Hrev_master
Veins and Lymphatics 2017; volume 6:6976
[Veins and Lymphatics 2017; 6:6976] [page 91]
Global and regional brain
atrophy is associated with
low or retrograde facial
vein flow in multiple sclerosis
Dejan Jakimovski,1 Karen Marr,1
Marcello Mancini,2
Maria Grazia Caprio,2 Sirin Gandhi,1
Niels Bergsland,1 Ivo Paunkoski,1
Jesper Hagemeier,1 Avinash Chandra,1
Bianca Weinstock-Guttman,3
Robert Zivadinov1,4
1Buffalo Neuroimaging Analysis Center,
Department of Neurology, Jacobs School
of Medicine and Biomedical Sciences,
University of Buffalo, State University of
New York, NY, USA; 2Institute of
Biostructure and Bioimaging, National
Research Council, Napoli, Italy; 3Jacobs
Multiple Sclerosis Center, Department
of Neurology, School of Medicine and
Biomedical Sciences, University at
Buffalo, State University of New York,
Buffalo, NY, USA; 4Translational
Imaging Center at Clinical Translational
Science Institute, University of Buffalo,
State University of New York, NY, USA
Abstract
Increased collateral facial vein (FV)
flow may be associated with structural dam-
age in patients with multiple sclerosis (MS).
The objective was to assess differences in
FV flow and magnetic resonance imaging
(MRI)-derived outcomes in MS. The study
included 136 MS patients who underwent
neck and head vascular system examination
by echo-color Doppler. Inflammatory MRI
markers were assessed on a 3T MRI using a
semi-automated edge detection and con-
touring/thresholding technique. MRI volu-
metric outcomes of whole brain (WB), gray
matter (GM), white matter (WM), cortex,
ventricular cerebrospinal fluid (vCSF),
deep gray matter (DGM), thalamus, caudate
nucleus (CN), putamen, globus pallidus
(GP), and hippocampus were calculated.
Independent t-test and ANCOVA, adjusted
for age, were used to compare groups based
on FV flow quartiles. Thirty-four MS
patients with FV flow ≤327.8 mL/min (low-
est quartile) had significantly lower WB
(P<0.001), WM (P<0.001), thalamus
(P=0.004), cortex (P=0.004), GM
(P=0.004), DGM (P=0.008), hippocampus
(P=0.005), and GP volumes (P=0.044) com-
pared to 102 patients with FV flow of
>327.8 mL/min (higher quartiles). There
were no differences in T1-, T2- and gadolin-
ium-enhancing lesion volumes between the
quartile groups.
The lack of an association between FV
blood flow and inflammatory MRI meas-
ures in MS patients, but an association with
brain atrophy, suggests that the severity of
neurodegenerative process may be related
to hemodynamic alterations. MS patients
with more advanced global and regional
brain atrophy showed low or retrograde FV
volume flow.
Introduction
Multiple sclerosis (MS) is a chronic
autoimmune-mediated demyelinating disor-
der of the central nervous system (CNS).
However, a neurodegenerative component
is being increasingly recognized as an
important contributor to the disease patho-
physiology. Global and regional brain atro-
phy in MS has been strongly associated
with both physical and cognitive decline.1
An emerging vascular hypothesis has
sparked intense research regarding the
anatomy and physiology of the vascular
system in association with the disease
pathophysiology.2 A variety of invasive and
non-invasive imaging modalities have been
used to describe changes in the venous sys-
tem.3 Despite the advantages and disadvan-
tages of each technique, color Doppler
ultrasound allows real-time, dynamic exam-
ination of both the structural and hemody-
namic properties of the venous system and
remains a valuable diagnostic test.4 The
internal jugular vein (IJV) is the main
venous drainage pathway for the brain in
the supine position, whereas in the upright
position, IJVs collapse and the flow shifts to
the vertebral veins (VV) and the vertebral
venous plexus.5 Additional recruitment of
further collateral vessels would alleviate the
possible flow disruption within the main
drainage pathways.
Along these lines, several magnetic res-
onance imaging (MRI) studies showed that
MS patients have increased collateralization
when compared to healthy controls (HC).6-8
From increased frequency of posterior
paraspinal collaterals,9 to trends of greater
occurrence in non-IJV collaterals,6 MS
patients exhibit changes of the extracranial
vascular system that are not fully under-
stood. Moreover, a recent hemodynamic
MRI study that enrolled 276 MS patients
and 106 HCs demonstrated that the MS sub-
jects had decreased flow within the IJVs
and increased flow in paraspinal collateral
veins.7 The possible obstruction in flow
within the major draining pathways can
cause substantial re-direction of flow
toward the anterior/external jugular veins,
facial vein (FV), thyroid veins and the ver-
tebral system. The FV is formed by union of
the anterior FV and the anterior branch of
the posterior FV. Inferiorly, the FV empties
into the IJV and drains the blood from areas
that largely correspond to the arterial terri-
tory of the external carotid artery.
Additionally, the cavernous sinus represents
an anatomical site of communication
between the major venous outflow (IJV)
and the FV, and therefore, can facilitate
compensatory venous redistribution.
Furthermore, it was shown that presence of
valves in the facial and ophthalmic veins
can regulate bidirectional flow opposing
gravitational flow.10 The distribution of
valves causes the blood flow from the
orbital veins to be directed caudally towards
the FV and the IJV. Confirming these
assumptions, an additional anatomy-based
lumped parameter model of the venous cir-
culation has also shown that any increase in
resistance of the main venous drainage can
cause retrograde flow changes within the
cavernous, inferior, and superior petrosal
sinuses.11 Similarly, a recent interventional
study showed that by restoring the main
drainage pathway, the collateral flow
decreased from 70% to 30%.12 More impor-
tantly, there was a 13-fold reduction in ven-
tricular size associated with decrease of col-
lateral flow lower than 20%.12 Additionally,
it was shown that the presence of venous
abnormalities is associated with decreased
perfusion in the gray matter (GM), the
white matter (WM) and changes in cere-
brospinal fluid dynamics.13,14
Against this background, we hypothe-
Correspondence: Robert Zivadinov, Center for
Biomedical Imaging at Clinical Translational
Science Institute, Buffalo Neuroimaging
Analysis Center, Jacobs School of Medicine
and Biomedical Sciences, University at
Buffalo, State University of New York, 100
High Street, Buffalo, NY 14203, USA.
Tel.: +1.716.859.7040 - Fax: +1.716.859.7066.
E-mail: rzivadinov@bnac.net
Key words: Facial vein; brain atrophy; multi-
ple sclerosis; Doppler sonography.
Received for publication: 4 August 2017.
Revision received: 8 September 2017.
Accepted for publication: 11 September 2017.
This work is licensed under a Creative
Commons Attribution 4.0 License (by-nc 4.0).
©Copyright D. Jakimovski et al., 2017
Licensee PAGEPress, Italy
Veins and Lymphatics 2017; 6:6976
doi:10.4081/vl.2017.6976
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[page 92] [Veins and Lymphatics 2017; 6:6976]
sized that changes in the venous flow of the
extra-cranial neck vessels may be associat-
ed with worse clinical and MRI-derived
measures in patients with MS. The ability to
examine associations between collateral
venous flow patterns like the FV and brain
inflammatory and neurodegenerative MRI
measures may advance the understanding of
the vascular pathology in MS.
Materials and methods
Subjects
This study utilized data from an ongo-
ing prospective case-control cardiovascular,
environmental and genetic (CEG) study.15
The study was approved by the local
Institutional Review Board (IRB) and all
subjects signed a written informed consent.
The inclusion criteria for this sub-study
were: i) age range of 18-75 years old; ii)
MRI and Doppler examination performed
within 30 days of the neurological visit; iii)
having an MS diagnosis as defined by the
2010 revised McDonald criteria.16 Based on
their disease course, the MS patients were
classified as relapsing-remitting MS
(RRMS) or secondary-progressive MS
(SPMS). Exclusion criteria for this study
consisted of presence of clinical relapse or
steroid treatment within 30 days of the MRI
scan, or being a nursing mother or pregnant
woman. Therefore, any differences within
the presence of gadolinium-enhancing
lesions is not representative and rendered to
only asymptomatic appearance. All subjects
underwent echo-color Doppler, MRI and
full clinical examination. Standard demo-
graphic and clinical information was col-
lected, along with assessing Expanded
Disability Status Scale (EDSS) by an expe-
rienced neurologist.
MRI acquisition and analysis
All brain scans were acquired on a 3T
GE Signa Excite HD 12.0 Twin Speed 8-
channel scanner (General Electric,
Milwaukee, WI, USA) using an 8-channel
head and neck (HDNV) coil. There were no
MRI hardware or software changes during
the study. Acquired MRI sequences includ-
ed axial 3D-spoiled-gradient recalled
(SPGR) T1 weighted image (WI), dual fast
spin-echo (FSE) T2/proton density (PD)
WI, 2D fluid attenuated inversion recovery
(FLAIR) and post contrast spin-echo (SE)
T1-WI 5 minutes after single 0.1 mmol/kg
gadobutrol injection. The slice thickness
was 1 mm for 3D sequences and 3 mm for
2D sequences. The MRI acquisition proto-
col was previously described.17
MRI-derived inflammatory measures
(T1, T2 and gadolinium-enhancing lesion
volume) were obtained using a semi-auto-
mated edge detection and contouring/
thresholding technique.18 For calculation of
whole brain (WB), GM, WM, ventricular
cerebrospinal fluid (vCSF), and cortex nor-
malized volumes, SIENAX cross-sectional
software tool was used (version 2.6).19 Prior
to SIENAX, lesions were filled to reduce
the impact of T1 hypointensities. Regional
tissue-specific normalized volumes of the
thalamus, caudate nucleus (CN), putamen,
globus pallidus (GP), hippocampus, and
amygdala were derived with FMRIB’s
Integrated Registration and Segmentation
Tool (FIRST).
Doppler sonography assessment
Echo-color Doppler (ECD Esaote -
Biosound My Lab 25 Gold) equipped with
2.5 and 7.5-10 MHz transducers (Genoa,
Italy) was used for extra cranial examina-
tion. For the purpose of examining the IJV,
the 7.5 MHz linear probe was used. The
subjects were instructed not to reveal their
disease status during the procedure.
Additional draping from the neck down was
applied in order to further eliminate visual
cues of disease. Each subject was evaluated
by the same blinded technologist (more
than 25 years of experience). The blood
flow of both IJVs was assessed. Section
above and below the entry of the FV into
IJV and levels were used as measurement
points for IJV respectively. The flow was
calculated by multiplying the time average
velocity (VMT) over 4 seconds time phase
and vein manually drawn CSA on axial
view. The VMT has been carefully calculated
using manual correction of the Doppler
angle, whereas the manually drawn CSA
was performed on color Doppler settings.
VMT= ΣVi*∆T (1)
Flow=VMT* CSA (2)
FV flow was calculated as the differ-
ence of the IJV flow measured below and
above the entrance of FV. Figure 1 shows
the sites of measurements with the FV into
the field of view. The step-wise methodolo-
gy is shown in Figure 2. The final variable
used for further analysis was derived by
summation of the blood flow measured
within both the left and right side and from
hereafter mentioned as FV blood flow. If the
blood flow measured above the entry of the
FV was higher than the flow measured
below the entry, the FV blood flow was
labeled as retrograde one.
Statistical analysis
Statistical analyses were performed
using SPSS 24.0 (IBM, Armonk, NY, USA).
Demographic and clinical characteristics
were compared by using χ2 cross tabulation
with Yates’ correction, Mann-Whitney-
Wilcoxon test, and Student’s t-test, as appro-
priate. In order to determine the difference in
MRI-derived inflammatory and neurodegen-
erative measures between groups, Student’s
t-test was used. Moreover, analysis of covari-
ance (ANCOVA), where FV status was con-
sidered a fixed factor, patients’ age was con-
sidered a covariance factor, and MRI-derived
measures the dependent measure, was per-
formed in order to assess the FV status influ-
ence on the MRI-derived measures, control-
ling for possible aging-related effects. Both
Kolmogorov-Smirnov and Shapiro-Wilk
tests were used to determine normality of all
variables used. Additionally, Q-Q plots were
used for visual inspection of the possible data
skewness. Four measures (vCSF, DGM, thal-
amus and GP) were not normally distributed;
therefore, normalization by logarithmic
transformation was performed. For all statis-
tical results, P<0.05 based on two-tailed tests
was considered significant.
Figure 1. Illustration of the determination of the entrance of the facial vein into the IJV.
Sites of measurements above and below the entry were consequently selected. FV, facial
vein; IJV, internal jugular vein; AFV, above facial vein; BFV, below facial vein; CCA, com-
mon carotid artery.
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Results
Demographic, clinical, and Doppler
characteristics
The demographic, clinical, and Doppler
characteristics of all MS patients (n=136)
are summarized in Table 1. The Doppler
characteristics of the FV blood flow ranged
from –339.7 mL/min to 2229.6 mL/min.
Only 8 MS patients had negative FV blood
flow. The mean FV flow was 707.0 mL/min
and the quartiles were 327.8 mL/min, 651.9
mL/min and, 985.0 mL/min (25th, 50th, and,
75th, respectively). Additionally, the initial
IJV Doppler measurements used for the cal-
culation (TAV, CSA, and flow) are also pre-
sented in Table 1. Based on the lowest quar-
tile of FV blood flow (327.8 mL/min), the
subjects were grouped into higher quartiles
and the lowest quartile of FV blood flow
(102 vs 34 MS patients, respectively) and
hereafter mention as FV status. The higher
quartiles group of MS patients, had a mean
age of 52.7 years old, a disease duration of
19.6 years, a median disability level of 3.0
EDSS score, and 70 of the patients had the
RR form of MS. On the other hand, patients
with the lowest quartile of FV blood flow
were on average 55.5 years old, had a dis-
ease duration of 21.8 years, and had a dis-
ability median level based on EDSS scoring
of 4.5. The lowest quartile group consisted
of proportionally more SPMS patients than
the higher quartile MS counterparts
(P=0.05). There were no significant differ-
ences in female to male ratio between the
groups (P=0.13). No significant differences
between the two MS groups were observed
for age (P=0.202), disease duration
(P=0.306), EDSS (P=0.066), and the type of
disease modifying therapies used
(P=0.891).
Facial vein blood flow and MRI-derived
outcomes
All MRI-derived outcome measures and
Table 1. Demographic and clinical characteristics of the multiple sclerosis cohort.
Demographic and clinical characteristics MS cohort (n=136) Higher quartiles (n=102) Lowest quartile (n=34) P value
Female, n (%) 100 (73.5) 72 (70.6) 28 (82.4) 0.13
Age in yrs, mean (SD) 53.4 (10.9) 52.7 (10.7) 55.5 (11.5) 0.202
Disease duration in yrs, mean (SD) 20.2 (10.6) 19.6 (10.3) 21.8 (11.4) 0.306
Disease course 0.050
RR, n (%) 87 (63.9) 70 (68.6) 17 (50.0)
SP, n (%) 49 (36.1) 32 (31.4) 17 (50.0)
EDSS, median (IQR) 3.0 (4.0) 3.0 (2.5) 4.5 (4.5) 0.066
Treatment status
IM IFN-beta-1a 30 (22.1) 21 (20.6) 9 (26.5) 0.891
SC IFN-beta-1a 10 (7.6) 7 (6.9) 3 (8.8)
Natalizumab 5 (3.7) 3 (2.9) 2 (5.9)
Glatiramer acetate 38 (27.9) 30 (29.4) 8 (23.5)
Other DMT 24 (17.6) 21 (20.6) 3 (8.8)
No DMT 27 (19.9)* 18 (16.7)* 9 (26.5)
Facial vein blood flow (mL/min) 707.0 (511.8) 909.3 (413.9) 100.2 (203.5) <0.001
AFV TAV (cm/sec) 20.5 (8.7) 20.5 (8.4) 20.5 (9.5) 0.987
AFV CSA (mm2) 36.3 (17.6) 35.6 (16.9) 38.4 (19.6) 0.433
AFV Flow (mL/min) 874.8 (438.4) 849.4 (413.5) 951.2 (505.1) 0.243
BFV TAV (cm/sec) 20.1 (7.5) 21.1 (7.3) 17.1 (7.3) 0.006
BFV CSA (mm2) 67.6 (29.6) 72.6 (28.3) 52.4 (28.6) <0.001
BFV Flow (mL/min) 1581.9 (621.6) 1758.7 (548.9) 1051.4 (521.8) <0.001
MS, multiple sclerosis; SD, standard deviation; RR, relapsing remitting; SP, secondary progressive; EDSS, Expanded Disability Status Scale; AFV, above the entry of the facial vein; BFV, below the entry of the facial vein;
TAV, time-averaged velocity; CSA, cross-sectional area; IQR, interquartile range; IM, intramuscular; SC, subcutaneous; IFN, interferon; DMT, disease modifying therapy. *0- DMT data was missing for 2 patients. χ2 - test,
Student’s t-test and Mann-Whitney test were used accordingly. Alpha level of 0.05 was considered as significant, and is shown in italics.
Figure 2. Illustration of the methodology used to measure the facial vein blood flow. IJV,
internal jugular vein; AFV, above facial vein; BFV, below facial vein; 1, cross-sectional area
measurement for above the facial vein segment of internal jugular vein; 2, cross-sectional
area measurement for the below facial vein segment below the facial vein; 3, time-average
velocity measurement for above the facial vein segment of internal jugular vein; 4, time-
average velocity measurement for below the facial vein segment of the internal jugular vein.
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differences between groups are summarized
in Table 2. Additionally, the differences in
volumes are graphically represented in
Figure 3. The lowest quartile of FV blood
flow group had significantly lower global
and regional brain volumes compared to
MS patients within the higher quartiles. In
particular, they had significantly lower WB
volume (P<0.001), WM volume (P<0.001),
GM volume (P=0.004), cortical volume
(P=0.004), and a trend for higher vCSF vol-
ume (P=0.051). Similarly, they had lower
total deep GM volume (P=0.008), thalamic
(P=0.003), GP (P=0.027), and hippocampal
(P=0.005) volumes. All findings were con-
firmed with ANCOVA analyses controlling
for age. Even though several deep gray mat-
ter structures did not reach statistical signif-
icance, their volumes were smaller in the
group within the lowest quartile.
There were no statistical differences
between the lowest and the higher quartiles
of FV blood flow regarding inflammatory
outcome measures, such as T2 hyperintense
lesion, gadolinium-enhancing, or T1-
hypointense lesion volumes.
Independently, we conducted a similar
statistical analysis on both disease sub-
groups. The differences in inflammatory
and neurodegenerative MRI-derived meas-
ures within the RRMS and SPMS patients
are shown in Table 3. Although in lesser
effect than compared with a whole sample,
the differences in brain atrophy still persist-
ed. In both the RRMS and SPMS sub-
groups, the patients with the lowest quartile
of FV blood flow had smaller WBV and
WMV (P=0.01, P=0.012 for RRMS, and
P=0.014, P=0.012 for SPMS, respectively).
Table 3. Differences based on facial vein status in MRI-derived global and regional brain volumes in individually relapsing-remitting
and secondary-progressive MS patients.
MRI characteristics RRMS P value ANCOVA SPMS P value ANCOVA
Higher Lowest age- Higher Lowest age-
quartiles quartile adjusted quartiles quartile adjusted
(n=70) (n=17) (n=32) (n=17)
T1-LV 1.65 (3.6) 3.3 (6.7) 0.35 0.003 4.1 (8.9) 3.9 (6.6) 0.921 0.467
T2-LV 11.6 (15.7) 11.1 (14.1) 0.91 0.527 21.1 (20.9) 19.8 (23.1) 0.834 0.732
Gd-LV 0.03 (0.2) 0.006 (0.02) 0.694 0.001 0.003 (0.02) 0.0 0.471 0.999
Whole brain volume 1488.8 (75.5) 1432.8 (92.8) 0.01 0.065 1407.9 (88.1) 1355.3 (69.9) 0.012 0.892
Grey matter volume 757.5 (54.1) 728.0 (62.7) 0.054 0.015 705.9 (55.5) 685.4 (52.9) 0.217 0.832
White matter volume 731.2 (38.3) 704.8 (41.9) 0.014 0.725 702.1 (43.5) 669.9 (36.1) 0.012 0.722
Cortical volume 614.4 (43.3) 588.2 (47.9) 0.031 0.009 575.7 (45.5) 558.7 (45.3) 0.217 0.898
Ventricular CSF volume* 47.7 (24.4) 53.1 (21.5) 0.247 0.378 57.7 (25.5) 67.8 (34.9) 0.316 0.872
Deep grey matter volume* 56.7 (5.8) 53.8 (7.6) 0.063 0.032 51.3 (7.1) 48.9 (6.4) 0.286 0.482
Thalamus volume* 18.8 (2.1) 17.5 (2.7) 0.020 0.118 16.9 (2.4) 16.1 (2.3) 0.307 0.690
Caudate volume 8.4 (1.1) 8.1 (1.2) 0.311 0.119 7.6 (1.3) 7.4 (0.9) 0.669 0.234
Putamen volume 12.1 (1.5) 11.9 (1.8) 0.666 0.007 10.9 (1.6) 10.4 (1.6) 0.300 0.757
Pallidal volume* 4.1 (0.7) 3.8 (7.6) 0.046 0.407 3.9 (0.9) 3.7 (0.7) 0.474 0.762
Hippocampus volume 9.1 (1.3) 8.6 (1.3) 0.139 0.044 8.5 (1.3) 7.7 (1.3) 0.071 0.306
Amygdala volume 3.1 (0.4) 2.8 (0.6) 0.015 0.511 2.7 (0.5) 2.9 (0.5) 0.386 0.085
RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; FV, facial vein; CSF, cerebrospinal fluid; LV, lesion volume, Gd, gadolinium. *Logarithmic transformation used. Student’s t-
test and analysis of covariance (ANCOVA) adjusted for age were used. Alpha level of 0.05 was considered as significant, and is shown in italics. The volumes are represented in milliliters (mean ± standard deviation).
Table 2. MRI differences between multiple sclerosis patients with lowest and the higher quartiles of bilateral facial vein blood flow.
MRI characteristics Higher quartiles (n=102) Lowest quartile (n=34) P value ANCOVA age-adjusted
T1-LV 2.4 (5.9) 3.6 (6.5) 0.343 0.381
T2-LV 14.6 (17.9) 15.4 (19.4) 0.819 0.951
Gd-LV 0.023 (0.2) 0.002 (0.02) 0.569 0.720
Whole brain volume 1463.4 (87.7) 1394.0 (89.9) <0.001 <0.001
Grey matter volume 741.3 (59.3) 706.7 (61.1) 0.004 0.010
White matter volume 722.1 (42.0) 687.3 (42.4) <0.001 <0.001
Cortical volume 602.3 (47.4) 573.4 (48.3) 0.004 0.006
Ventricular CSF volume* 50.8 (25.1) 60.4 (29.5) 0.051 0.103
Deep grey matter volume* 54.9 (6.7) 51.3 (7.3) 0.008 0.017
Thalamus volume* 18.2 (2.3) 16.8 (2.6) 0.003 0.008
Caudate volume 8.2 (1.3) 7.8 (1.1) 0.101 0.191
Putamen volume 11.7 (1.6) 11.1 (1.8) 0.096 0.177
Pallidal volume* 4.0 (0.8) 3.7 (7.2) 0.027 0.034
Hippocampus volume 8.9 (1.3) 8.2 (1.3) 0.005 0.013
Amygdala volume 2.9 (0.5) 2.8 (0.5) 0.115 0.180
FV, facial vein; CSF, cerebrospinal fluid; LV, lesion volume, Gd, gadolinium. *Logarithmic transformation used. Student’s t-test and analysis of covariance (ANCOVA) adjusted for age were used. Alpha level of 0.05 was
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Discussion
We evaluated the relationship between
collateral venous outflow and MRI-derived
outcome measures in MS patients. This
study suggests that MS patients within the
lowest quartile of FV blood flow presented
with decreased global and regional MRI-
derived brain volumes. Additionally, the
lowest quartile group was no different in
terms of inflammatory MRI-derived out-
come measures when compared to the high-
er quartile groups.
Studies have shown that MS patients
have larger measured arterial inflow than
venous drainage, also known as a mismatch
between the arterial and venous flow, which
may indicate that the venous blood is
drained through supplementary, non-previ-
ously detected smaller veins.20 Additionally,
in a global mathematical model, the effect
of extra cranial obstacles has been calculat-
ed to increase the intracranial pressure, con-
sequently causing a flow reduction up to
70% in the primary affected vessel, and
flow increase in the collateral pathways.21
One way of explaining the results of our
study is that due to possible obstruction
within the IJV, a redistribution of the blood
flow through the FV has occurred. The cav-
ernous sinus, as an anatomical communica-
tion between the major venous outflow
(IJV) and the FV, may facilitate this com-
pensatory mechanism.
Therefore, due to the venous abnormal-
ities, compensatory physiological mecha-
nisms of increased collateralization in MS
have been hypothesized. Increased IJV flat-
tening in MS patients was associated with
development of more non-IJV collaterals.6
Similarly, this morphological development
of collateral vessels has been confirmed
with corresponding hemodynamic analysis.
A recent phase-contrast MR study showed
that MS patients had increased quantified
paraspinal and collateral veins flow, cou-
pled with reduced blood flow in the IJV.7
On the other hand, by using quantitative
Doppler ultrasound measurements of the
venous blood flow, several studies showed
global venous hemodynamic differences
associated with MS. A contrast-enhanced
ultrasonography study showed heterogene-
ity in the venous outflow system consistent
with slow washout dynamic.22
All the aforementioned changes have
been previously described as part of chronic
cerebrospinal venous insufficiency
(CCSVI) condition which is characterized
by anomalies of the main extracranial cere-
brospinal venous routes that interfere with
normal blood outflow.2 Higher prevalence
of CCSVI has been reported not only in MS
patients, but also in Parkinson disease,24 and
Meniere disease.25 Other entities like tran-
sient global amnesia and chronic migraine
have also been associated with jugular
reflux and changes in the venous
dynamics.26,27 Additionally, well-known MS
susceptibility factors like cardiovascular,
infectious, and inflammatory risks have
been associated with increased prevalence
of CCSVI.28
The paucity of differences in any of the
conventional inflammatory outcome meas-
ures may be explained by the recent find-
ings, which suggest that the cortical atro-
phy, and specifically cortical hemispheric
volume loss lateralization, could influence
the homeostasis of autonomic nervous sys-
tem (ANS).29 For example, autonomic
mechanisms related to cardiovascular con-
trol are located in the neuronal circuitry of
the insular cortex, dorsal anterior cingulate,
prefrontal cortex, and hippocampus.30 It has
been reported that dysregulation of the ANS
is associated with variability of the heart
rate, and fluctuations of the blood pressure,
all of which can contribute to reaching a
critical closing pressure that leads to the
collapse of the cerebral venous system.31
Therefore, it may be hypothesized that an
extensive neurodegenerative pathology
within cortical regions associated with ANS
system function can alter regional venous
flow redistribution. The change of the pos-
ture and the change of the physical forces
acting on the vasculature are creating nor-
mal physiological shift from the IJV-driven
venous outflow in supine position to more
vertebral and paraspinal flow in erect posi-
ton. The initial reports of MS patients hav-
ing increased IJV venous return in the seat-
ed position were supported by other inde-
pendent studies.23 On this basis, a quantita-
tive evaluation study that enrolled patients
with RRMS and primary-progressive (PP)
MS, and healthy controls showed that the
postural dependency was pronounced in the
more disabled patients. In that study, 52.9%
of RRMS and 75.9% of PPMS versus only
13.4% of HCs showed increased supine IJV
flow.32 Additionally, this alteration of
venous blood outflow was able to discern
MS patients against other neurological dis-
eases and versus HCs.33
Both concepts of i) lack of differences
in inflammatory MRI-derived measures;
and ii) increased prevalence of hemody-
namic changes within more disabled MS
patients (RR vs SP), further converge on the
neurodegenerative etiology of the hemody-
namic flow changes seen in MS.
Lastly, this study extends the need of
more comprehensive vascular analysis.
Examining the IJVs only, on several pre-
determined levels of measurement might
not be sufficient in order to detect the possi-
ble global hemodynamic changes. We
Figure 3. Graphical representation of the differences in brain volumes between groups of
lowest quartile and higher quartiles of facial vein blood flow. Orange, multiple sclerosis
patients with lowest quartile of facial vein blood flow; blue, multiple sclerosis patients
with higher quartiles of facial vein blood flow. *both significant at level of <0.05; **cor-
relation significant at level of <0.001.
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[page 96] [Veins and Lymphatics 2017; 6:6976]
showed that flow measured within collater-
al vessels were able to differentiate patients
based on their neurodegenerative pheno-
type. Well-designed, longitudinal studies
comprehensively examining the secondary
vascular system and its associations with
clinical/MRI measures may overcome the
contradictory results reported in the litera-
ture.
Despite recent improvements of the
pulse-wave Doppler ultrasound, a number
of technical limitations in flow measure-
ments still remain inherent to the technique.
Conventional ultrasound transducers pro-
duce an intensity distribution, which varies
continuously across the beam, and conven-
tional pulsed Doppler systems are designed
to achieve high spatial resolution rather
than uniformity of insonification.
Additionally, the method employed also
assumes several factors as i) accurate meas-
urement of the CSA, ii) non-turbulent flow,
iii) correct angle of insonation, and iv)
cylindrically symmetric flow profile.
Possible use of newly developed 3D/4D
probes that acquire multivolume color
Doppler data might circumvent the previ-
ously mentioned limitations. Until further
standardization of the methods used is
achieved, any experimental assessment
should serve as a research tool, which might
help disentangle the vascular pathology
seen in MS patients.
A limitation in this study was the indi-
rect measurement of the FV blood outflow.
Color Doppler ultrasound can detect
extracranial collateral veins; however, it has
limited ability in fully following the com-
plete course of smaller size vessels.
Additionally, the available ultrasound flow-
outflow data has already been acquired, and
therefore our hypothesis was tested in a
post-hoc manner. With the FV used as an
anatomical marker for the IJV flow meas-
urements, the flow difference between the
below and above the entrance of facial vein
IJV segment can only be attributed to the
actual FV blood flow. In order to determine
if the increased collateral flow within the
FV has primary pathology or it is a byprod-
uct by the associated neurodegeneration, a
prospective Doppler-MRI study is needed.
Conclusions
MS patients within the lowest quartile
of FV blood flow showed more advanced
global and regional brain atrophy. The FV
can be a substantial alternative venous
draining pathway for the head and neck
structures and should be considered in
future comprehensive venous examinations.
Furthermore, we showed that the ability of
the FV to compensate and contribute into
the venous drainage is associated with high-
er global and regional brain volumes. The
lack of associations between inflammatory
MRI measures in MS patients, but an asso-
ciation with brain atrophy, suggests that the
severity of neurodegenerative process may
be related to hemodynamic alterations.
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