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Wednesday, October 27, 2010 11:00 PM
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Ken Torbert
- Correspondence to Dr R W Tarr, University Hospitals Case Medical Center, Cleveland, OH 44102, USA; robert.tarr@uhhospitals.org
- Accepted 29 September 2010
- Published Online First 23 October 2010
IntroductionRecently, a radically different concept regarding the pathogenesis of multiple sclerosis (MS) has been proposed. Termed chronic cerebrospinal venous insufficiency
(CCSVI), it suggests that macro occlusive abnormalities of the
extracranial venous drainage pathways of the brain and spinal cord can
cause or contribute to MS. As a consequence of this theory, it has been
suggested that angioplasty and possibly stenting of the internal jugular
and/or azygos veins can improve the signs and symptoms of MS. These
interventions have been performed sporadically across the globe in an
open label fashion and never in the context of a well designed,
controlled, randomized and blinded clinical trial. Despite this, the
procedure has been labeled by some as ‘liberation procedure’ and caused a
firestorm of interest in the medical and MS communities, both for and
against its utilization. The arguments on all sides are passionate,
ranging from the belief that venous intervention is a miracle cure that
must not be withheld from patients, to the feeling that the procedure is
ineffective and unwarranted at best and dangerous at worst. The various
camps commonly protest that those with differing views are not acting
in the best interest of their patients. As neurointerventionalists interested in interventional treatment of neurological disorders, it is time to take a thorough
and objective look at CCSVI. This
commentary will examine the origin of the CCSVI theory and discuss the
data supporting and
refuting its existence. An attempt will
be made to critically analyze the available data and provide
constructive recommendations
about whether or not endovascular
therapy represents a reasonable option at this point in time for
patients with MS.
Brief review of multiple sclerosisMS is a fearful and unpredictable disease that brings an enormous physical, emotional and financial burden on patients, family, relatives, friends and society in
general. It is the most common cause of physical disability, with
estimated 250?000–350?000 individual diagnosed with MS in the USA. The
peak age at onset is 20–40 years. It affects women more so than men and
is more common among Caucasians. MS can present with just about any
neurological symptom in any part of the nervous system, sensory, motor,
cranial nerves, visual, autonomic, coordination and myelopathic on
different occasions with cumulative disability.1
Diagnosis is based on clinical and imaging criteria (McDonald criteria)
to establish the dissemination in place (different CNS sites) and time
(at least 30 days between clinical relapses and 90 days for new MRI
lesion without clinical relapse). The clinical course of MS is most
commonly relapsing remitting, with return to baseline after each
relapse, followed by secondary progressive starting as relapsing
remitting, then primary progressive MS.1
The most prevalent hypothesis regarding the pathophysiological basis
for MS is that it is an autoimmune inflammatory disease
triggered by environmental factors
(toxic and infectious triggers) with genetic predisposition leading to
myelin and axonal
destruction in the brain and spinal
cord by the immune system.1
To date, MS management has been limited to the indefinite
administration of ‘disease modifying’ medications and immune modulating
agents which may reduce the number and severity of relapses.1 These agents are not only costly but are associated with a wide spectrum of side effects ranging from mild to severe.
The CCSVI theory and supportive dataIn 2006, Zamboni, an Italian vascular surgeon, in an article titled ‘The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple
sclerosis’ suggested that there were similarities between chronic venous
disease of the extremities and MS.2 He raised the possibility that venous reflux or obstruction in cerebral and spinal veins might have a relationship to MS.2 Several years later, Zamboni et al reported on blinded transcranial and extracranial color Doppler sonographic findings in patients with MS and matched healthy controls and those with other neurological disorders.3 They focused on five findings: (1) reflux in the internal jugular vein
(IJV) or vertebral veins >0.88 s; (2) reflux propagated in at least
one out of the three deep cerebral veins >0.55 s; (3) high resolution
B mode evidence of proximal IJV stenosis; (4) flow not Doppler
detectable in the IJV or vertebral veins despite deep inspirations; and
(5) negative difference of the cross sectional area of the IJV comparing
the value obtained in the supine versus the sitting position. The
authors concluded that detection of two or more of these findings
constitutes the diagnosis of CCSVI. They found CCSVI in all MS patients
and in none of the controls. The sensitivity, specificity, positive
predictive value and negative predictive value of the test were all
100%. They concluded that there was CCSVI in MS patients.3 In a second paper, Zamboni et al published that catheter venography in patients who met CCSVI Doppler criteria showed stenosis in the azygos vein 86% of the
time and one or both IJV were affected
in 91%. In this study, the venographer was not blinded to the patients'
diagnosis.4
The study proposed four venographic patterns: (A) large IJV with one
IJV or proximal azygous vein stenosis; (B) both IJV
and proximal azygos vein stenosis; (C)
both IJV and normal azygous system; and (D) multilevel azygous stenosis
with or without
IJV involvement.
Finally, in 2009, Zamboni et al reported their results on the endovascular treatment of 65 MS patients with CCSVI.5 No isolated venous lesion was found, and the distribution of venographic patterns was 30%, 38%, 14% and 18% of types A to D, respectively.5 They performed percutaneous transluminal angioplasty (PTA) on all but
one azygos lesion that did not respond to PTA alone and required stent
placement. Pretreatment pressures beyond the stenosis were not
significantly different than normal venous pressure and there was no
significant change in pressure after angioplasty. Mean follow-up using
extracranial Doppler was 18 months, with an overall restenosis rate of
47%; more common in the jugular than azygos veins. Clinical outcome at
18 months was reported as showing relapse free of 50% versus 27%
preoperatively. It is important to note that the interpretation of the
clinical results of this uncontrolled study is confounded since patients
were continued on ‘immunomodulating’ therapy after endovascular
therapy. These medical therapies have been shown to significantly reduce
relapse rates as well as the accumulation of MRI detectable enhancing
lesions1 Finally, there was no improvement in patients with primary progressive or secondary progressive MS.5 Data against CCSVI role in MSAlthough the Zamboni papers have been quite supportive of CCSVI, there are a growing number of papers that raise serious questions
about its validity. In early 2010, Khan
et al described a number of independently accepted characteristics of venous disease and MS that contradict the CCSVI theory.6
Similar to other autoimmune diseases, MS is more common in young women while chronic venous insufficiency syndromes are not.
There are well known strong epidemiological associations between MS and geography, ethnicity, sun exposure, low vitamin D
levels, gender, genetics and
immigration studies that are not mirrored by chronic venous
insufficiency.
Central veno-occlusive disease can lead to syndromes of idiopathic intracranial hypertension, ischemic and hemorrhagic infarcts and edema, none of which is typically seen in MS patients.
Vascular abnormalities related to chronically diminished venous flow would be expected to increase over time, yet after the age of 50 years the incidence of MS is
quite low.
There is no other model of decreased venous drainage and an organ specific immune response.
Transient global ischemia is known to occur with jugular insufficiency but this entity is not seen in MS.
Radical neck dissections remove all jugular veins but they have never been seen to cause MS.6
The above cited challenges to the Zamboni thesis are based on largely theoretical considerations. In an attempt to replicate the Doppler findings of Zamboni, Doepp et al studied 56 MS patients and 20 controls using similar CCSVI criteria.7 The authors found no patients in either the MS or control groups who
had the two or more criteria required for a diagnosis
of CCSVI. They concluded based on these
results as well as their extensive longitudinal experience with cranial
venous Doppler
ultrasound, that there is typically
tremendous reserve capacity of the extrajugular pathways for cerebral
venous drainage
and that it is highly unlikely that IVJ
stenosis would cause central venous congestion. Furthermore, they went
on to discourage
interventional procedures for CCSVI
outside of the context of appropriately designed clinical research
studies.8 Additionally, Sundstrom et al looked at MRI of 21 patients with relapsing remitting MS and 20 healthy controls, and found no differences in internal jugular venous outflow between the two groups.9et al, from the MS research group at the State University of New York in
Buffalo, presented findings in the first 500 participants studied with
venous Doppler looking at the prevalence of CCSVI in MS patients and
controls. Using the requirement that =2 CCSVI Doppler criteria be met,
CCSVI was found in 62.5% of MS patients, 25.9% of healthy controls and
45% of other neurological disorders.10 At least preliminarily, these results are different from the 100% sensitivity and specificity found by Zamboni and colleagues.3 Finally, preliminary data from Zivadinov CommentaryThere is little debate as to the potential ravages of MS and the sincere desire to improve outcomes in patients suffering
from this terrible disease. As such,
when seemingly miraculous cures are proffered, we believe that it is our
responsibility
as neurointerventionalists to
rationally review its use.
There are few data to support the validity of CCSVI. The lack of data seems counterbalanced by the great hope for the miracle
of an endovascular treatment for MS.
The topic has caused widespread attention and debate in the media,
medical literature
and the internet.11–17
As of late August 2010, a Google search on ‘liberation procedure’
yielded about 2?650?000 results and approximately 181?000 for ‘CCSVI’.
Sponsored links appear for treatment in Mexico, Poland, Costa Rica,
India and other locations. At least one toll free telephone number akin
to ‘1-800-I Treat MS’ has been created.18 The prospect of opening an open label, non-study related MS endovascular CCSVI practice can be very seductive. For physicians,
the barriers to entry are small since
most interventionalists are technically able to perform these procedures
and the required
devices are readily available. At the
same time, there are many patients who are desperate for a procedure
which might improve
their condition despite the lack of
evidence to support its benefits and almost regardless of its potential
risks. Indeed,
some might argue that because the
procedure is safe, if there is any possibility of ameliorating some of
the symptoms of MS
patients the procedure should be
offered to them. However, no invasive procedure is completely safe. In
fact, there are increasing
reports of complications related to PTA
or stenting for CCSVI, including intracranial hemorrhage, stent
migration into the
heart and jugular vein thrombosis19 The moniker, ‘liberation procedure’, is a marketer's dream and by itself suggests unrealistic but compelling expectations. Many patients are willing to pay cash,
sometimes tens of thousands of dollars, for a single procedure. Many
patients rave about their procedures, yet outside of a well controlled
trial, it is hard to disprove the placebo effect and prove the true
clinical benefits. In view of the forgoing, and in an attempt to help resolve the CCSVI conundrum, it would seem that the fundamental questions are:
Is there a cause and effect relationship between CCSVI and MS, and in which direction does this work?
If CCSVI does cause or worsen MS, should this be treated with endovascular therapies?
If endovascular treatment is contemplated, which therapy should be offered and under what technical and clinical circumstances should they be applied?
There is paramount need for credible scientific evidence that will allow us to address these questions. Firstly, we should encourage trials using non-invasive
studies to test if CCSVI–MS actually exists. At the current time, the
corroboratory evidence supporting Zamboni's initial findings of an
association between CCSVI and MS are limited. In fact, the majority of
additional evidence—including the work of Doepp et al and Sundstrom et al, cited in this review—actually failed to replicate the findings of Zamboni and colleagues.7–9 Moreover, the early results of Zivadinov et al are also not very compelling.10 In addition, the initial claim by Zamboni et al that they had developed a perfect test for CCSVI–MS raises serious questions about the credibility of their evidence. As pointed out by
Novella, few if any tests in medicine have 100% sensitivity and 100%
specificity.20 Fortunately, the US and Canadian MS societies have undertaken seven studies to investigate the CCSVI–MS association.14,15 The necessity of requiring an invasive diagnostic study such as catheter venography to evaluate the CCSVI–MS association is more
difficult to reconcile at this point, particularly since the seminal
findings of Zamboni et al which initiated this entire controversy were based on non-invasive Doppler ultrasound.
If the association between CCSVI and MS cannot be confirmed, then further studies evaluating CCSVI treatment are unnecessary. While it could be argued that even if the
prevalence of venous ‘abnormalities’ is similar in patients with MS and
controls, venous intervention in MS should still be studied since MS
patients might be more susceptible to the detrimental effects of CCSVI
than normal patients, this position seems tenuous at best. If an association between CCSVI and MS can be established, then the next logical step would be to design multicenter randomized clinical trials to assess the benefits of endovascular interventions.
ConclusionMore evidence is needed to establish the association between CCSVI and MS. If more solid clinical evidence can confirm that the CCSVI–MS relationship is real, randomized
clinical trials will be required to assess the benefits of endovascular
interventions. If these trials establish a benefit for endovascular
therapy, then at that point treatment can be made widely available.
However, until these steps are taken, in our opinion, there is no role
for the endovascular treatment of CCSVI in the MS patient outside of
approved clinical trials.
http://jnis.bmj.com/content/early/2010/10/23/jnis.2010.003947.full
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