glym-phatic system. Indeed, a recent study demonstrated thatcerebral arterial pulsatility is a key driver of paravas-cular CSF influx and subsequent CSF-ISF exchange inthe brain (6). Loss of elasticity in aging cerebral arterieswith progressive atherosclerosis, or cessation of pulsa-tions, might contribute to failure of the clearance ofinterstitial waste, including amyloid-b, from the brain,and might play a role in the pathogenesis ofAlzheimer’s disease (6).The above findings indicate that the VRSs have animportant role in the homeostasis of cerebral fluids inthe central nervous system (7), and suggest a possiblecorrelation between VRS enlargement and a disturbanceof CSF dynamics. Indeed, if CSF outflow is reduced as aconsequence of either CSF flow obstruction or cerebralartery pulsatility inefficiency, or cerebrospinal venousinsufficiency and lymphatic disorders, local perivascularCSF recirculation may be impaired and, consequently,1Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium2Department of Ophthalmology, Antwerp University Hospital, Antwerp,Belgium3Laboratory of Neurochemistry and Behavior, Institute Born-Bunge,University of Antwerp, Department of Biomedical Sciences, Antwerp,Belgium4Department of Neurology and Alzheimer Research Center, Universityof Groningen and University Medical Center Groningen, Groningen,The Netherlands5Department of Psychiatry, Ghent University Hospital, Ghent, Belgium6Department of Ophthalmology, Kantonsspital Aarau, Aarau, Switzerland7Department of Neurology and Memory Clinic, Middelheim GeneralHospital (ZNA), Antwerp, BelgiumCorresponding author:Peter Wostyn, Department of Psychiatry, PC Sint-Amandus,Reigerlostraat 10, 8730 Beernem, Belgium.Email: wostyn.peter@skynet.beActa Radiologica Open5(8) 1–2! The Foundation Acta Radiologica2016Reprints and permissions:sagepub.co.uk/journalsPermissions.navDOI: 10.1177/2058460116653630arr.sagepub.comCreative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided theoriginal work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).the VRSs may dilate due to fluid retention (7).Interestingly, dilated VRSs are a known histological fea-ture of cerebral small vessel disease and can be demon-strated on magnetic resonance imaging (8).Since the ON is a direct extension of the brain, thequestion is whether there is also evidence for the exist-ence of a paravascular transport system in the ON. Theobservation of such an anatomically distinct clearingsystem in the ON could also provide new insights intothe pathogenesis of glaucoma. Indeed, if confirmed,one might expect that a dysfunctional glymphaticsystem could ultimately result in reduced neurotoxinclearance in the ON and lead to glaucomatous neuro-degeneration (4).Many studies have demonstrated vascular-relatedrisk factors for glaucoma. Atherosclerotic cerebrovas-cular disease is a risk factor for glaucomatous opticneuropathy, and both systemic hypertension and sys-temic arterial stiffness have been reported to be asso-ciated with primary open-angle glaucoma (POAG)(9,10). Given that impairment of the arterial pulsa-tion-driven ‘‘perivascular pump’’ may lead to CSFflux disturbance, and given that distension of theVRSs may be related to the fluid retention in andalong the paravascular circulation (7), we postulatethat dilated VRSs could occur in POAG in associationwith arterial stiffening or loss of arterial pulsatility.Interestingly, in accordance with this view, a veryrecent study showed significantly higher deep whitematter lesion load and increased numbers of dilatedVRSs in association with POAG suggesting the pres-ence of significant cerebral small vessel disease (8). Ifdilation of VRSs may result from a disturbed interplaybetween the vascular and glymphatic system, thenpreventing arterial stiffness may protect against glau-coma, at least in part, by promoting solute clearancevia the CSF.Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest withrespect to the research, authorship, and/or publication of thisarticle.FundingThe author(s) received no financial support for the research,authorship, and/or publication of this article.References1. Promelle V, Daouk J, Bouzerar R, et al. Ocular bloodflow and cerebrospinal fluid pressure in glaucoma. ActaRadiol Open 2016;5:2058460115624275.2. Berdahl JP, Allingham RR. Intracranial pressure andglaucoma. Curr Opin Ophthalmol 2010;21:106–111.3. Killer HE, Miller NR, Flammer J, et al. Cerebrospinalfluid exchange in the optic nerve in normal-tension glau-coma. Br J Ophthalmol 2012;96:544–548.4. Wostyn P, Van Dam D, Audenaert K, et al. A new glau-coma hypothesis: a role of glymphatic system dysfunc-tion. Fluids Barriers CNS 2015;12:16.5. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathwayfacilitates CSF flow through the brain parenchyma andthe clearance of interstitial solutes, including amyloid b.Sci Transl Med 2012;4:147ra111.6. Iliff JJ, Wang M, Zeppenfeld DM, et al. Cerebral arterialpulsation drives paravascular CSF-interstitial fluidexchange in the murine brain. J Neurosci 2013;33:18190–18199.7. Gallina P, Scollato A, Conti R, et al. Ab Clearance,‘‘hub’’ of multiple deficiencies leading to Alzheimer dis-ease. Front Aging Neurosci 2015;7:200.8. Mercieca K, Cain J, Hansen T, et al. Primary open angleglaucoma is associated with MR biomarkers of cerebralsmall vessel disease. Sci Rep 2016;6:22160.9. Nakazawa T. Ocular blood flow and influencing factorsfor glaucoma. Asia Pac J Ophthalmol (Phila) 2016;5:38–44.10. Shim SH, Kim CY, Kim JM, et al. The role of systemicarterial stiffness in open-angle glaucoma with diabetesmellitus. Biomed Res Int 2015;2015:425835.2 Acta Radiologica Open 5(8)

Peter Wostyn

Veva De Groot

Debby Van Dam

Kurt Audenaert

Hanspeter Esriel Killer

Peter Paul De Deyn

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Acta Radiologica Open

Dilated Virchow-Robin spaces in primary open-angle glaucoma: a biomarker of glymphatic waste clearance dysfunction?

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Institutional Repository Universiteit Antwerpen

Dilated Virchow-Robin spaces in primary open-angle glaucoma : a biomarker of glymphatic waste clearance dysfunction?

   University of GroningenDilated Virchow-Robin spaces in primary open-angle glaucomaWostyn, Peter; De Groot, Veva; Van Dam, Debby; Audenaert, Kurt; Killer, Hanspeter Esriel;De Deyn, Peter PaulPublished in:Acta radiologica openDOI:10.1177/2058460116653630IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2016Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Wostyn, P., De Groot, V., Van Dam, D., Audenaert, K., Killer, H. E., & De Deyn, P. P. (2016). DilatedVirchow-Robin spaces in primary open-angle glaucoma: a biomarker of glymphatic waste clearancedysfunction? Acta radiologica open, 5(8). https://doi.org/10.1177/2058460116653630CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 31-10-2023Case ReportDilated Virchow-Robin spaces in primaryopen-angle glaucoma: a biomarker ofglymphatic waste clearance dysfunction?Peter Wostyn1, Veva De Groot2, Debby Van Dam3,4,Kurt Audenaert5, Hanspeter Esriel Killer6and Peter Paul De Deyn3,4,7We read with great interest the article entitled ‘‘Ocularblood flow and cerebrospinal fluid pressure in glau-coma’’ by Promelle et al. (1). The authors review themost recent research on alterations in ocular blood flowand/or cerebrospinal fluid (CSF) flow in glaucoma.They state that blood–CSF flow interactions may beinvolved in glaucoma, and also note that ‘‘the CSF’sbehavior is supposedly linked to blood pulsatility.’’ Wefully agree with this notion, as we believe that the vas-cular system could play a role in the pathogenesis ofglaucoma through a mechanical interplay with the CSFcirculation.The subarachnoid space (SAS) of the optic nerve(ON) is contiguous with the SAS of the brain in anormal population. Growing evidence in the literatureprovides strong support for the concept that CSF pres-sure and composition in the SAS surrounding the ONmay have fundamental significance in the pathogenesisof glaucoma (2,3). As an extension of the brain, the ONdisplays remarkable similarities to the brain in terms ofanatomy and functionality (4). Knowledge obtainedfrom brain research could therefore lead to new insightsinto the ON and vice versa. Recently, the ‘‘glymphaticsystem’’ of the brain has been discovered in rodents byIliff et al. (5). The authors argued that this system wascritical to the efficient clearance of interstitial solutes,including amyloid-b, from the brain (5). Their findingssuggested a brain-wide paravascular pathway in whichCSF flows from the SAS along the arteries and arteri-oles into the paravascular Virchow-Robin spaces(VRSs) to exchange with interstitial fluid (ISF), andISF is cleared from the brain into the VRSs surround-ing the exiting veins. As ISF exits the brain through theparavenous route, it travels to the lymphatic vesselsin the neck, and eventually returns its contents to thesystemic circulation.Paravascular CSF recirculation and ISF solute clear-ance is dependent upon water transport via astroglialaquaporin-4 water channels, which are localized toperivascular astrocytic endfeet ensheathing the cerebralvasculature (5). Importantly, there is also evidencedemonstrating that there is a mechanical interplaybetween the intracranial vascular system and the glym-phatic system. Indeed, a recent study demonstrated thatcerebral arterial pulsatility is a key driver of paravas-cular CSF influx and subsequent CSF-ISF exchange inthe brain (6). Loss of elasticity in aging cerebral arterieswith progressive atherosclerosis, or cessation of pulsa-tions, might contribute to failure of the clearance ofinterstitial waste, including amyloid-b, from the brain,and might play a role in the pathogenesis ofAlzheimer’s disease (6).The above findings indicate that the VRSs have animportant role in the homeostasis of cerebral fluids inthe central nervous system (7), and suggest a possiblecorrelation between VRS enlargement and a disturbanceof CSF dynamics. Indeed, if CSF outflow is reduced as aconsequence of either CSF flow obstruction or cerebralartery pulsatility inefficiency, or cerebrospinal venousinsufficiency and lymphatic disorders, local perivascularCSF recirculation may be impaired and, consequently,1Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium2Department of Ophthalmology, Antwerp University Hospital, Antwerp,Belgium3Laboratory of Neurochemistry and Behavior, Institute Born-Bunge,University of Antwerp, Department of Biomedical Sciences, Antwerp,Belgium4Department of Neurology and Alzheimer Research Center, Universityof Groningen and University Medical Center Groningen, Groningen,The Netherlands5Department of Psychiatry, Ghent University Hospital, Ghent, Belgium6Department of Ophthalmology, Kantonsspital Aarau, Aarau, Switzerland7Department of Neurology and Memory Clinic, Middelheim GeneralHospital (ZNA), Antwerp, BelgiumCorresponding author:Peter Wostyn, Department of Psychiatry, PC Sint-Amandus,Reigerlostraat 10, 8730 Beernem, Belgium.Email: wostyn.peter@skynet.beActa Radiologica Open5(8) 1–2! The Foundation Acta Radiologica2016Reprints and permissions:sagepub.co.uk/journalsPermissions.navDOI: 10.1177/2058460116653630arr.sagepub.comCreative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided theoriginal work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).the VRSs may dilate due to fluid retention (7).Interestingly, dilated VRSs are a known histological fea-ture of cerebral small vessel disease and can be demon-strated on magnetic resonance imaging (8).Since the ON is a direct extension of the brain, thequestion is whether there is also evidence for the exist-ence of a paravascular transport system in the ON. Theobservation of such an anatomically distinct clearingsystem in the ON could also provide new insights intothe pathogenesis of glaucoma. Indeed, if confirmed,one might expect that a dysfunctional glymphaticsystem could ultimately result in reduced neurotoxinclearance in the ON and lead to glaucomatous neuro-degeneration (4).Many studies have demonstrated vascular-relatedrisk factors for glaucoma. Atherosclerotic cerebrovas-cular disease is a risk factor for glaucomatous opticneuropathy, and both systemic hypertension and sys-temic arterial stiffness have been reported to be asso-ciated with primary open-angle glaucoma (POAG)(9,10). Given that impairment of the arterial pulsa-tion-driven ‘‘perivascular pump’’ may lead to CSFflux disturbance, and given that distension of theVRSs may be related to the fluid retention in andalong the paravascular circulation (7), we postulatethat dilated VRSs could occur in POAG in associationwith arterial stiffening or loss of arterial pulsatility.Interestingly, in accordance with this view, a veryrecent study showed significantly higher deep whitematter lesion load and increased numbers of dilatedVRSs in association with POAG suggesting the pres-ence of significant cerebral small vessel disease (8). Ifdilation of VRSs may result from a disturbed interplaybetween the vascular and glymphatic system, thenpreventing arterial stiffness may protect against glau-coma, at least in part, by promoting solute clearancevia the CSF.Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest withrespect to the research, authorship, and/or publication of thisarticle.FundingThe author(s) received no financial support for the research,authorship, and/or publication of this article.References1. Promelle V, Daouk J, Bouzerar R, et al. Ocular bloodflow and cerebrospinal fluid pressure in glaucoma. ActaRadiol Open 2016;5:2058460115624275.2. Berdahl JP, Allingham RR. Intracranial pressure andglaucoma. Curr Opin Ophthalmol 2010;21:106–111.3. Killer HE, Miller NR, Flammer J, et al. Cerebrospinalfluid exchange in the optic nerve in normal-tension glau-coma. Br J Ophthalmol 2012;96:544–548.4. Wostyn P, Van Dam D, Audenaert K, et al. A new glau-coma hypothesis: a role of glymphatic system dysfunc-tion. Fluids Barriers CNS 2015;12:16.5. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathwayfacilitates CSF flow through the brain parenchyma andthe clearance of interstitial solutes, including amyloid b.Sci Transl Med 2012;4:147ra111.6. Iliff JJ, Wang M, Zeppenfeld DM, et al. Cerebral arterialpulsation drives paravascular CSF-interstitial fluidexchange in the murine brain. J Neurosci 2013;33:18190–18199.7. Gallina P, Scollato A, Conti R, et al. Ab Clearance,‘‘hub’’ of multiple deficiencies leading to Alzheimer dis-ease. Front Aging Neurosci 2015;7:200.8. Mercieca K, Cain J, Hansen T, et al. Primary open angleglaucoma is associated with MR biomarkers of cerebralsmall vessel disease. Sci Rep 2016;6:22160.9. Nakazawa T. Ocular blood flow and influencing factorsfor glaucoma. Asia Pac J Ophthalmol (Phila) 2016;5:38–44.10. Shim SH, Kim CY, Kim JM, et al. The role of systemicarterial stiffness in open-angle glaucoma with diabetesmellitus. Biomed Res Int 2015;2015:425835.2 Acta Radiologica Open 5(8)

University of GroningenDilated Virchow-Robin spaces in primary open-angle glaucomaWostyn, Peter; De Groot, Veva; Van Dam, Debby; Audenaert, Kurt; Killer, Hanspeter Esriel;De Deyn, Peter PaulPublished in:Acta radiologica openDOI:10.1177/2058460116653630IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2016Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Wostyn, P., De Groot, V., Van Dam, D., Audenaert, K., Killer, H. E., & De Deyn, P. P. (2016). DilatedVirchow-Robin spaces in primary open-angle glaucoma: a biomarker of glymphatic waste clearancedysfunction? Acta radiologica open, 5(8). https://doi.org/10.1177/2058460116653630CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 24-12-2025Case ReportDilated Virchow-Robin spaces in primaryopen-angle glaucoma: a biomarker ofglymphatic waste clearance dysfunction?Peter Wostyn1, Veva De Groot2, Debby Van Dam3,4,Kurt Audenaert5, Hanspeter Esriel Killer6and Peter Paul De Deyn3,4,7We read with great interest the article entitled ‘‘Ocularblood flow and cerebrospinal fluid pressure in glau-coma’’ by Promelle et al. (1). The authors review themost recent research on alterations in ocular blood flowand/or cerebrospinal fluid (CSF) flow in glaucoma.They state that blood–CSF flow interactions may beinvolved in glaucoma, and also note that ‘‘the CSF’sbehavior is supposedly linked to blood pulsatility.’’ Wefully agree with this notion, as we believe that the vas-cular system could play a role in the pathogenesis ofglaucoma through a mechanical interplay with the CSFcirculation.The subarachnoid space (SAS) of the optic nerve(ON) is contiguous with the SAS of the brain in anormal population. Growing evidence in the literatureprovides strong support for the concept that CSF pres-sure and composition in the SAS surrounding the ONmay have fundamental significance in the pathogenesisof glaucoma (2,3). As an extension of the brain, the ONdisplays remarkable similarities to the brain in terms ofanatomy and functionality (4). Knowledge obtainedfrom brain research could therefore lead to new insightsinto the ON and vice versa. Recently, the ‘‘glymphaticsystem’’ of the brain has been discovered in rodents byIliff et al. (5). The authors argued that this system wascritical to the efficient clearance of interstitial solutes,including amyloid-b, from the brain (5). Their findingssuggested a brain-wide paravascular pathway in whichCSF flows from the SAS along the arteries and arteri-oles into the paravascular Virchow-Robin spaces(VRSs) to exchange with interstitial fluid (ISF), andISF is cleared from the brain into the VRSs surround-ing the exiting veins. As ISF exits the brain through theparavenous route, it travels to the lymphatic vesselsin the neck, and eventually returns its contents to thesystemic circulation.Paravascular CSF recirculation and ISF solute clear-ance is dependent upon water transport via astroglialaquaporin-4 water channels, which are localized toperivascular astrocytic endfeet ensheathing the cerebralvasculature (5). Importantly, there is also evidencedemonstrating that there is a mechanical interplaybetween the intracranial vascular system and the glym-phatic system. Indeed, a recent study demonstrated thatcerebral arterial pulsatility is a key driver of paravas-cular CSF influx and subsequent CSF-ISF exchange inthe brain (6). Loss of elasticity in aging cerebral arterieswith progressive atherosclerosis, or cessation of pulsa-tions, might contribute to failure of the clearance ofinterstitial waste, including amyloid-b, from the brain,and might play a role in the pathogenesis ofAlzheimer’s disease (6).The above findings indicate that the VRSs have animportant role in the homeostasis of cerebral fluids inthe central nervous system (7), and suggest a possiblecorrelation between VRS enlargement and a disturbanceof CSF dynamics. Indeed, if CSF outflow is reduced as aconsequence of either CSF flow obstruction or cerebralartery pulsatility inefficiency, or cerebrospinal venousinsufficiency and lymphatic disorders, local perivascularCSF recirculation may be impaired and, consequently,1Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium2Department of Ophthalmology, Antwerp University Hospital, Antwerp,Belgium3Laboratory of Neurochemistry and Behavior, Institute Born-Bunge,University of Antwerp, Department of Biomedical Sciences, Antwerp,Belgium4Department of Neurology and Alzheimer Research Center, Universityof Groningen and University Medical Center Groningen, Groningen,The Netherlands5Department of Psychiatry, Ghent University Hospital, Ghent, Belgium6Department of Ophthalmology, Kantonsspital Aarau, Aarau, Switzerland7Department of Neurology and Memory Clinic, Middelheim GeneralHospital (ZNA), Antwerp, BelgiumCorresponding author:Peter Wostyn, Department of Psychiatry, PC Sint-Amandus,Reigerlostraat 10, 8730 Beernem, Belgium.Email: wostyn.peter@skynet.beActa Radiologica Open5(8) 1–2! The Foundation Acta Radiologica2016Reprints and permissions:sagepub.co.uk/journalsPermissions.navDOI: 10.1177/2058460116653630arr.sagepub.comCreative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided theoriginal work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).the VRSs may dilate due to fluid retention (7).Interestingly, dilated VRSs are a known histological fea-ture of cerebral small vessel disease and can be demon-strated on magnetic resonance imaging (8).Since the ON is a direct extension of the brain, thequestion is whether there is also evidence for the exist-ence of a paravascular transport system in the ON. Theobservation of such an anatomically distinct clearingsystem in the ON could also provide new insights intothe pathogenesis of glaucoma. Indeed, if confirmed,one might expect that a dysfunctional glymphaticsystem could ultimately result in reduced neurotoxinclearance in the ON and lead to glaucomatous neuro-degeneration (4).Many studies have demonstrated vascular-relatedrisk factors for glaucoma. Atherosclerotic cerebrovas-cular disease is a risk factor for glaucomatous opticneuropathy, and both systemic hypertension and sys-temic arterial stiffness have been reported to be asso-ciated with primary open-angle glaucoma (POAG)(9,10). Given that impairment of the arterial pulsa-tion-driven ‘‘perivascular pump’’ may lead to CSFflux disturbance, and given that distension of theVRSs may be related to the fluid retention in andalong the paravascular circulation (7), we postulatethat dilated VRSs could occur in POAG in associationwith arterial stiffening or loss of arterial pulsatility.Interestingly, in accordance with this view, a veryrecent study showed significantly higher deep whitematter lesion load and increased numbers of dilatedVRSs in association with POAG suggesting the pres-ence of significant cerebral small vessel disease (8). Ifdilation of VRSs may result from a disturbed interplaybetween the vascular and glymphatic system, thenpreventing arterial stiffness may protect against glau-coma, at least in part, by promoting solute clearancevia the CSF.Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest withrespect to the research, authorship, and/or publication of thisarticle.FundingThe author(s) received no financial support for the research,authorship, and/or publication of this article.References1. Promelle V, Daouk J, Bouzerar R, et al. Ocular bloodflow and cerebrospinal fluid pressure in glaucoma. ActaRadiol Open 2016;5:2058460115624275.2. Berdahl JP, Allingham RR. Intracranial pressure andglaucoma. Curr Opin Ophthalmol 2010;21:106–111.3. Killer HE, Miller NR, Flammer J, et al. Cerebrospinalfluid exchange in the optic nerve in normal-tension glau-coma. Br J Ophthalmol 2012;96:544–548.4. Wostyn P, Van Dam D, Audenaert K, et al. A new glau-coma hypothesis: a role of glymphatic system dysfunc-tion. Fluids Barriers CNS 2015;12:16.5. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathwayfacilitates CSF flow through the brain parenchyma andthe clearance of interstitial solutes, including amyloid b.Sci Transl Med 2012;4:147ra111.6. Iliff JJ, Wang M, Zeppenfeld DM, et al. Cerebral arterialpulsation drives paravascular CSF-interstitial fluidexchange in the murine brain. J Neurosci 2013;33:18190–18199.7. Gallina P, Scollato A, Conti R, et al. Ab Clearance,‘‘hub’’ of multiple deficiencies leading to Alzheimer dis-ease. Front Aging Neurosci 2015;7:200.8. Mercieca K, Cain J, Hansen T, et al. Primary open angleglaucoma is associated with MR biomarkers of cerebralsmall vessel disease. Sci Rep 2016;6:22160.9. Nakazawa T. Ocular blood flow and influencing factorsfor glaucoma. Asia Pac J Ophthalmol (Phila) 2016;5:38–44.10. Shim SH, Kim CY, Kim JM, et al. The role of systemicarterial stiffness in open-angle glaucoma with diabetesmellitus. Biomed Res Int 2015;2015:425835.2 Acta Radiologica Open 5(8)

Ghent University Academic Bibliography

Case ReportDilated Virchow-Robin spaces in primaryopen-angle glaucoma: a biomarker ofglymphatic waste clearance dysfunction?Peter Wostyn1, Veva De Groot2, Debby Van Dam3,4,Kurt Audenaert5, Hanspeter Esriel Killer6and Peter Paul De Deyn3,4,7We read with great interest the article entitled ‘‘Ocularblood ﬂow and cerebrospinal ﬂuid pressure in glau-coma’’ by Promelle et al. (1). The authors review themost recent research on alterations in ocular blood ﬂowand/or cerebrospinal ﬂuid (CSF) ﬂow in glaucoma.They state that blood–CSF ﬂow interactions may beinvolved in glaucoma, and also note that ‘‘the CSF’sbehavior is supposedly linked to blood pulsatility.’’ Wefully agree with this notion, as we believe that the vas-cular system could play a role in the pathogenesis ofglaucoma through a mechanical interplay with the CSFcirculation.The subarachnoid space (SAS) of the optic nerve(ON) is contiguous with the SAS of the brain in anormal population. Growing evidence in the literatureprovides strong support for the concept that CSF pres-sure and composition in the SAS surrounding the ONmay have fundamental signiﬁcance in the pathogenesisof glaucoma (2,3). As an extension of the brain, the ONdisplays remarkable similarities to the brain in terms ofanatomy and functionality (4). Knowledge obtainedfrom brain research could therefore lead to new insightsinto the ON and vice versa. Recently, the ‘‘glymphaticsystem’’ of the brain has been discovered in rodents byIliﬀ et al. (5). The authors argued that this system wascritical to the eﬃcient clearance of interstitial solutes,including amyloid-b, from the brain (5). Their ﬁndingssuggested a brain-wide paravascular pathway in whichCSF ﬂows from the SAS along the arteries and arteri-oles into the paravascular Virchow-Robin spaces(VRSs) to exchange with interstitial ﬂuid (ISF), andISF is cleared from the brain into the VRSs surround-ing the exiting veins. As ISF exits the brain through theparavenous route, it travels to the lymphatic vesselsin the neck, and eventually returns its contents to thesystemic circulation.Paravascular CSF recirculation and ISF solute clear-ance is dependent upon water transport via astroglialaquaporin-4 water channels, which are localized toperivascular astrocytic endfeet ensheathing the cerebralvasculature (5). Importantly, there is also evidencedemonstrating that there is a mechanical interplaybetween the intracranial vascular system and the glym-phatic system. Indeed, a recent study demonstrated thatcerebral arterial pulsatility is a key driver of paravas-cular CSF inﬂux and subsequent CSF-ISF exchange inthe brain (6). Loss of elasticity in aging cerebral arterieswith progressive atherosclerosis, or cessation of pulsa-tions, might contribute to failure of the clearance ofinterstitial waste, including amyloid-b, from the brain,and might play a role in the pathogenesis ofAlzheimer’s disease (6).The above ﬁndings indicate that the VRSs have animportant role in the homeostasis of cerebral ﬂuids inthe central nervous system (7), and suggest a possiblecorrelation between VRS enlargement and a disturbanceof CSF dynamics. Indeed, if CSF outﬂow is reduced as aconsequence of either CSF ﬂow obstruction or cerebralartery pulsatility ineﬃciency, or cerebrospinal venousinsuﬃciency and lymphatic disorders, local perivascularCSF recirculation may be impaired and, consequently,1Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium2Department of Ophthalmology, Antwerp University Hospital, Antwerp,Belgium3Laboratory of Neurochemistry and Behavior, Institute Born-Bunge,University of Antwerp, Department of Biomedical Sciences, Antwerp,Belgium4Department of Neurology and Alzheimer Research Center, Universityof Groningen and University Medical Center Groningen, Groningen,The Netherlands5Department of Psychiatry, Ghent University Hospital, Ghent, Belgium6Department of Ophthalmology, Kantonsspital Aarau, Aarau, Switzerland7Department of Neurology and Memory Clinic, Middelheim GeneralHospital (ZNA), Antwerp, BelgiumCorresponding author:Peter Wostyn, Department of Psychiatry, PC Sint-Amandus,Reigerlostraat 10, 8730 Beernem, Belgium.Email: wostyn.peter@skynet.beActa Radiologica Open5(8) 1–2! The Foundation Acta Radiologica2016Reprints and permissions:sagepub.co.uk/journalsPermissions.navDOI: 10.1177/2058460116653630arr.sagepub.comCreative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided theoriginal work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).the VRSs may dilate due to ﬂuid retention (7).Interestingly, dilated VRSs are a known histological fea-ture of cerebral small vessel disease and can be demon-strated on magnetic resonance imaging (8).Since the ON is a direct extension of the brain, thequestion is whether there is also evidence for the exist-ence of a paravascular transport system in the ON. Theobservation of such an anatomically distinct clearingsystem in the ON could also provide new insights intothe pathogenesis of glaucoma. Indeed, if conﬁrmed,one might expect that a dysfunctional glymphaticsystem could ultimately result in reduced neurotoxinclearance in the ON and lead to glaucomatous neuro-degeneration (4).Many studies have demonstrated vascular-relatedrisk factors for glaucoma. Atherosclerotic cerebrovas-cular disease is a risk factor for glaucomatous opticneuropathy, and both systemic hypertension and sys-temic arterial stiﬀness have been reported to be asso-ciated with primary open-angle glaucoma (POAG)(9,10). Given that impairment of the arterial pulsa-tion-driven ‘‘perivascular pump’’ may lead to CSFﬂux disturbance, and given that distension of theVRSs may be related to the ﬂuid retention in andalong the paravascular circulation (7), we postulatethat dilated VRSs could occur in POAG in associationwith arterial stiﬀening or loss of arterial pulsatility.Interestingly, in accordance with this view, a veryrecent study showed signiﬁcantly higher deep whitematter lesion load and increased numbers of dilatedVRSs in association with POAG suggesting the pres-ence of signiﬁcant cerebral small vessel disease (8). Ifdilation of VRSs may result from a disturbed interplaybetween the vascular and glymphatic system, thenpreventing arterial stiﬀness may protect against glau-coma, at least in part, by promoting solute clearancevia the CSF.Declaration of conflicting interestsThe author(s) declared no potential conﬂicts of interest withrespect to the research, authorship, and/or publication of thisarticle.FundingThe author(s) received no ﬁnancial support for the research,authorship, and/or publication of this article.References1. Promelle V, Daouk J, Bouzerar R, et al. Ocular bloodflow and cerebrospinal fluid pressure in glaucoma. ActaRadiol Open 2016;5:2058460115624275.2. Berdahl JP, Allingham RR. Intracranial pressure andglaucoma. Curr Opin Ophthalmol 2010;21:106–111.3. Killer HE, Miller NR, Flammer J, et al. Cerebrospinalfluid exchange in the optic nerve in normal-tension glau-coma. Br J Ophthalmol 2012;96:544–548.4. Wostyn P, Van Dam D, Audenaert K, et al. A new glau-coma hypothesis: a role of glymphatic system dysfunc-tion. Fluids Barriers CNS 2015;12:16.5. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathwayfacilitates CSF flow through the brain parenchyma andthe clearance of interstitial solutes, including amyloid b.Sci Transl Med 2012;4:147ra111.6. Iliff JJ, Wang M, Zeppenfeld DM, et al. Cerebral arterialpulsation drives paravascular CSF-interstitial fluidexchange in the murine brain. J Neurosci 2013;33:18190–18199.7. Gallina P, Scollato A, Conti R, et al. Ab Clearance,‘‘hub’’ of multiple deficiencies leading to Alzheimer dis-ease. Front Aging Neurosci 2015;7:200.8. Mercieca K, Cain J, Hansen T, et al. Primary open angleglaucoma is associated with MR biomarkers of cerebralsmall vessel disease. Sci Rep 2016;6:22160.9. Nakazawa T. Ocular blood flow and influencing factorsfor glaucoma. Asia Pac J Ophthalmol (Phila) 2016;5:38–44.10. Shim SH, Kim CY, Kim JM, et al. The role of systemicarterial stiffness in open-angle glaucoma with diabetesmellitus. Biomed Res Int 2015;2015:425835.2 Acta Radiologica Open 5(8)

Dilated Virchow-Robin spaces in primary open-angle glaucoma : a biomarker of glymphatic waste clearance dysfunction?

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