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Wednesday, December 1, 2010 9:49 PM
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Ken Torbert
CHRONIC CEREBRO-SPINAL VENOUS INSUFFICIENCY (CCSVI) AND MULTIPLE
SCLEROSIS
A. Ghezzi *, G. Comi **, A. Federico ***
* Coordinator MS Study Group, Italian Neurological Society
** Elected President Italian Neurological Society
*** President Italian Neurological Society
key words: multiple sclerosis, CCSVI, Doppler sonography, extracranial venous stenosis, MRI.
Abstract:
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System
caused by the interplay of genetic and environmental factors. In the last years it has been
suggested that an abnormal drenage of venous blood due to stenosis or malformation of the
internal jugular and/or azygous veins may play a major pathogenetic role in MS. This abnormality
called Chronic Cerebro-Spinal Venous Insufficiency (CCSVI) could result in increased permeability
of blood brain barrier in perivenular regions with local iron deposition and secondary multifocal
inflammation. In the present paper literature data in favour and against this hypothesis are
reported. A great variability of CCSVI has been found in both multiple sclerosis patients (ranging
from 0% to 100%) and in control subjects (from 0% to 23%). This large variability is explained by
methodological aspects, problems in assessing CCSVI, differences among clinical series. It is
urgent to perform appropriate epidemiological studies to define the possible relationship between
CCSVI and MS
Background
Multiple sclerosis is an inflammatory demyelinating immunomediated disease of the Central
Nervous System affecting subjects from 20 to 40 years of age in the majority of cases (1-3). The
initial course is generally relapsing-remitting, followed by progressive deterioration of neurological
symptoms (secondary progressive course) after a variable interval form onset, with or without
superimposed relapses, leading to severe fixed disability: about 50% of cases reach EDSS 6 (loss
of autonomy) after 15-20 years from onset (4-8). In Italy it is reasonable to estimate that 50.000-
70.000 subjects are affected by MS.
There is strong evidence that MS is caused by the interplay of genetic and environmental factors,
only partially known (1, 9-11).
In the last two years the so called “vascular hypothesis” has caused an international uproar in the
scientific community and media: in this paper we will discuss the more relevant scientific data
related to this issue.
CCSVI and multiple sclerosis
Studies conducted by Zamboni and coworkers has suggested the new hypothesis that an
abnormal drenage of venous blood due to stenosis or malformation of the internal jugular and/or
azygous veins can be the cause of MS. He called this abnormality “Chronic Cerebro-Spinal
Venous Insufficiency (CCSVI)”. In a preliminary study of 89 MS subjects who had been
investigated by means of transcranial color-coded duplex sonography (TCCS) technique, Zamboni
et al. found that haemodynamic alterations of brain venous drenage were significantly more
frequent in MS compared to 60 healthy subjects (12). The abnormalities were more pronounced in
patients with a higher disability scores. He concluded that these findings were consistent with the
role of an altered venous flow in the inflammatory process, probably related to an increased
expression of adhesion molecules, macrophage and T lymphocyte infiltration, matrix
metalloproteinases hyperactivation, increased iron deposition.
In a second study CCSVI was investigated in 65 clinically definite MS patients (30 males, 35
females) and 235 controls by means of high-resolution echocolour Doppler (ECD) and transcranial
colour Doppler sonography (TCCS) (13). Five parameters of anomalous venous outflow were
identified, and the final diagnosis of CCSVI was made if at least two of them were fulfilled. Venous
outflow anomalies appeared to be dramatically associated to MS (p<0.0001). None of the controls
were positive for more than one of the CCSVI criteria.The risk of MS related to an abnormal
venous return increased by 43-fold compared to controls. Venography demonstrated the presence
of multiple severe extracranial stenosis affecting the principal cerebrospinal venous segments in
MS, but not in control subjects.
In a cohort of 109 MS subjects and 177 controls including both healthy subjects and other
neurological diseases, CCSVI criteria were found in all MS patients and in none control subject
(sensitivity 100%, sensibility 100%, positive predictive value 100, negative predictive value 100%)
(14).
The abnormal venous return pattern has been found to be correlated with an abnormal flow
dynamics of cerebrospinal fluid, studied with a specific MRI technique (15). Increased iron
deposition in the brain revealed by MRI and pathological studies (16, 17) was considered an
indirect evidence of an abnormal venous dreinage, supporting the pathogenetic role of CCSVI in
MS.
Many other contributions have been provided by Zamboni et al. and other research groups, most of
them published in a recent issue of Int. Angiol. (Minerva Medica) (18-28). In particular Al-Omari &
Rousan found that 84% of 25 MS patients and none of 25 controls showed evidence of CCSVI
(27). Simka et al. found that CCSVI criteria were fulfilled in 90% of 63 MS patients (28).
Two recent position papers challenged the view of the pathogenetic relevance of CCSVI in MS (29,
30). Very recently some studies failed to confirm the high frequency of abnormal brain venous flow
on MS patients (31-36), moreover some abnormalities were reported in other neurological
conditions such as transient global amnesia and neurodegenerative diseases (37, 38).
Zivadinov et al. have presented the results of their studies in many International Congresses
American Academy of Neurology, Toronto 2010, ECTRIMS, Gothenburg 2010). Briefly, 289 MS
patients, 163 healthy controls and 26 subjects with other neurological diseases were evaluated
with the same approach described by Zamboni et. al., finding the pattern of CCSVI respectively in
56%, 22,7% e 42,3% of cases (38). Venous abnormalities were correlated to the severity of brain
damage, to measures of brain atrophy (39), and to the severity involvement of motor, cerebellar
and brainstem involvement (40).
Doepp et al. (31) studied 56 MS patients and 20 healthy subjects with extra- and transcranial colorcoded
sonography, finding no venous stenosis in any of them; none of the subjects investigated in
this study fulfilled >1 criterion for CCSVI leading to conclusion that cerebral venous congestion is
unlikely to play a significant role in the pathogenesis of MS.
Sundstrom et al. (32) studied 21 relapsing-remitting and 20 healthy controls with phase-contrast
MRI to evaluate the flow direction and flow rate of intracranial blood and CSF, and e contrastenhanced
MR angiography to evaluate venous anatomy and pathology (only in MS patients): no
differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the
presence of internal jugular blood reflux were found. Using MR angiography, a venous stenosis of
the internal jugular vein was found in only 3 of 21 MS cases.
Worthington et al. (33) measured the levels of ferritin in a cohort of 1408 subjects (MS patients
and OND), given the presumed mechanism of venous stasis-related parenchymal iron deposition
and upregulation of proteins involved in intrathecal iron transport : ferritin was increased in 10 % of
relapsing-remitting, in11% of primary progressive, and 23% of secondary progressive MS patients,
as well as in 4% oft he control patients, in 91% of patients with superficial siderosis, in 73% of
patients with subaracnoid hemorrhage, and in 23% of patients with meningoencephalitis. The
Authors concluded thast their data do not support an etiological role for CCSVI-related
parenchymal deposition in MS.
Wattjes et al. (34) used the technique of magnetic resonance venography in 20 MMS patients and
19 healthy controls: intracranial stenosis was found in 4 e 1 cases, extracranial abnormalities in 8 e
7, concluding that venous abnormalities are an anatomical variant, without any correlation with the
neurological condition,
Yamout et al. (35) performed selective venous angiography in 42 MS patients in various phases of
the disease: at onset, in subjects with a disease dursation less than 5 years or more than 10 years.
Extracranial venous stenosis were very rare at onset (7/29) but became more frequent in subjects
with a longer lenght of MS (12/13), suggesting they are a secondary phenomenon, due to chronic
brain damage,
Baracchini et al. (36) performed a doppler sonography study in 50 CIS (Clinically Isolated
Syndrome) patients with MRI and CSF pattern suggestive of MS, and in 50 healthy matched
controls. Transcranial color-coded venous sonography was normal in all subjects, whereas
extracranial color-coded venous sonography was abnormal in 52% of patients and in 32% of
control subjects. Of the eight patients who met the CCSVI criteria, seven underwent selective
venography, resulting normal in six and showing hypoplasia of the right internal jugular vein in one.
The authors concluded that cerebral venous congestion does not have a causative role in the
pathogenesis of MS.
Other studies have been recently presented at the recent ECTRIMS Congress:
- Alikhani et al. (41) submitted 21 MS patients and 25 controls to MRI-venography.
Abnormalities of venous vassels were found in 23,8% of MS patients and in 21,4% of
controls, without any correlation with MS diagnosis,
- Khalil et al. (42), using the technique of MRI R2-relaxometry, observed an increased iron
deposition within the basal ganglia of MS patients; as this finding was correlated to cerebral
atrophy and lesion load, it was thought to be the effect and not the cause of brain damage,
- Simka e coll (43) did not find a correlation between the venous abnormalities findings and
MS severity or type of course in a cohort of 331 MS patients with CCSVI, suggesting that
this condition is congenitally present.
Based on the assumption of a potential role of CCSVI in MS, Zamboni et al. performed
percutaneous transluminal angioplasty in a cohort of 65 patients (35 relapsing-remitting,20
secondary progressive, 10 primary progressive) (44). After a mean follow up of 18 months, a
significant improvement of clinical outcome measures, including increase of proportion of relapse
free patients and decrease of Gd enhancing lesions, was observed. Physical and mental QoL also
improved, especially in RR patients. However restenosis occurred in 47% of cases. The
intervention was safe and well tolerated, but the relatively low number of cases and of follow up
length, the lack of controls, the unblind evaluation preclude to reach conclusions on the efficacy of
this intervention. No relevant adverse events occurred in another cohort of MS subjects
treated with balloon angioplasty (414 subjects) or stent implantation (73 subjects)
(45). However two severe adverse events have been reported in two cases (46): one patient died
because of cerebral hemorrhage while on anticoagulant following a stent insertion.
Another patient had to be submitted open heart surgery to remove the stent that,
placed in the jugular vein dislodged into the right ventricle (15).
CONCLUSIONS
To conclude, literature data show very different results regarding the presence and frequency of
CCSVI: it has been found in 90-100% of MS cases and never in control subjects (13, 27, 28), in
about 55% of MS patients but also in 23% of controls, in about ¼ of both MS and control subjects
(38), in only a few or no case with MS and never in controls (31, 36). An abnormal brain venous
outflow has been excluded by other Authors using neuroimaging techniques (32, 34-36, 41) The
presence of CCSVI according to doppler sonography has been confirmed by venous angiography
in one study as proof of its presence (13), but not in another study, as a proof against its presence
(36).
Moreover it is not clear which is the gold standard to assess CCSVI: if doppler sonography, venous
MRI, or venous angiography.
In studies demonstrating the presence of CCSVI, this finding has been considered a congenital
abnormality, strictly related to the development of MS (12, 26, 43), but in other studies it has been
demonstrated that is the consequence of disease progression, related to brain damage, disease
duration, iron deposition in the CNS (40-42). Moreover, patients who underwent Doppler
sonography at the first episode of MS did not show an abnormal cranial venous outflow, against
the hypothesis of a predisposing factor (36, 41).
Iron deposition in the CNS has been reported as a proof of an abnormal venous outflow (17), but
other studies have not confirmed this finding, showing no abnormal deposition (33), or a deposition
secondary to brain damage (42).
As recently agreed in a dedicated symposium during 2010 ECTRIMS annual congress in
Gothenburg (Sweden) involving some of the key researchers in the CCSVI area, including
Zamboni and Zivadinov, the available information does not support the view that CCSVI is the
cause of MS. The evidences from a large body of epidemiological and pathogenetic studies
indicating the role genetic and environmental factors demonstrate the complexity of factors
underlying MS (1, 9-11). Old epidemiological studies demonstrated the individual risk of having MS
changes if subjects move early in life from a high risk to a low risk area and vice-versa, a change
that cannot be explained by a vascular pathogenesis of MS (1, 10). Recent genome-wide
multicentre studies revealed more than 100 genes playing some role in MS, all of them except one
linked to the immune system (9, 47-49), an observation speaking against the CCSVI causative role
in MS.
Nevertheless the Zamboni’s theory is interesting and the influence of an abnormal venous flow in
extracerebral veins on disease risk and disease evolution must be explored with a appropriate
methodologies. Subgoups of MS patients with different disease courses and variable disease
severity should be examined for the presence of CCSVI in comparison with normal controls and
with patients with other neurological diseases. Studies should be blind and the assessment of
CCSVI should be performed with rigorous Doppler sonography examination and appropriate
quality control of all the procedures. Similar studies are ongoing or planned in many European and
North-American countries.
Until the role of CCSVI has not been fully elucidated, clinical trials evaluating the impact of
endovascular interventions to widen extracranial veins should not be performed. For this reason
angioplasty or stenting in individual patients is not admissible and, if performed, may open the
possibility of legal queries.
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