Hrev_master
Veins and Lymphatics 2017; volume 6:6533
[page 40] [Veins and Lymphatics 2017; 6:6533]
Chronic cerebro-spinal
insufficiency in multiple
sclerosis and meniere disease:
same background, different
patterns?
Pietro Maria Bavera,1,2
Federica Di Berardino,3 Piero Cecconi,2
Laura Mendozzi,2 Valentina Mattei,2
Dario Carlo Alpini2,4
1Vascular Imaging Diagnostician for
Medick-Up Vascular Lab, Milan;
2Department of Clinical Sciences,
University of Milan, and Audiology
Unit, Fondazione IRCCS Ca’ Granda
Ospedale Maggiore Policlinico, Milan;
3IRCCS S. Maria Nascente don Carlo
Gnocchi Foundation, Milan;
4Vertigo School, Milan Italy
Abstract
Multiple sclerosis (MS) is a chronic dis-
ease of the central nervous system charac-
terized by demyelinating lesions with acute
phases and progressive loss of sensori-
motor functions. Mèniére disease (MD) is a
disorder of the inner ear characterized by
acute spells of vertigo and hearing loss and
progressive loss of cochleo-vestibular func-
tion. Both the diseases have a multifactorial
pathogenesis and quite the same chronic
cerebro-spinal insufficiency (CCSVI) fre-
quency. However, as far as Author’s knowl-
edge concerns, no patients affected with
both diseases are described so far. The aim
of this paper is to investigate whether MS
and MD present different CCSVI patterns.
Three groups of patients were enrolled: 60
definite MS - 27 definite unilateral MD
(MEN) - 41 with other no-Mèniére, audio-
vestibular disorders (OVD). All subjects
underwent magnetic resonance venography
(MRV) and venous Duplex (ECD) and only
patients that satisfied both MRV and ECD
CCSVI diagnostic criteria were considered.
J1 was normal in 57% of MS, 88% of MEN
and 95% of OVD. Stenosis (ST) were
detected, respectively, in 30% of MS and
2% in MEN and OVD. J2 was normal in
78% of MS, 64% of MEN and 95% of
OVD. At this level alterations of the trunk
(AT) were detected in 17% in MS and 26%
in MEN; J3 was normal in 74% of MS, 64%
of MEN and 86% of OVD. AT were found
in 15% of MS, 26% of MEN and 8% of
OVD. Hyperplasia of the Vertebral Veins
was observed in 35% of MS, 40% of MEN
and in 15% of OVD. Other compensatory
collaterals were detected in 25% in MS and
only in 5% in MEN and OVD. Our results
indicate that the MS pattern is characterized
by J1 stenosis, J2 trunk alterations, a preva-
lence of J1-J2 medial-distal alterations,
compensatory collaterals besides vertebral
venous system. MD pattern is characterized
by trunk alteration in J3, a prevalence of J3-
J2 medial-proximal alterations and verte-
bral veins hyperplasia without other
detectable collaterals. Although the group
of patients with venous alterations is very
small, OVD patients show a CCSVI pattern
that is more similar to MD than MS pattern.
The difference between MS and MD pat-
terns indicates that CCSVI is not a unique
entity and it could be an explanation of the
fact that subjects affected with both the dis-
eases are not reported.
Introduction
Multiple Sclerosis (MS) is a chronic
disease of the Central Nervous System char-
acterized by demyelinating lesions. Typical
course is alternating of acute phases fol-
lowed by unpredictable periods of remis-
sion but, usually, with a progressive loss of
sensorial-motor functions. A multifactorial
pathogenesis is nowadays accepted1 even if
a unique final autoimmune mechanism is
usually considered. Mèniére Disease is a
disorder of the inner ear characterized by
acute spells of vertigo, tinnitus and hearing
loss followed by unpredictable period of
remission but, usually, with a progressive
loss of vestibular and cochlear function. A
multifactorial pathogenesis is accepted2
even if a unique final hydraulic mechanism,
the so called Endolymphatic Hydrops (EH),
is usually considered.3 Both MS4-6 and
MD7-9 presents quite the same frequency of
cerebro-cervical venous abnormalities as
evaluated by means of Magnetic Resonance
Venography (MRV) or Duplex exam (ECD)
adopting the criteria for the diagnosis of
chronic cerebro-spinal insufficiency
(CCSVI).10 Despite this, as far as Author’s
knowledge concerns, no patients affected
with MS and MD are reported in Literature,
so far.
The aim of this paper is to investigate if
MS and MD present different CCSVI pat-
terns.
Materials and Methods
Three groups of patients were enrolled:
60 definite Multiple Sclerosis (MS, 43
females and 17 males, mean age 43.7 yy);
27 definite unilateral Ménière Disease
(MEN, 17 females and 10 males, mean age
41.5 yy);11 41 other vestibular disorders
(OVD, 28 females and 13 males, mean age
43.3 yy). These subjects presented unilater-
al hearing loss and vestibular hypofunction
due to different cases: 8 otosclerosis, 3
acoustic neuroma in the othologic phase, 9
inner ear vascular disorders (so called
Lyndasy-Hemenway Syndrome), 21
vestibular neuritis.12
Multiple Sclerosis diagnoses were per-
formed by a trained neurologist (ML).
Diagnosis of MEN or OVD were based on
clinical and audio-vestibular investigations
by the same audiologist (MV) that was
unaware of the MRV and ECD results. The
exclusion criteria comprised, for all three
groups of patients: retro cochlear lesion or
other known anatomic/structural lesions of
the ear, temporal bone or head trauma, syn-
drome features or congenital othologic
abnormalities. Furthermore in MEN and
OVD groups any known central nervous
system disease.
The work was carried out in accordance
with the Declaration of Helsinki, including,
but not limited to there being no potential
harm to participants, guaranteed anonymity
Correspondence: Dario Carlo Alpini, Vertigo
School, via Lomellina 58, 20133 Milan, Italy.
Fax: +39.02.70105197.
E-mail: vertigoschool5@gmail.com
Key words: Chronic cerebro-spinal insuffi-
ciency; vertebral veins; multiple sclerosis;
Mèniére disease.
Contribution: PMB designed the experiment
and performed Duplex evaluations; PC
designed the experiment and analyzed, MRV
data; VM performed oto-neurological tests to
select audio-vestibular patients; DCA
designed the experiment and wrote the manu-
script, Mendozzi L designed the experiment
and selected multiple sclerosis patients; FDB
analyzed the data, wrote the manuscript and
critically revised the paper for important intel-
lectual content. All the authors contributed to
the preparation of the paper
Conflict of interest: the authors declare no
potential conflict of interest.
Received for publication: 3 January 2017.
Revision received: 12 February 2017.
Accepted for publication: 14 February 2017.
This work is licensed under a Creative
Commons Attribution 4.0 License (by-nc 4.0).
©Copyright P.M. Bavera et al., 2017
Licensee PAGEPress, Italy
Veins and Lymphatics 2017; 6:6533
doi:10.4081/vl.2017.6533
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[Veins and Lymphatics 2017; 6:6533] [page 41]
of participants, and informed consent.
All subjects underwent magnetic reso-
nance imaging of the brain during which
contrast enhanced imaging of the venous
cerebro cervical system was also performed
in order to assess the condition of the
Internal Jugular Veins (IJVs) and vertebral
veins (VVs) and evaluated by the same neu-
roradiologist (CP) who had no knowledge
of the clinical diagnosis. Magnetic
Resonance was performed using a 1.5 T
scanner with a standardized imaging proto-
col consisting of axial and coronal fast spin-
echo T2-weighted imaging and axial and
sagittal spin-echo T1-weighted imaging.
The intracranial and cervical venous sys-
tems were investigated using computer-
based magnetic resonance venography
(MRV) performed in three standard orienta-
tions (transverse, coronal, and sagittal). A
maximum-intensity projection algorithm
was used to display three-dimensional
MRV reconstruction angiograms. The sub-
jects underwent contrast-enhanced MRV in
the supine position and the right and left
cross-sectional areas (CSA) of the IJVs and
VVs were compared. Asymmetrical venous
flow in the IJVs and VVs was functionally
investigated using venous Duplex (ECD)
(randomly carried out by Esaote or General
Electric with similar probes and settings, by
well-trained specialists (BPM), that was
unaware of the clinical diagnosis. Duplex
was performed at 0° and 90° according to
the CCSVI protocol and was considered
confirmatory of MRV findings when at least
two of the five CCSVI criteria were satis-
fied.10,13,14
Three pathological conditions have
been taken in account: stenosis (ST), VVs
hyperplasia (VVH) and alterations of the
trunk (AT).
ST was so defined when CSA was less
than 0.5 cm2, or, at ECD evaluation, if CSA
in supine position was smaller than in
upright position VVH was so defined when
CSA was more than 0.5 cm2.
AT was based on ECD findings and
included structural abnormalities such as
flaps, septa or malformed/immobile valves.
Statistical analysis
The statistical analysis was carried out
by an independent well-trained audiologist
(DF) with Statistics 6.1 software (Stat. Soft
Inc., Tulsa, OK, USA). Between-group
comparisons were made using analysis of
variance (ANOVA). Frequencies were com-
pared using the Chi-squared. A P value of
<0.05 was considered to be statistically sig-
nificant.
Results
MRV-ECD showed IJVs alterations,
any level, in 32 (53%) MS, 13 (46%) MEN
and 6 (16%) OVD with significant differ-
ence between MS-MEN and OVD but not
between MS and MEN.
J1 was normal in 34 (57%) MS, 24
(88%) MEN and 38 (95%) OVD. While
comparison between MS and MEN was sig-
nificant (P<0.001), difference between
MEN and OVD were not. ST were detected,
respectively, in 30% in MS and 2% in MEN
and OVD; AT in 13% of MS, 10% of MEN
and 3% of OVD. Therefore, J1 stenosis
specifically regards MS rather than MEN
and OVD (P<0.001).
J2 was normal in 47 (78%) MS, 17
(64%) MEN and 38 (95%) OVD. While
comparison between MS and MEN versus
OVD was significant (P<0.001) difference
between MS and MEN were not, but AT
were detected in 10(17%) MS and 7 (26%)
MEN. Thus, even if the P-level is low
(P<0.05) J2 AT is more represented in MS
than in MEN.
J3 was normal in 44 (74%) MS,
17(64%) MEN and 35 (86%) OVD. At this
level difference between MEN and OVD is
low (P=0.04). Even the difference between
MS and MEN is less stronger than in J1 and
J2 (P=0.005).
ST were detected, respectively, in 7
(11%) MS and 3 (10%) MEN and 2 (6%)
OVD; AT were found in 9 (15%) MS, 7
(26%) MEN and 3 (8%) OVD. Even differ-
ences are not statistically significant, J3 AT
seems more represented in MEN than in the
Figure 1 Distribution of IJVs anatomic alterations in relationship with topographic seg-
ments. IJVs alterations are substantially rare in OVD and, above all, how in MS J1 alter-
ations are more represented while J3 is the specific MEN abnormal segment.
Figure 2. Regional distribution of IJVs alterations. Regional distribution is significantly
different between MS and MEN with medial-distal prevalence in MS and medial-proxi-
mal prevalence in MEN.
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[page 42] [Veins and Lymphatics 2017; 6:6533]
other two groups. Figure 1 clearly shows
the different patterns of topographic seg-
ment alterations distribution, into the three
groups with prevalence of alterations in J1
in MS and in J3 in MEN.
Adopting a “regional” criterion, J1-J2
may be considered as medial-distal IJVs
alterations while J2-J3 as medial-proximal
alterations. “Regional” IJVs abnormalities
difference between MS and MEN (Figure 2)
with a higher prevalence of J2-J3 alterations
in MEN (10 patients, 37%) than in MS (14
patients, 23%) and a higher prevalence of
J1-J2 in MS (19 patients 32%) than in MEN
(6 patients 22%). Differences are significant
at P<0.05.
Hyperplasia of the Vertebral Venous
system was observed in 21 (35%) MS, 11
(40%) MEN and in 6 (15%) OVD. While
difference between MS and MEN versus
OVD was significant, difference between
MS and MEN was not. Other compensatory
collaterals were detected in 15 (25%) MS
and only in 2 (5%) MEN and OVD.
Discussion and Conclusions
Our results clearly show that CCSVI
may be considered as a typical condition
both in MS and MD but is substantially rare
in other kind of audio-vestibular disorders.
If CCSVI may be considered a cause
per se or the anatomical condition for trig-
gering the effect of other factors may be
debated. Anyway, our experience points out
that CCSVI is not a unique disorder and that
the venous abnormalities pattern might be
disease specific. MS is a typical demyeli-
nating disease but demyelination of the
vestibular nerve has been described in
patients affected with MD, too.15 Although
the hydraulic mechanism of EH is substan-
tially worldwide accepted, there are evi-
dence of MD patients without EH16 and EH
without MD symptoms17 and Gacek18 pro-
posed a neuropathic viral mechanism in
MD pathogenesis.
May CCSVI, that is considered to be
correlated to MS Central Nervous System
demyelination, be connectable to vestibular
nerve demyelination in MD, too? It is diffi-
cult to answer but our experience highlights
the fact that in MD patients IJVs alterations
regard the proximal segment.
Anyway, CCSVI pattern seems to be
substantially different in MS and in MD.
Our results indicate that the MS pattern
is characterized by J1 stenosis, J2 alter-
ations trunk, a prevalence of J1-J2 medial-
distal alterations, compensatory collaterals
besides vertebral venous system. On the
other hand, MEN pattern is characterized by
alteration trunks in J3, a prevalence of J3-J2
medial-proximal alterations and vertebral
venous hyperplasia without other detectable
collaterals.
On the other hand the role of the origin
of the IJVs, that to say the jugular bulb in
Ménière Disease is known.19
Several studies analyzing the temporal
bone imaging20 or anatomy in MD patients
have found consistent alterations in the
arrangement of the sigmoid sinus, anteriorly
or medially displaced, and jugular bulb
abnormalities. According to Redfern et al.21
and Park et al.22 there is a higher frequency
of jugular bulb abnormalities in patients
with MD than in patients without inner ear
symptoms, particularly, the mediolateral
and anteroposterior position of the jugular
bulb determines encroachment of the sur-
rounding structures. Authors postulated that
abnormal position contributes to MD devel-
opment and that temporal bones of MD
patients might be constituted anatomically
different, carrying predisposing factors for
the development of clinically apparent MD.
These findings resemble to our findings:
IJVs in general and J3 alterations are signif-
icantly highest in MD than in OVD.
The disease-specificity of venous
abnormalities was recently reported also by
Vannini et al.23 that described different mor-
phology of IJVs’ valves in MD patients with
respect to Normals and Sudden
Neurosensorial Hearing Loss patients.
It is interesting to note that Burcon24
observed in MD patients a frequent involve-
ment of the upper cervical spine dysfunc-
tion, particularly C1 and C2, that the author
correlated to vertigo, C1, and hearing loss,
C2. It is interesting to underline that in
OVD VVs hypeplasia is highly represented
than J1-J2 alterations but similarly to J3
abnormalities: VVs 15% - J3 14%. Both
Vertebral Veins and proximal Jugular seg-
ment are anatomically placed in C1-C2
region and this fact supports the role of
upper cervical venous drainage to explain
Burcon’s paper. Furthermore, Franz et al.25
postulated a cervicogenic disorder, mainly
trigeminal based mechanism, as forerunner
of MD. Also in this case a venous explana-
tion might be coupled to Franz’s trigeminal
mechanism as happens in migraine
patients.26
The key point of the paper of Merchant
et al.17 conducted on temporal bone cases
with a clinical diagnosis of MD or a
histopathologic EH diagnosis, is that
hydrops per se is not the cause of MD while
there are evidences of cellular and molecu-
lar bases of the various MD symptoms.11
Thus, a specific anatomical abnormality
of the temporal bone, regarding the jugular
bulb, and/or the highest portion of the cere-
bro-cervical venous drainage system, as
shown in this paper through MRV and ECD,
may lead to abnormal clearance of audio-
vestibular structures inducing citochemical
changement similar to those observed in
MS CCSVI positive patients.
It is interesting to reveal that, although
the group of patients with venous alter-
ations is very small, OVD patients show a
CCSVI pattern more similar to MD than
MS pattern, thus it is reasonable to conclude
that CCSVI is not an unique entity and that
neurological (MS) pattern is distinguish-
able from the audiologic (MD and OVD)
pattern. In Author’s opinion this explains
the fact that no patients affected with MS
and MD are reported in Literature.
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