Chronic cerebrospinal venous insufficiency in
patients with multiple sclerosis
P Zamboni,1R Galeotti,1E Menegatti,1A M Malagoni,1G Tacconi,1S Dall’Ara,1
I Bartolomei,2F Salvi2
See Editorial Commentary,
1Vascular Diseases Center,
University of Ferrara, Ferrara,
Italy;2Department of Neurology,
Bellaria Hospital, Bologna, Italy
Professor P Zamboni, Vascular
Diseases Center, University of
Ferrara, 44100 Ferrara, Italy;
Received 2 July 2008
Revised 7 November 2008
Accepted 10 November 2008
Published Online First
5 December 2008
This paper is freely available
online under the BMJ Journals
unlocked scheme, see http://
Background: The extracranial venous outflow routes in
clinically defined multiple sclerosis (CDMS) have not
previously been investigated.
Methods: Sixty-five patients affected by CDMS, and 235
controls composed, respectively, of healthy subjects,
healthy subjects older than CDMS patients, patients
affected by other neurological diseases and older controls
not affected by neurological diseases but scheduled for
venography (HAV-C) blindly underwent a combined
transcranial and extracranial colour-Doppler high-resolu-
tion examination (TCCS-ECD) aimed at detecting at least
two of five parameters of anomalous venous outflow.
According to the TCCS-ECD screening, patients and HAV-
C further underwent selective venography of the azygous
and jugular venous system with venous pressure
Results: CDMS and TCCS-ECD venous outflow anomalies
were dramatically associated (OR 43, 95% CI 29 to 65,
p,0.0001). Subsequently, venography demonstrated in
CDMS, and not in controls, the presence of multiple
severe extracranial stenosis, affecting the principal
cerebrospinal venous segments; this provides a picture of
chronic cerebrospinal venous insufficiency (CCSVI) with
four different patterns of distribution of stenosis and
substitute circle. Moreover, relapsing-remitting and
secondary progressive courses were associated with
CCSVI patterns significantly different from those of
primary progressive (p,0.0001). Finally, the pressure
gradient measured across the venous stenosies was
slightly but significantly higher.
Conclusion: CDMS is strongly associated with CCSVI, a
scenario that has not previously been described,
characterised by abnormal venous haemodynamics
determined by extracranial multiple venous strictures of
unknown origin. The location of venous obstructions plays
a key role in determining the clinical course of the
Multiple sclerosis (MS) is an inflammatory demye-
linating disease of the central nervous system
(CNS) of unknown pathogenesis.1 2MR venogra-
phy3–6and postmortem studies7have demonstrated
a topographic correspondence between MS plaques
and cerebral venous system. The drainage through
the extracranial venous outflow routes has not
previously been investigated in MS patients.
Postureandthemechanic movementof respiration
play a fundamental role in ensuring the correct
cerebrospinal venous outflow.8At the time of expira-
tion, the intrathoracic pressure is approximately
25 cm H2O, and inspiration causes a respiratory
muscular action that can generate an even lower
intrathoracic pressure, 28 cm H2O. The resulting
gradient favours venous return to the right heart,
which can be easily assessed with high-resolution
echocolour Doppler (ECD) and transcranial colour-
coded Doppler sonography (TCCS), which represent
an ideal method by which to investigate the haemo-
dynamics of cerebral venous return.9–19In addition,
ECD clarified the postural control of the extracranial
outflow pathways, as follows:8–12
the internal jugular vein (IJV) is the predomi-
nant pathway in the supine position, con-
firmed by an increased cross-sectional area of
the internal jugular vein (CSA) related to
increased blood volume in that posture; and
redirection of venous flow to the vertebral
veins (VVs) occurs in the upright position, with
compliant reduction of the CSA of the IJV.
In contrast, MR and selective injection venogra-
phy are of course limited in evaluating cerebral
venous haemodynamics under different postural
and respiratory conditions. However, the latter
especially provide excellent morphological but
We present the results of a study that evaluated
the abnormalities of the cerebral venous outflow in
patients with MS using ECD-TCCS and selective
Patients and controls
We investigated 65 patients affected by clinically
defined MS (CDMS) and diagnosed according to
included 35 patients with a relapsing-remitting
(RR) clinical course, 20 with secondary progressive
(SP), and 10 with primary progressive
course.21 22A relative expanded disability disease
score (EDSS) was attributed to each group.23
Detailed data regarding their clinical, demographic,
and genetic characteristics, MRI examination,
presence of oligoclonal bands in the cerebrospinal
fluid (CSF) are provided in table 1. PP patients and
18 out of 55 RR-SP were not under treatment at
the time of the evaluation.
As controls, we investigated 235 subjects sub-
divided as follows:
1.60 healthy subjects matched for age and
gender with MS patients (HM-C).
2. 82 healthy subjects older than the median age
of onset of CDMS (HA-C);21had haemody-
namic anomalies been present in the second
control group, we would not have been able
to maintain that they have a role in MS, since
the disease is not more expected in this age
392 J Neurol Neurosurg Psychiatry 2009;80:392–399. doi:10.1136/jnnp.2008.157164
3.45 patients affected by other neurological diseases (OND)
(table 2); this group was composed of patients affected by
neurodegenerative disorders (Parkinson disease and amyo-
trophic lateral sclerosis-ALS), other neuroimmunological
disorders including myasthenia gravis and multifocal
motor neuropathy (MMN), and cerebrovascular disease
(ischaemic stroke, transient ischaemic attack (TIA)).
48 other controls not affected by neurological diseases
(table 2), but scheduled for venography (HAV-C) for other
pathologies: diagnostic sampling of the IJVs for primary/
secondary hyperparathyroidism, varicocele and/or pelvic
congestion syndrome, Cockett and thoracic outlet syn-
dromes, indwelling central venous catheters or pacemaker
wires, stenosis of venous access for haemodialysis and
removal of temporary cava filters.
We excluded subjects who had Behc ¸et disease, vasculitis,
cerebral vascular malformations and congenital vascular mal-
Martorell and Budd–Chiari syndromes).
Patients and controls underwent a non-invasive study of
cerebrospinal venous return at the Vascular Lab; the ultrasound
technicians and physicians interpreting the data were blinded to
the patient diagnostic category.
Study of cerebrospinal venous drainage
Cerebrospinal venous return was examined with the subject
positioned on a tilt bed by combining the extracranial ECD
methodology for investigating the IJVs and VVs with that of
the TCCS for studying the deep cerebral veins (DCVs).9–19We
focused in particular on the detection of five parameters, which
are absent in normal subjects:
1.reflux in the IJVs and/or VVs in sitting and supine posture;
2. reflux in the DCVs;
3. high-resolution B-mode evidence of IJV stenoses;
4.flow not Doppler-detectable in the IJVs and/or VVs;
5. reverted postural control of the main cerebral venous
Reflux in the IJVs and/or VVs in sitting and supine posture
In normal subjects, flow in the IJVs and VVs is directed toward
the heart in any position of the head.8–15According to a recent
study on reflux time cut-off values, we considered reflux a flow
reversal from its physiological direction for a duration of
.0.88 s.13Flow was assessed during a short period of apnoea
following a normal exhalation,9and never in a forced condition
such as the Valsalva manoeuvre.13 14
We assessed the presence of reflux with the body positioned
respectively at 0u and +90u, in the four extracranial venous
Reflux in the DCVs
Physiological intracranial venous flow is monodirectional.16–19
TCCS investigation assessed the presence of reflux in at least
one of the DCVs (internal cerebral vein, basal vein of Rosenthal,
great vein of Galen). Participants were examined in both sitting
and supine positions, and the venous flow was elicited by
inviting the subject to breathe and setting the reflux time to a
value .0.5 s.18 19
High-resolution B-mode evidence of proximal IJV stenoses
We assessed the presence of stenosing venous imaging by means
of a complete ECD high resolution B-mode exploration of the
cervical vessels, and measurement of the CSA of the IJV. A CSA
(0.3 cm2, never measured in normal subjects, was taken as
Flow not Doppler detectable in the IJVs and/or VVs
We assessed the lack of a Doppler detectable venous flow in the
IJVs and/or VVs despite numerous deep inspirations, with the
head positioned at 0u and +90u in the four extracranial venous
drainage pathways. In normal subjects this finding was never
observed with the head in any position,9but was reported in the
supine position in 6% of cases.12
Clinical and demographic characteristics of clinically defined multiple sclerosis (MS) patients
MS secondary progressive
MS primary progressive
Sex: percentage male, male/female
Disease duration (years)
HLA2 (DR15) haplotype carriers (C)+%+/tot
Cerebrospinal fluid oligoclonal bands+%+/tot
Compliance with at least three of four MRI revised
41 (34 to 48)
2.5 (1 to 5)
6 (3 to 13)
35 (29 to 41)
1.5 (0.5 to 2)
4 (1 to 7)
45 (42 to 52)
5 (3.5 to 6.5)
13 (6 to 21)
58 (46 to 60)
4.3 (3 to 6.5)
10 (5 to 14)
No significant differences were found among MS subgroups for age, expanded disability disease score (EDSS), or disease duration (ANOVA). HLA2 (DR15) genetic analysis was
available in 28/65 patients, and cerebrospinal fluid in 44/65.
Demographics of the control populations
Age median (25th to 75th percentile)
Sex %M M/F
37 (28 to 49)
58 (51 to 72)
55 (32 to 70)
60 (51 to 77)
HA-C, healthy aged controls; HAV-C, older controls not affected by neurological diseases but scheduled for venography; HM-C,
healthy controls matched for age and gender with multiple sclerosis patients; OND, controls affected by other neurological
J Neurol Neurosurg Psychiatry 2009;80:392–399. doi:10.1136/jnnp.2008.157164393
Reverted postural control of the main cerebral venous outflow
DCSA in the IJVs, obtained by subtracting the CSA measured in
the supine from that in the sitting position, is a positive value in
normal subjects.8–11 19We assessed the occurrence of a negative
DCSA value, representing the loss of postural control of the
predominant outflow route in the supine position.
ECD-TCCS criteria for venography
Diagnosis of suspicious abnormal extracranial cerebral venous
outflow required at least two of the five above listed criteria to
be fulfilled, and was taken as an indication to continue the
study using selective venography in all suspected subjects.
This study was approved by the Ethics Committee of the
Ferrara University Hospital. Our Ethics Committee approved
the use of selective venography only in subjects (patients or
controls) with abnormal venous ultrasonographic examination.
An invasive investigation (potential harmful radiation/cathe-
terisation to healthy subject) was felt unnecessary when the
ECD scan was negative at the level of the neck.
We therefore used ultrasonography as a screening to
venography. Finally, the Committee approved an additional
venographic investigation to be carried out on patients without
neurological disease, even if preoperative screening for venous
return anomalies was negative but who, for other reasons,
should have had a venographic examination (HAV-C group).
Sixty-five subjects with MS fulfilling the ECD-TCCS screening
criteria and 48 controls of the HAV-C group underwent
selective catheterism of the azygous and IJV system via the
transfemoral route. Venography was performed, being aware of
patients’ diagnoses. We considered a significant stenosis to be
any venous lumen reduction greater than 50%.24–28In addition,
selective venography allowed us to measure with a manometer
the pressure expressed in cm/H2O in the superior vena cava, in
the azygous vein, and in both the IJVs.
Clinical and demographic data are expressed as the median and
25th–75th percentile, and venous pressure as the mean (SD).
Differences among groups were tested for significance with the
one-way ANOVA analysis of variance. The two-sided Fisher
exact test followed by the determination of odds ratio (95% CI)
was used for determining the associated risk of MS in case of
positive ultrasonographic findings, by comparing the whole MS
group with the control group.
(CC) with cerebral inflow (red), and right internal jugular vein (IJVr) with regular cerebral outflow (blue). (B) Same patient, left side: stenoses of the left
internal jugular vein (IJVl) due to annulus (black arrows) with reflux (red) and severe reduction of the lumen.
B-mode detection of venous stenosis. (A) Right cervical side, high-resolution B-mode image, transversal access: common carotid artery
Transcranial and extracranial colour-Doppler high-resolution examination (TCCS-ECD) criteria of highly suspected anomalous venous outflow
(N; %)Whole MS (N; %)Control populations (N; %)
Odds ratio all MS
vs all controls
(95% CI) p Value
1. Reflux constantly present in IJVs and/or
VVs with the head at 0u and +90u
2. Reflux in the deep cerebral veins
3. High resolution B-mode evidence of
proximal IJV stenoses
4. Flow not Doppler detectable in the IJVs
and/or VVs despite numerous deep
inspirations with the head at 0u and +90u
5. Negative DCSA in the IJV
27/35 77%15/20 75%4/10 40% 46/65 71% 0/235 0% 1123 (67 to 19 000) ,0.0001
748 (45 to 12 542) ,0.0001
137 (18 to 1041)
22/35 63% 7/20 35% 5/10 50%34/65 52% 7/235 3%36 (15 to 88)
18/35 51% 13/20 65%5/10 50%36/65 55% 25/235 11%10 (5 to 20)
OR was calculated for each ultra-sonographic criterion by means of the two-sided Fisher exact test, by comparing the whole MS population with the control group.
CSA, cross-sectional area of the internal jugular vein; IJV, internal jugular vein; MS, multiple sclerosis; VV, vertebral vein.
394J Neurol Neurosurg Psychiatry 2009;80:392–399. doi:10.1136/jnnp.2008.157164
The two-sided Fisher exact test was also used for testing
differences in the number of extracranial venous strictures
between CDMS patients treated and not treated with drugs.
Differences in venous pressure between patients and controls, as
well as across the stenosies, were analysed with the Mann–
Finally, the x2test for independence was used for assessing
clinical differences of MS patients among the different patterns
of extracranial venous outflow obstruction.
p Values up to 0.05 were considered statistically significant.
Table 3 reports the five TCCS-ECD criteria used for investigat-
ing the presence of abnormal extracranial venous outflow, and
the relative distribution in RR, SP and PP cases and in controls,
followed by OR. None of the controls, including those who had
HAV-C, were positive for more than one of the criteria. In MS
patients, we found 180 positive criteria and 145 negative criteria
(table 3); in contrast, merging all control groups, positive criteria
were 33 and negative criteria 1142. Consequently, the risk of
MS was dramatically increased by 43-fold (OR 43, 95% CI 29 to
65, p,0.0001), Fisher exact test). Finally, in 37% of cases, B-
mode high-resolution imaging allowed directly closed stenosies
to be detected in the IJVs (fig 1A,B, table 3).
Selective venography demonstrated that the detection of at
least 2/5 TCCS-ECD criteria of suspected anomalous extra-
cranial venous outflow (which never occurred in the control
populations) was always related to multiple significant extra-
cranial venous stenosis, localised at the cervical, thoracic and,
less commonly, abdominal level of the principal cerebrospinal
venous segments. In none of the HAV-C subjects who under-
went venographic investigation with negative ultrasound were
there any stenotic patterns in the IJVs, azygous and lumbar
territory (fig 2A (a), B (e), C (i)).
In particular, the azygous vein in the MS group was affected
in 86% of cases. Most cases involved membranous obstruction
of the junction with the superior vena cava, twisting, or, less
frequently, septum and atresia, as can be seen in the x rays in
fig 2A (b, c, d); in 12 cases the azygous system presented
stenoses at several points up to even atresia of the lumbar
plexuses (18%) (fig 2C (j, k, l)).
As for the jugular veins, they were found to be stenosed
unilaterally or bilaterally in 59/65 patients (91%). The stenoses
were frequently annulus and septum, followed by atresia; no
twisting was observed (fig 2B (f, g, h)).
differ significantly in patients treated with immunosuppressant/
immunomodulator agents or in never-treated patients (p=ns,
Fischer exact test).
Pressures measured in patients and controls respectively were
not significantly different (Mann–Whitney) (superior vena cava
13 (SD 4) vs 13 (4), azygous 16 (7) vs 14 (4), IJVs 14 (4) vs 12
(5)). In contrast, the pressure gradient measured in CDMS
across the stenosies was significantly different. For instance,
pressure in the stenotic proximal azygous vein was 3.9 cm/H2O
higher as compared with the pressure measured in the adjacent
superior vena cava of the same subjects (p,0.01; Mann–
Whitney); equally, pressure in the stenotic IJVs was 1.8 cm/
H2O higher with respect to the cava (p,0.04; Mann–Whitney).
Patterns of chronic cerebrospinal venous insufficiency
Selective venography enabled us to localise exactly not only the
places of venous steno-obstruction, but also, by comparing the
flow direction data collected by the ECD-TCCS method, to
identify the pathways of venous reflux and substitute collateral
circles. In this way it was possible to delineate a picture of
chronic cerebrospinal venous insufficiency (CCSVI) associated
with MS, for which we found four principal patterns, as shown
in fig 3.
Relationship between patterns of CCSVI and clinical course
We also found a highly significant difference in the distribution
of the clinical courses among the CCSVI patterns (p,0.0001, x2
test) (table 4). In particular, the location of venous obstruction
seems to be a key element influencing the clinical course of the
disease. Types A and B correlated with a RR course (83%) with a
conversion in the SP course in 70% of cases. In contrast, the PP
forms occurred more frequently in the type D pattern (75%).
In this study we described the association between MS and the
altered modality of venous return determined by extracranial
multiplevenous strictures. In
resembled the normal imaging of extracranial cerebrospinal
veins.25The hampered cerebrospinal venous drainage in patients
with MS determines a complex haemodynamic picture defined
as CCSVI. It is characterised by multiple substitute circles, with
a very high incidence of reflux in both intracranial and
extracranial venous segments, and loss of the postural regula-
tion of cerebral venous outflow.
The mechanism underlying this reflux differs from the reflux
caused by incompetence of the jugular valve. In the latter case,
valvular insufficiency tested with Valsalva can be related to a
picture of transient global amnesia.14In our study, the reflux
occurred in any body position without the need to elicit it by a
forced movement, suggesting that it is not an expression of
valvular incompetence but rather of a stenosing lesion that
cannot be crossed with postural or respiratory mechanisms,
thereby becoming a long-lasting reverse flow.
Substitute circles are alternative pathways or vicarious
venous shunts29(fig 3) that allow for the piping of blood
toward available venous segments outside the CNS. In
accordance with the pattern of obstruction, both the intracra-
nial and the intrarachidian veins can also become substitute
circles; they permit redirection of the deviated flow, preventing
intracranial hypertension. However, over time, they become
overloaded because they carry two different flows, their own
draining flow and the shunted flow (fig 3).
Patterns of venous obstruction according to the clinical course
J Neurol Neurosurg Psychiatry 2009;80:392–399. doi:10.1136/jnnp.2008.157164 395
The ECD-TCCS protocol was performed once by a single
team of investigators (EM and PZ: vascular technician and
interpreting physician, respectively), thus not permitting the
assessment of the intraobserver and interobserver variability
coefficient. This is a limitation of our study because the
assessment of the reproducibility of the proposed protocol,
and descending trunk (AZY); H, heart; SVC, superior vena cava. (b) Twisting (arrow) just below the azygous arch. (c) Membranous obstruction (arrow)
at the junction of the AZY with the SVC. (d) Septum (arrow) of the proximal AZY. (B) Selective venography of the internal jugular vein (IJV) in a control
case (HAV-C) (e) and in multiple sclerosis (MS) cases (f, g, h). (e) Normal right IJV (IJVr) with normal outflow and without stenosis after injection. (f)
Annulus of the left jugular vein, JVl (IJVl, arrow) at the junction with the brachiocephalic trunk (BCT). (g) Closed stenosis of the IJVl (arrow) with reflux
after injection and collateral circles (CC) depicted by small arrows. (h) Annulus of the IJVr (arrow) with reflux and activation of numerous cervical
collateral circles involving the thyroid veins (CC); one of them re-enters the SVC. (C) Selective venography of the lumbar veins in a control case (HAV-C)
(i) and in MS cases (j, k, l). (i) Selective venography of the ascending lumbar vein (LV) from the iliac vein (IV): normal appearance with characteristic
hexagonal shape of the intrarachidian plexus draining outward into the LV and upward to the azygous system. (j, k, l) Dramatic bare venous lumbar tree
in MS cases with combination of agenesia and atresia. This picture is further associated with multilevel stenosis of the azygous system configuring the
chronic cerebrospinal venous insufficiency type D pattern.
(A) Selective venography of the azygous vein in a control case (HAV-C) (a) and in MS cases (b, c, d). (a) Normal azygous vein, azygous arch
396 J Neurol Neurosurg Psychiatry 2009;80:392–399. doi:10.1136/jnnp.2008.157164
although beyond the aim of the present study, certainly
deserves further investigation. However, it should be noted
that our ultrasonic assessment can be easily performed in the
clinical setting, and, despite the operator-dependency of
ultrasounds, there is general agreement on the proposed
Our results need to address two main questions:
1. Does CCSVI influence the clinical course of MS?
2. Are venous stenoses the cause or products of MS?
First, we identified four main patterns of CCSVI, according to
the location, number and association of venous stenosis, and the
modality of collateral circulation.
We also observed that the PP course was related to a CCSVI
pattern significantly different as compared with RR and SP,
suggesting that the location of venous obstruction plays a key
role in determining the clinical course.
For instance, PP course, characterised by a slowly progressive
syndrome with spastic paraparesis and MRI demonstration of MS
venous outflow direction. In particular, the black arrows depict the drainage of the internal jugular vein (IJV) system into the superior vena cava (SVC),
and of the vertebral plexus (Vplex) outward from the spinal cord into the azygous system (AZY). Type A (30%): this pattern is characterised by a steno-
obstruction of the proximal azygous, associated with a closed stenosis of one of the two IJVs (red crosses). Reflux is always present, under all postural
conditions, in the stenosed IJV (red arrow), with a compensatory controlateral IJV that appears with an ample cross-sectional area of the IJV. Reflux in
the deep cerebral veins (DCVs) was detected by means of transcranial colour-coded Doppler sonography in 60% of cases. In the azygous vein the reflux
has an effect as far as the lumbar veins, being able to re-enter the caval circle either through the system of the hemiazygous vein–left renal vein, or by
rising again inside the rachis. Type B (38%): this pattern is characterised by significant stenoses of both IJVs and the proximal azygous (red crosses).
Reflux is present in all three venous segments (red arrows). Cerebral venous outflow for overcoming the IJVs stenosis re-enters the heart mainly
through cervical collateral circles (fig 1B); for the hampered azygous vein outflow, the collateral circles include again the intrarachidian pathway, or the
system of the renal-hemiazygous. Type C (14%): this pattern is characterised by bilateral stenosis in both IJVs, with a normal azygous system (red
crosses). Reflux (red arrows) occurs in the IJVs but not in the vertebral veins, with cervical or intracranial collateral circles that shunt blood towards the
superior vena cava or the azygous vein system, respectively. The resulting overload of the azygous system is depicted by black bold arrows. Type D
(18%): in this pattern the azygous system was constantly affected in various segments (red crosses), resulting in a forced venous drainage towards the
intrarachidian circles in an upward direction (red arrows). The vertebral veins appeared to be refluent, and the intracranial collateral circles seek to gain
the IJVs, as confirmed by reflux detection in DCVs in 90% of cases. At times, the IJVs were also affected (six cases, 50%), causing an additional
obstruction in these patients. IVC, inferior vena cava; L-REN, left renal vein.
Patterns of chronic cerebrospinal venous insufficiency observed in multiple sclerosis (MS) cases. Normal: example of normal extracranial
J Neurol Neurosurg Psychiatry 2009;80:392–399. doi:10.1136/jnnp.2008.157164397
plaques in the spinal cord,20 30–32was significantly associated with
obstruction at several levels of the azygous vein and of the lumbar
plexuses (type D pattern, fig 3, table 4). In this situation, venous
blood of the spinal cord can be drained only in an upward
direction and is shunted toward the venous plexuses inside the
spine (figs 3, 4), thus helping to explain the correlation between
type D and spinal cord involvement in PP patients.
In contrast, the RR course was significantly associated with
type A and B patterns (83% of cases), and particularly to type A,
a group in which three-quarters of patients were RR (table 4).
The more favourable clinical course could be explained in the
latter by the presence of a patent IJV (fig 3), with a
compensatory outflow function proved by increased CSA (data
not shown). Finally, the conversion to SP course was
consistently observed in type A, B, C patterns (95%), but
proportionally higher in patients with both the IJVs blocked
(56% of type C). However, longitudinal studies are needed, with
clinical and advanced MRI analyses3of MS diffusion over time
and space in relation to the CCSVI patterns discovered and
described in this study.
Second, regarding the causative role of CCSVI in MS, our
review of the literature revealed descriptions of associations
between the extracranial venous obstructive malformations
described herein and disabling neurological pictures however,
the latter were defined by these authors generically as myelo-
pathies, without a precise diagnosis and any mention of MS.27 28
Venous hypertension has been hypothesised as a cause of
MS,33 34but in our study blood pressure was not found to be
has been recently demonstrated that a pressure gradient across a
central vein stenosis of 2.2 cm/H2O corresponds to a CSA
reduction greater than 50%.35In our study the pressure gradient
across the stenosies between the cava and the azygous arch was
significantly different and measured 3.9 cm/H2O (fig 2A). The
gradient between the stenotic IJVsandthesuperior venacavawas
lower, 1.8 cm/H2O, but again significantly different.
Moreover, the absence of Doppler and venographic features of
CCSVI in controls suggests that venous obstructions may be
causative of MS rather than a coincidental finding.
Interestingly, similar venous stenoses considered to be
congenital malformations have been described in other human
diseases, that is, membranous obstruction of the inferior vena
cava and a minor group of chronic venous diseases of the lower
limbs.27 28Such venous obstruction brings about an insufficient
venous drainage, respectively, at the level of the liver and of the
cutaneous tissue, subsequently causing inflammation, sclerosis,
and degenerative lesions.24 25 36
In contrast with the malformation hypothesis, cases have
been reported of white cell infiltration and endophlebohyper-
trophy in venous valves where endocarditis is present.37
Even though this correlation has never been studied in MS,
reports of valvulitis in the course of significant inflammatory
disease should certainly be taken into consideration, since they
support the hypothesis that these malformations are a result of
CDMS rather than a cause. However, if vessel abnormalities
were due to an inflammatory-autoimmune disease, they would
be less frequent in patients treated with immunomodulating/
immunosuppressant agents. On the contrary, our analysis in
the RR-SP group did not demonstrate an increased number of
extracranial venous stenosing lesions in untreated as compared
with treated patients.
Finally, an additional possibility could be related to the side
effects of MS drugs on the venous wall, although these have
never been reported.38
The hypothesis of venous malformations of congenital/
developmental origin associated with CDMS seems to be
plausible. Nevertheless, additional longitudinal studies are
necessary to confirm this hypothesis, as well as to understand
the contribution of chronic insufficient venous drainage of the
CNS to the process of inflammation and neurodegeneration.
Finally, on the basis of our study, we propose the introduction
of the ECD-TCCS protocol when a patient presents the first
acute episode of demyelinating origin, mostly involving the
optic nerve, the so-called clinically isolated syndrome (CIS).
Currently, only longitudinal clinical and MRI observation in
time and space is capable of establishing the possible conversion
of a CIS into a CDMS.20
Acknowledgements: We wish to thank F Roncaroli (Department of Neuropathology,
Imperial College, London), for his critical revision of the manuscript. We thank P J
Ennis, for her revision of the English language.
Funding: Research supported by the Italian Ministry for University and Scientific
Research and by the Foundation Cassa di Risparmio di Ferrara.
Competing interests: None.
sclerosis case with chronic cerebrospinal venous insufficiency pattern D.
Left: selective venography showing membranous obstruction of the
outlet of the azygous vein (AZY) combined with atresia of the descending
azygous vein (arrow). Due to multilevel obstruction of the azygous
system, the vertebral plexus is dilated below the atresia, and the blood is
drained through intrarachidian collateral circles (IRC) in an upward
direction. Top right: sagittal T1 weighted imaging after gadolinium
injection of the same case, showing typical multiple sclerosis lesions of
the spinal cord. The enhanced gadolinium image shows intrarachidian
venous plexuses in the form of small spots. Bottom right: axial merge T2
of the same patient at the cervical level with dilated extrarachidian
venous plexuses. SVC, superior vena cava.
Selective venography and MRI in a clinically defined multiple
398 J Neurol Neurosurg Psychiatry 2009;80:392–399. doi:10.1136/jnnp.2008.157164
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