Endovascular Treatment of Cerebrospinal Venous Insufficiency Safe, May Provide Benefit in MS
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Endovascular Treatment of Cerebrospinal Venous Insufficiency Safe, May
Provide Benefit in MS
Susan Jeffrey/Medscape Writer
December 3, 2009 — New data from a pilot open-label study suggest that
endovascular treatment of strictures in extracranial cerebrospinal
veins is safe in patients with multiple sclerosis (MS) and may provide
some neurological benefit for these patients, researchers conclude.
The controversial approach, which has recently been making headlines
in consumer media outlets, proposes that narrowing in the veins
draining the brain, called chronic cerebrospinal venous insufficiency
(CCVI), may be an early step in the disease process causing MS, and
further, this narrowing may respond to simple angioplasty.
Left: location of venous stenosis with relative rate found in CCVI
associated with multiple sclerosis. Right: the minimally invasive
technique of balloon angioplasty eliminates the stricture in the
cerebral venous system.
Lead author Paolo Zamboni, MD, director of the Vascular Diseases
Center at the University of Ferrara, Italy, emphasized that the
current report should be viewed as an interesting finding that
urgently requires replication by other groups.
"What we know is that MS is very complex and multifactorial," Dr.
Zamboni told Medscape Neurology. "I have identified an unknown factor
and possible treatment for this factor."
The study is published as an online article in the December issue of
the Journal of Vascular Surgery.
CCVI and MS
In a previous study published online in December 2008, Dr. Zamboni and
colleagues assessed venous outflow routes in 65 patients with
clinically definite MS (CDMS) and 235 control patients using a
combined transcranial and extracranial color Doppler high-resolution
examination. They reported that CDMS and venous outflow abnormalities
were "dramatically" associated, with an odds ratio of 43 (95%
confidence interval, 29 - 65; P < .0001).
Venography showed the presence of multiple severe extracranial
stenoses affecting the principal venous segments in the patients with
MS but not the control patients. "This provides a picture of chronic
cerebrospinal venous insufficiency with 4 different patterns of
distribution of stenosis and substitute circle," the authors write.
"Moreover, relapsing-remitting and secondary progressive courses were
associated with CCVI patterns significantly different from those of
primary progressive (P < .0001)" (Zamboni P, et al. J Neurol Neurosurg
Psychiatry 2009;80:392-399).
In an editorial accompanying that publication, Claude Franceschi, MD,
from Saint Joseph and Pitié-Salpétrière Hospitals in Paris wrote that,
"in light of the association between such a previously overlooked
vascular picture and MS, a further stimulating research field is
opened by this article. This should be addressed in understanding the
contribution of venous drainage to the different aspects of
inflammation, autoimmunity and neurodegeneration characterising the
intriguing puzzle of MS" (Franceschi C. J Neurol Neurosurg Psychiatry
2009;80:358).
Dr. Zamboni stressed that this association between venous stenoses in
extracranial arteries and MS is not contradictory to what is already
known about the disease. "What I've found is a previously unknown
factor, widely diffuse in my MS population, which could trigger or
facilitate both immune reaction and inflammation," he told Medscape
Neurology. "If you have elevated pressure and difficulty of drainage
in the brain, you have the possibility of extravazation of blood
components crossing the blood–brain barrier, and this could trigger
inflammation and also immune reaction."
Restenosis a Problem
In the current report, the researchers describe the safety and early
outcomes in these same patients after endovascular treatment of
stenoses in the internal jugular vein and the azygous vein.
Of the 65 patients, 35 had relapsing-remitting disease, 20 had
secondary-progressive disease, and 10 had primary progressive MS. All
underwent percutaneous transluminal angioplasty to address strictures
in these veins. All procedures were done as day surgery under local
anesthesia, and no operative or postoperative complications were seen,
including vessel rupture, thrombosis, or adverse effects from
contrast.
Postoperative headache was reported in 6 patients, which resolved
spontaneously, and minor hemorrhages with hematoma occurred at
vascular access sites "occasionally," the authors report.
After the procedure, venous pressure was significantly lower in the
internal jugular and azygous veins (P < .001). Stenoses in these
venous pathways "were never found to be isolated," the researchers
note, but always combined in the internal jugular, azygous veins, or
lumbar system in 4 main patterns of distribution.
At a mean follow-up of 18 months, the risk for restenosis after
intervention was higher in the internal jugular vein, Dr. Zamboni
noted, with a patency rate of 53% compared with 96% in azygous veins
(95% confidence interval, 3.5 - 72.5; P < .0001).
Patency at follow-up depended on the type of obstruction faced,
including membranous obstructions, twisting, and hypoplasia. A stent
was placed in 1 patient to resolve a twisted vein, but a second case
retwisted, the authors note.
Using the patients as their own control, the researchers found
improvement with treatment on some clinical outcome measures after the
intervention, particularly for the relapsing-remitting patients. In
this group, 27% were relapse-free before surgery and 50% were so after
treatment (P < .001). Gadolinium-enhancing lesions on magnetic
resonance imaging (MRI) fell from 50% to 12% (P < .001).
Significant improvement over the preoperative assessment was seen at 1
year on the Multiple Sclerosis Functional Composite again for
relapsing-remitting patients (P < .008), but not among those with a
secondary or primary progressive course.
Physical quality-of-life measures also improved significantly in
relapsing-remitting MS patients and in primary-progressive patients,
with a positive trend among those with secondary progressive disease.
Mental quality of life also was significantly improved for the
relapsing-remitting and primary progressive groups, but not for those
with secondary progressive MS.
The authors conclude that although improved endovascular techniques
are needed to approach the internal jugular vein, "the results of this
pilot study warrant a subsequent randomized control study."
It is possible that the addition of stents to this endovascular
approach that he calls the "liberation procedure" may improve
outcomes, Dr. Zamboni noted. "However, the results are really
interesting, if you think that all treated patients were already under
the best treatment for MS and had adjunctive neurological benefits
from the liberation procedure compared to the previous 2 years."
Mixed Response From Neurology Community
Asked for comment on these findings, Lily Jung, MD, from the Swedish
Neuroscience Institute, Seattle, Washington, speaking on behalf of the
American Academy of Neurology, was cautious in her assessment. She
feels some of the strong claims in the current report are not
supported by the data.
For example, the number of patients in the report is small, "and to
make the correlation between the patterns of venous obstruction and
the categories of MS is a real stretch," Dr. Jung said. Assessment was
done by unblinded neurologists, which is "not ideal." She also noted
that the MRI results used different techniques, different protocols,
and different study intervals.
We would welcome some randomized, controlled, double-blinded
studies...but before then would not be encouraging our patients to
jump in with both feet to do this procedure.
"The bottom line is that my colleagues and I have been flooded by
calls and emails from patients who have been led by the publicity
around this article to believe that there is a cure for MS, and to
make such a claim with such preliminary results is premature," Dr.
Jung said. "We would welcome some randomized, controlled, double-
blinded studies to look at the issue, but before then would not be
encouraging our patients to jump in with both feet to do this
procedure, which has significant risks and has not been proven to be
safe."
As a vascular interventionalist, Dr. Zamboni says he is keen to
collaborate with neurologists in the setting of MS, but acknowledged
that his work has had a mixed response from the neurology community.
Some, he says, have been excited and at least curious, which in his
view is important in research. Researchers from institutions including
Stanford, Harvard, the Mayo Clinic, and others have asked to discuss
the technique so that they may attempt to reproduce these findings in
their own populations.
To the contrary, of course, I've also found big opposition, but I
think that probably it is a prejudgement.
"To the contrary, of course, I've also found big opposition, but I
think that probably it is a prejudgement, and they have not read the
paper carefully," he said. "But it's not important. What is important
is to have other people interested in doing the research and
understanding more."
The first step will be to understand how widespread the presence of
CCVI is among patients with MS, he said. "We need to test patients
very rapidly to have the epidemiological data, which are very
important."
Already, Dr. Zamboni is collaborating with Robert Zivadinov, MD, and
colleagues at Buffalo General Hospital in New York on an open-label,
MRI-blinded study of 16 relapsing-remitting patients with MS with
confirmed strictures in the cerebrospinal venous outflow routes. Half
— 4 randomly selected patients in Italy and 4 in New York — will
undergo early intervention to address the blockages at 3 months, and 8
patients will have a delayed procedure at 6 months of follow-up.
Safety and preliminary efficacy will be monitored using MRI and
clinical examination, and outcomes will be compared at 1 year. Dr.
Zamboni and Dr. Zivadinov presented their protocol at the 25th
Congress of the European Committee for the Treatment and Research in
Multiple Sclerosis earlier this year in Düsseldorf, Germany.
In Buffalo, they are also conducting a larger epidemiological study
aimed at determining the prevalence of CCVI among their MS patients.
Dizzying Excitement, Desperate Hope
Although Dr. Zamboni has published previously on this procedure, a
news report by a national Canadian news organization with an
associated documentary on the same network recently profiled this
work, generating a dizzying excitement for many patients in Canada,
where MS rates are among the highest in the world. Their subsequent
comments on various Internet news and patient sites reflect a
desperate hope that this new approach may provide those with MS a
possible alternative to lifelong drug therapy and the steady
encroachment of disability.
In a public statement issued December 1, the National Multiple
Sclerosis Society cautioned that the findings are preliminary. "Many
questions remain about how and when this phenomenon [CCVI] might play
a role in nervous system damage seen in MS, and at the present time
there is insufficient evidence to prove that this phenomenon is the
cause of MS."
However, the society also notes that it is very interested in seeing
more data on this procedure and is prepared to put its money where its
mouth is, calling for research proposals to generate that data.
"If confirmed, these findings may open up new research avenues into
the underlying pathology of MS, as well as potential new approaches to
therapy," the statement notes. "The National MS Society has invited
research proposals to investigate this lead, and is in active
discussions with the MS Society of Canada about the possibility of
collaborative funding of [CCVI] research."
The authors have disclosed no relevant financial relationships.
J Vasc Surg. 2009;50:1348-1358.
[CLOSE WINDOW]
Authors and Disclosures
Journalist
Susan Jeffrey
Susan Jeffrey is the news editor for Medscape Neurology &
Neurosurgery. Susan has been writing principally for physician
audiences for nearly 20 years. Most recently, she was news editor for
thekidney.org and also wrote for theheart.org; both of these Web sites
have been acquired by WebMD. Prior to that, she spent 10 years
covering neurology topics for a Canadian newspaper for physicians. She
can be contacted at SJef...@webmd.net.
Medscape Medical News © 2009 Medscape, LLC
Send press releases and comments to ne...@medscape.net.
janice
>
> Medscape Medical News © 2009 Medscape, LLC
I have not been diagnosed with MS however I have been told that I have
all the systems. My situation came from a 10 fall landing on the back
of my head in 1983. Since that time I have this horrible pressure on
the back of my head and neck and nothing can touch it. I fall a lot,
am dizzy, sometimes have total urine retention and horrible mental fog
and about every 5 years the blood pressure which is usually 118/78
zooms up to over 270 and have this horrible sensation of being pushed
to the ground. The reason I am so interested in this is that in 1993
I had a doppler test done on the subclavical veins and the veins
totally occluded bilaterally when the head was in a slight down
position. The doctors involved didn't know how to fix me. I went to
the ER during one of the high blood events and they did an angioplasty
and afterward the doctor said that he would never do it again because
my veins are too small. It all makes sense. I would give anything to
get rid of this condition, this sounds like the answer to my
situations. I am truly excited.
Peter Black
symptoms a patient experiences depends on what part of the brain is
affected.