Perspectives in Medicine (2012) 1, 371374

Bartels E, Bartels S, Poppert H (Editors):

New Trends in Neurosonology and Cerebral Hemodynamics an Update.
Perspectives in Medicine (2012) 1, 371374
journal homepage: www.elsevier.com/locate/permed

Fact or ction: Chronic cerebro-spinal insufciency

Claudio Baracchini , Paolo Gallo
Department of Neurological Sciences, University of Padua, Via Giustiniani 5, 35128 Padova, Italy

KEYWORDS
CCSVI;
Ultrasound;
Multiple sclerosis

Summary Multiple sclerosis (MS) is a chronic inammatory and neurodegenerative disease

of the central nervous system (CNS). Its autoimmune origin has been recently challenged by a
substantially different mechanism termed chronic cerebrospinal venous insufciency (CCSVI),
which has attracted worldwide attention in the scientic community, in the media and among
MS patients. According to this hypothesis, a congestion of cerebrovenous outow induces an
increased intracranial pressure and a disintegration of the bloodbrain barrier in perivenular
regions promoting local iron deposition and activation of pro-inammatory factors, ultimately
leading to MS. After the initial report of a perfect association between CCSVI and MS, different
independent groups were not able to replicate these results, casting doubts on the credibility
of the CCSVI concept in MS. In spite of this, interventional procedures like venous angioplasty
named the liberation treatment have been claimed as a cure of MS or at least as a major
improvement of MS symptoms. As a result, an increasing number of MS patients are undergoing
endovascular treatment, in spite of a lack of an evidenced-based benet and recent reports
of serious adverse events. This review represents a critical appraisal of the CCSVI hypothesis,
discusses its basis, the diagnostic criteria and its relationship with MS.
2012 Elsevier GmbH. Open access under CC BY-NC-ND license.

Introduction
Multiple sclerosis (MS) is a chronic inammatory, neurodegenerative disease of the central nervous system (CNS).
Its autoimmune origin is supported by immunological,
genetic, histopathological, and therapeutic observations,
even though the mechanisms that initiate this autoimmune
attack are still unknown [14]. A disorder of cerebrospinal
blood ow named chronic cerebrospinal venous insufciency (CCSVI) has been proposed by Zamboni to play a
possible etio-pathogenetic role in multiple sclerosis [5,6].
This big idea, a term used by Zamboni himself to dene

Corresponding author. Tel.: +39 049 8213600;

fax: +39 049 8751770.
E-mail addresses: claudiobaracchini@tin.it (C. Baracchini),
paolo.gallo@unipd.it (P. Gallo).

2211-968X 2012 Elsevier GmbH. Open access under CC BY-NC-ND license.

doi:10.1016/j.permed.2012.01.005

his theory, rises from observations on systemic venous diseases and the possible parallels between these and brain
inammation [5]. Zambonis working hypothesis is that
brain inammation is iron-dependent [7]: he postulated
that multiple extracranial venous anomalies of the internal
jugular and/or azygos veins [8] cause a venous reux into
the cerebrospinal compartment, determining an increased
intra-venous pressure that disaggregates the bloodbrain
barrier, thus causing the deposition of iron in brain tissue and evoking a local inammatory response. By applying
ve parameters of abnormal venous outow, indicative of
CCSVI, Zamboni and co-workers were able to demonstrate
a strong relationship between CCSVI and MS. Indeed, in
their pivotal study, they analyzed 109 patients with clinically denite MS and 177 control subjects by means of
transcranial and extracranial color Doppler sonography and
found that all patients with MS had abnormal venous parameters: the presence of at least 2 of those 5 parameters was

372
Table 1

C. Baracchini, P. Gallo
Ultrasound CCSVI criteria.

1. Reux (t > 0.88 s) in the IJVs and/or in the VVs in sitting

and supine position
2. Reux (t > 0.5 s) in the DCVs
3. High-resolution B-mode evidence of proximal IJV
stenoses (local reduction of CSA 50% in the recumbent
position or CSA 0.3 cm2 )
4. Flow not Doppler-detectable in the IJVs and/or VVs
despite numerous deep inspirations with the head at 0
and +90
5. Reverted postural control of the main cerebral venous
outow pathways: negative CSA in the IJV
CSA, cross-sectional area of the internal jugular vein; IJV, internal jugular vein; VV, vertebral vein; DCVs, deep cerebral veins;
CSA = CSAsitting CSAsupine .

observed as being diagnostic of MS with 100% specicity,

100% sensitivity, and positive and negative predictive values
for MS of 100%. Zamboni and co-workers went on to perform
unblinded selective venography in 65 patients with MS as
well as in some control subjects, and reported that patients
with MS had multiple severe extracranial stenoses, while
these abnormalities were never found in normal controls
[9]. Furthermore, in a retrospective study, the same authors
found that the distribution of the pathological hemodynamic
patterns was highly predictive of the symptoms at onset and
of the following clinical course [10]. In this review, we try
to analyze critically the various aspects of Zambonis theory
and address several questions not only on the relationship
between CCSVI and MS, but also on the scientic basis of
CCSVI and thus, on its real existence.

The ultrasound puzzle

The diagnosis of CCSVI is based on ve ultrasonographic criteria (Table 1), four extracranial and one intracranial [11].
According to Zambonis initial ndings the presence of at
least two of these criteria provides indirect evidence of
impaired cerebral venous drainage and should be consistent
with the diagnosis of MS. Several independent investigators have tried to reproduce with various methodological
approaches the striking results obtained by Zamboni, but
none have succeeded [1219]. In particular, we performed
two large studies. In the rst study, we aimed at analyzing the occurrence of CCSVI at MS onset, to elucidate the
possible causative role of CCSVI in MS as suggested by Zamboni, who surprisingly did not study these patients. Fifty
patients presenting a clinically isolated syndrome (CIS) and
having evidence of dissemination in space of the inammatory lesions underwent a comprehensive diagnostic workup,
including extracranial and transcranial venous echo-color
Doppler sonography. Patients who showed evidence of CCSVI
were further evaluated by selective venography. Fifty MSmatched normal controls (NC), 60 patients with transient
global amnesia (TGA), and 60 TGA-matched NC were studied. Transcranial venous echo-color Doppler was normal in
all patients with CIS. One or more abnormal extracranial
venous echo-color Doppler ndings were observed in 26 of
50 (52.0%) of the patients with CIS, 35 of 110 (31.8%)

of the controls and 41 of 60 (68.3%) of the patients with TGA.

The eight (16%) patients with CIS who fullled the diagnosis
of CCSVI were further evaluated blindly by selective venography, which did not disclose any venous anomalies. Thus,
we could not demonstrate any causative effect of CCSVI on
MS [14]. The second study was focused on the progressive
forms of MS, to investigate whether CCSVI could play a role
in determining disease progression. We analyzed 60 patients
with chronic progressive forms of MS (35 SP, 25 PP) and 60
age-/gender-matched NC. TCDS was normal in all patients.
ECDS showed one or more abnormal ndings in 9/60 (15.0%)
patients [7/35 (20.0%) SPMS, 2/25 (8.0%) PPMS] and in 14/60
(23.3%) NC (p not signicant for all comparisons). CCSVI
criteria were fullled in 0 NC and 4 (6.7%) MS patients: 3
SPMS and 1 PPMS. VGF, performed blindly in 6/9 patients,
was abnormal only in one case that had bilateral internal
jugular vein (IJV) stenosis [17]. These ndings indicate that
CCSVI is not a late secondary phenomenon of MS and is not
responsible for disability progression.

The ultrasound method

On the basis of these contradictory results, it is absolutely
necessary to question the validity of the ve ultrasound criteria proposed by Zamboni for the diagnosis of CCSVI. In the
rst criterion, Zamboni et al. used the threshold value of
0.88 s to discriminate IJV and vertebral vein (VV) physiological back ow due to valve closure from pathological reux
without performing the Valsalva maneuver (VM) [8] and they
found that 71% of MS patients had a pathological reux vs. 0%
of controls. This threshold value comes from a totally different study on IJV valve insufciency during a controlled
VM [20] where it was chosen to differentiate VM-induced
insufciency through insufcient valves lasting >1.23 s, from
physiological backward ows during normal valve closure,
lasting 0.220.78 s. In this study it was found that about
30% of normal subjects have a physiological (t < 0.88 s) back
ow during normal valve closure. Furthermore, the utilization of this threshold by Zamboni for assessing reux in other
vessels (i.e. VVs) other than IJV valve insufciency is also
scientically incorrect.
For the second criterion, the intracranial veins and
sinuses were not examined through the transtemporal bone
window for which there are published ultrasound criteria and velocity data [21,22]. Zamboni et al. used a
new bone window (supracondylar) for which there are
neither accepted published criteria nor normative data,
and the gures published are not compatible with normal
anatomy [8,11]. With regard to venous reux, this evaluation requires a Doppler spectrum analysis, because a
color-based approach is inadequate and can easily lead to
the misinterpretation of ow direction. More importantly,
the rationale of adopting a threshold value of 0.5 s to discriminate pathological reux in the deep cerebral veins is
unclear. This value was derived from studies in the veins
of the leg where it served to quantify venous valve insufciency following deation of a tourniquet [23,24]. The
rationale for transferring this value from the legs to the brain
is very questionable since it has never been validated for
deep cerebral veins. The validity and signicance of data
collected by this method are therefore unclear especially

CCSVI: fact or ction?

if it is used to diagnose CCSVI, where cerebral reux is
not described by the same author as associated with valve
incompetence.
The third criterion denes a stenosis of the IJV as a local
reduction of the cross sectional area (CSA) 50% in the
recumbent position or CSA 0.3 cm2 [8]. This latter cut-off
value was derived from a study on intensive care patients
[25], with possible confounders such as mechanical ventilation and hypovolemia. It can, therefore, not be used as
a reference point in healthy subjects. Furthermore, it is
difcult to decide where to measure the diameter of the
vein since IJVs are normally tortuous and the most proximal and distal parts near the superior and inferior bulb are
physiologically dilated more than others. It is important to
stress that even mild pressure exerted by the ultrasound
probe or by a contraction of the cervical musculature itself
can alter the diameter of the vein leading to false-positive
results.
The fourth criterion, which is the inability to detect ow
in the IJVs and/or in the VVs during deep inspiration, according to Zamboni et al., provides indirect evidence of venous
obstruction [8]. This criterion has never been validated. A
lack of ow is not necessarily due to obstruction since it can
occur, e.g. at 15 in both IJVs in healthy subjects [22]. In
the upright position, there is a dramatic reduction and frequently a complete cessation of blood ow in the IJV. In the
supine position there may also be no ow in the VVs [26].
Furthermore, an inadequate setting of ultrasound indices
such as pulse repetition frequency might lead to an apparent absence of color-coded signal and a misinterpretation
of no-ow.
The fth criterion examines the presence of a physiological shift of cerebral venous drainage from the jugular
venous system to the vertebral plexus with postural change:
from the supine to the sitting position. In normal subjects,
subtracting the CSA measured in the supine position from
that in a sitting position (CSA) is usually negative [22].
Instead, Zamboni wrongly considered that a negative CSA
value would represent a reverted postural control of the
main cerebral venous outow pathways [8]. Furthermore,
similarly to criterion three, a mild pressure exerted by the
ultrasound probe or by a contraction of the cervical muscles may alter the diameter of the vein possibly leading to
false-positive results. A more correct method would be to
calculate the difference of blood ow (CSA velocity) in the
two positions (supine and sitting) as has been recently performed [12], not conrming the hypothesis of Zamboni and
co-workers.
A very important issue is the cut-off point of these criteria to diagnose CCSVI. In fact, it is unclear how Zamboni
decided that two or more of the ve ultrasound criteria may
be used to diagnose CCSVI. Diagnostic criteria using a new
alternative method (i.e. ultrasound) are usually compared
with a validated gold-standard investigation (venography
according to Zamboni et al.). However, Zamboni et al.s
comparison of venography in 65 CCSVI ultrasound-positive
MS patients was not blinded and is therefore open to
bias. There was also no validation of the CCSVI-criteria by
different and independent observers. Finally, subsequent
studies using MR-venography could not conrm differences
regarding cerebrospinal drainage in MS patients and controls
[2730].

373

Conclusions
Ultrasound investigation of intracranial and cervical veins is
highly operator dependent owing to the wide anatomic and
physiological variability of these vessels. Therefore a study
of cerebral venous drainage requires very experienced neurosonographers, but most importantly, blinding algorithms
are mandatory in assessing MS patients especially during
venographic verication of ultrasound ndings; these were
completely omitted in Zambonis studies. To this day, a
scientically sound validation of each of the ve criteria
proposed by Zamboni for the diagnosis of CCSVI is missing,
not to mention their combined application. Concurrently,
there is growing evidence which rejects the role of CCSVI
in the pathogenesis of MS and which suggests that the proposed CCSVI criteria are questionable due to miscitation,
manipulation of known data and methodological aws. Thus,
any potentially harmful interventional treatment such as
transluminal angioplasty and/or stenting should be strongly
discouraged, not only for the lack of any evidence, but also
for the risk of serious peri-procedural complications.

Author contributions
Claudio Baracchini: Conception, organisation and execution of the research project; writing and review of the
manuscript.
Paolo Gallo: Conception, organisation and execution of
the research project; writing and review of the manuscript.

Disclosures
Dr. Baracchini serves on the executive committee of the
European Society of Neurosonology and Cerebral Hemodynamics; has received funding for travel and speaker
honoraria from Pzer, Sano-Aventis, Laboratori Guidotti
and Novartis; serves as Associate Editor for BMC Neurology;
and has given expert testimony in a medico-legal case.
Dr. Gallo serves on scientic advisory boards, as a consultant, and on speakers bureaus for and has received
funding for travel and speaker honoraria from Novartis, Biogen Idec/Elan Corporation, Merck Serono, Sano-Aventis,
and Bayer Schering Pharma; and receives research support from Novartis, Biogen Idec/Elan Corporation, Merck
Serono, Sano-Aventis, and Bayer Schering Pharma, the
Veneto Region of Italy, the University of Padova, and the
Ministry of Public Health of Italy.

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