and MS Society of Canada Joint Invitational Meeting on

Multiple Sclerosis Research

Dr. Ashton Embry, Direct-MS,

, the Canadian Institutes of Health Research (CIHR) and the

Multiple Sclerosis Society of Canada (MSSOC) convened a meeting of a group

of scientists from various disciplines

to review evidence, current international

efforts, and knowledge gaps related to the etiology and treatment of MS, with a

special emphasis on neurovascular issues including the recently proposed

)”. The chair

of the committee was Dr Alain Beaudet, the current president of CIHR and the

report is herein referred to as the Beaudet Report. It can be accessed at

(http://www.cihr-irsc.gc.ca/e/42381.html). Because of the great importance of

CCSVI research, Direct-MS, Canada’s second largest MS charity, undertook an

In-Depth Analysis of the Beaudet Report to determine if the Report was

scientifically acceptable and free of ethical breeches.

The committee assembled by Dr Beaudet, with help from officials from the MS

Society of Canada, consisted of five CIHR executives, including Dr Beaudet,

three executives from MSSOC, ten clinical/research MS neurologists, two neuroimaging

specialists, one neurosurgeon, one vascular surgeon and one

interventional radiologist. Notably, not a single committee member had any

previous experience in any aspect of CCSVI research or treatment although two

of the neurologists will be leading small studies on MS and CCSVI over the next

two years. Notably, only two of the twenty three committee members brought

critical expertise in extra-cranial vascular practice and research to the table.

The only scientific topic discussed by the Beaudet Committee was CCSVI and its

relationship to MS and the only recommendations that were made related to

future research directions for CCSVI and MS. There apparently was no

discussion on other important topics such as

“current international efforts and

knowledge gaps related to the etiology and treatment of MS

” and there are no

recommendations regarding any MS research topic except CCSVI. This is most

surprising given that Dr Beaudet had earlier testified before the Parliamentary

Subcommittee on Neurological Diseases in June that “

This meeting is to be held

in August and will focus on how best to accelerate research and innovation in

MS…. The expected outcome will be a richer understanding of clinical research

priorities regarding potential innovations related to diagnosis and treatment of

.” There is no resemblance whatsoever between what Dr Beaudet had

promised Parliament and what actually was delivered by the Beaudet Report.

Given that the meeting was dedicated to a discussion of CCSVI, it is clear from

the content of the Beaudet Report that the participants did not have adequate

knowledge of:

1) the origin, manifestation and detection of CCSVI,

2) the CCSVI literature,

3) the substantial international effort which is currently going on regarding

CCSVI treatment.

When one considers the committee members’ lack of any expertise and

experience with CCSVI and MS, this is exactly what one would have expected.

Although the failure of the committee members to properly collect and analyze

the available data on CCSVI is predictable and understandable, such a failure is

unacceptable and it unequivocally negates the validity of the recommendations

of the Beaudet Report.

Another major problem with the Beaudet Report is that a review of the committee

members’ past research and/or executive activities has revealed that many have

an overt conflict of interest in the regards to the potential introduction of an

effective, non-drug therapy, such as CCSVI treatment, for MS. Such a potential

ethical problem calls into question the objectivity of the discussions and the

resulting recommendations of the Beaudet Report and provides another reason

why the recommendations cannot be taken seriously.

In summary, if an important scientific issue needs discussion so as to generate

recommendations to help guide government policy, it is absolutely imperative

that those involved have:

considerable expertise, knowledge, and experience in the topic at hand,

that all sides of the topic are adequately discussed,

that no one involved has a conflict of interest.

The Beaudet Committee fails on all three counts in that not a single participant

has any expertise or experience with CCSVI, nothing positive about CCSVI was

discussed, and not one, but many, participants have clear conflicts of interest.

Finally, given the importance of CCSVI research to Canadians, there is no doubt

that a government-led investigation is required to determine how such a

scientifically inappropriate and ethically challenged committee came into

existence in the first place. Canadians, especially those with MS, deserve better

than this.

patients who

develop blood clots in these veins, or who have these veins removed during

” are completely inappropriate

and valueless and show a lack of understanding of Dr Zamboni’s work. No one

involved in CCSVI research is claiming everyone with CCSVI has or will develop

MS and it is well recognized and accepted that genetic and environmental factors

besides CCSVI are important factors in MS etiology and pathogenesis.

The report also tries to discredit Dr Zamboni’s clinical research (Zamboni et al,

2009a) by claiming it was not a controlled, randomized, double-blind trial. Once

again, given that the Zamboni clinical trial was simply a pilot trial, and the first of

its kind, it is entirely inappropriate to criticize it for not being controlled,

randomized and double-blinded.

. Dr

Zamboni’s pilot research, like all pilot trials, was done to demonstrate the safety

of the procedure and to determine if any improvements occurred in treated

patients. Notably, both safety and possible efficacy were shown. Finally, Dr

Zamboni concluded that the results of his pilot trial indicated that more rigorous

clinical research was required.

In summary, the criticisms of the Zamboni work in the Beaudet Report have no

substance and are inappropriate. No one is claiming Dr Zamboni’s initial trial is

anything more than a pilot study. However, as such,

its results more than

justify the need for more rigourous clinical treatment research

.

The most serious scientific flaws in the Beaudet Report are found in the two

sections entitled “

Is there such a condition as “chronic cerebrospinal venous

insufficiency, or CCSVI?”

Is “venous insufficiency” linked to MS?”

There is no doubt that both of these questions are valid and critical questions to

examine when it comes to determining the need for further clinical research into

the effectiveness of CCSVI treatment. The problems with the Beaudet Report lie

not with the questions themselves, but with how the questions are answered.

In the first section,

Is there such a condition as “chronic cerebrospinal venous

insufficiency, or CCSVI?,

the report points out that venous drainage of the brain

is a highly flexible system. This is well accepted and is the reason why CSSVI is

not an acute problem but rather is a subtle, chronic one associated with delayed

drainage times and hypoperfusion. This creates problems over decades rather

than days. The report completely misses this key aspect of CCSVI.

In this section, it is stated that “

A proportion of the brain’s venous drainage runs

through the Internal Jugular Veins when standing, however when lying down, that

.

The jugular veins are important drainage paths in the supine position and are

often collapsed when one is in the standing position. Such a fundamental error

reflects the inexplicable and inexcusable, near absence of extra-cranial vascular

expertise on the Beaudet Committee.

All other statements in this section are either irrelevant or inappropriate to the

question at hand. The final statement in this section that

there is little support

for the notion that venous insufficiency for the brain or spinal cord contributes to

” is a completely unsupported opinion which telegraphs

the strong negative bias of the Beaudet Committee.

In the section “

, the report has missed a

number of very important references, has emphasized a few, scientifically

questionable, negative studies and has completely ignored what is happening in

numerous CCSVI clinics throughout the world. The question of association of

CCSVI and MS is an important one and must be established before clinical

treatment research would be deemed necessary.

The Zamboni research (Zamboni et al 2009b) found a greater than 95%

association of CCSVI with MS although less than 200 patients were tested. Most

importantly, the results were checked and corroborated with selective

venography, the accepted gold standard for the determination of CCSVI, and

thus can be considered to be reliable. On the other hand, any scientific studies

which do not include venography to corroborate the determination of CCSVI can

be considered highly suspect and have to be given little weight. The reason for

this is that non-invasive techniques such as Doppler and MRV have a very high

rate of false negatives and can be highly operator dependent.

The subsequent University of Buffalo work demonstrated an almost 3X higher

prevalence of CCSVI is persons with MS in a large study of 500 people

(University of Buffalo, 2010). Notably, the person doing the determination of

whether or not CCSVI was present with a Doppler technology was properly

trained and had months of experience. Furthermore, the reliability of the Doppler

results was checked with venography (Hojnacki et al, 2010).

It was very surprising that the Beaudet Report did not refer to other published

studies of CCSVI/MS association which include Al-Omari and Rousan (2010)

which found 84% of persons with MS had CCSVI (sample size 25) and no

healthy controls had CCSVI (sample size 25) and Simka et al (2010) which found

CCSVI in 90% of persons with MS (70 sample size). Notably, both these results

were based on selective venography which leaves no doubt as to the accuracy of

these data.

It is also worth noting that Dr Simka updated his findings at the June

Parliamentary Subcommittee meeting which was attended by Dr Beaudet. At that

time Dr Simka reported “

total number of people who have been treated is now

about 400. CCSVI has been found to highly correlate with multiple sclerosis. Only

3% of the multiple sclerosis patients we have seen were not diagnosed with

CCSVI, using colour Doppler sonography, magnetic resonance venography, and

” Given there are not a large number of references on

CCSVI and MS, the omission of these key references, which are readily found on

Pubmed, shows a definite lack of familiarity of the Beaudet Committee with the

CCSVI literature.

The Beaudet Report, in keeping with its very negative bias, emphasized two

small negative studies (Doepp et al, 2010; Krogias et al,

which reported

finding essentially no CCSVI associated with MS. Notably, both studies used only

operator-dependent, non-invasive techniques and did not use any selective

venography. Thus the results are very unreliable and contribute very little to the

question of MS/CCSVI association. The Beaudet Report neglected to mention

the critical lack of selective venography for the negative studies.

Perhaps one of the most important pieces of evidence regarding the association

of MS and CCSVI is the fact that over 100 persons with MS are being treated for

CCSVI every day (2000 a month) and well over 5000 persons with MS have

already been treated for CCSVI worldwide. Notably, the daily number of CCSVI

treatments is increasing every week as more and more clinics open up,

especially in the USA. Clearly, if CCSVI was not associated with MS, there would

not be such a booming and ever expanding medical practice of treating persons

with MS for CCSVI. If CCSVI was not highly associated with MS, the treatment of

CCSVI in MS patients would never have gotten off the ground. By ignoring this

major phenomenon, as well as various key references, the Beaudet Committee

loses all credibility when it comes to the analysis of the association of CCSVI with

MS.

The last line in this section “

These recent studies have demonstrated a wide

variation in the patterns of venous drainage of the brain in both MS patients and

people with no evidence of MS (controls), underlining the difficulty involved in

.” applies only

to studies which use non-invasive, detection techniques and reveals a lack of

familiarity of the Beaudet committee members with how CCSVI is best detected.

Does venous angioplasty

work?.

Venous angioplasty is rarely used because the

incidence of re-stenosis is so high

.” However, given the obvious dearth of venous

angioplasty expertise on the Beaudet Committee, such an unreferenced

statement has to be questioned. In contrast to this statement, Dr Robert

Maggisano, a vascular surgeon with 30 years experience, testified before the

June Parliamentary Subcommittee that “

We treat veins and arteries with

angioplasty routinely”

. Furthermore, in a recent position statement of the Society

of Interventional Radiologists, it was stated that “

balloon angioplasty and stent

placement of central thoracic veins have been performed safely for many years

Vedantham et al, 2010).

In summary, there is no doubt that venous angioplasty works because it has

been used for many years and is in use today. If it didn’t work, such a procedure

would have been abandoned years ago.

The fact that it is currently being used

for CCSVI treatment in many clinics around the world, including the prestigious

Arizona Heart Institute, shows that many interventional radiologists and their

review boards are satisfied that it works. A claim that it doesn’t work by a

committee dominated by neurologists and executives cannot be taken seriously,

especially given the unrelenting negativity which pervades the report.

The final question of the report “

Is the venous angioplasty treatment safe and

efficacious?”

is really two questions, one on safety and one on efficacy. Both are

important and both need proper, well supported answers. By combining them,

the Beaudet Report does not answer each separately and this is very misleading.

For example the report states “

In order to evaluate whether any treatment is

efficacious and safe, it is essential to compare the treatment in a blinded fashion

.” This statement is

both erroneous and correct. This statement is completely wrong in terms of

determining safety but is basically right in terms of determining efficacy.

So let’s look at the question of safety first and the answer to this is paramount for

any recommendation of whether clinical trial research should be funded at this

time. Overall, the evidence shows that venous angioplasty is very safe and this is

emphasized by Dr Maggisano in his testimony

We treat veins and arteries with

angioplasty routinely. It has a low-risk and a very minimally invasive component

Dr Simka in his

testimony stated that “

The group of 347 CCSVI patients with associated multiple

sclerosis have undergone a total of over 500 endovascular procedures, including

414 balloon angioplasties and 173 stent implantations. In this group, there were

only a few rather minor and occasional complications or technical problems

” These data are now in a scientific paper (Ludyga et

al, in press) and the failure of the Beaudet Committee to consult Dr Simka on the

safety issue when they knew he had a large and reliable data base on the issue

reveals a lack of initiative in obtaining important data on a key question.

In summary, there is no question, based on published work and long years of

experience with venous angioplasty, that such a procedure is very safe. As Dr

Beaudet testified in June, “

I know of no procedure, even eating natural food, that

is 100% safe.

” However, the data and long years of experience indicate that

venous angioplasty is about as safe as any medical procedure can be.

In terms of the question of the efficacy of venous angioplasty for MS, the

Beaudet Report went back to bemoaning the lack of rigour of the Zamboni pilot

trial and that the results can not be taken as proof of efficacy. Everyone agrees

with this but that is not the point. There is no doubt we do not know if venous

angioplasty is effective for relieving symptoms and/or slowing disease

progression. Only a proper clinical trial will determine this. The Beaudet Report

presents a Catch 22 in that they cannot recommend funding a proper clinical

CCSVI treatment trial until we know it works. The absurdity of such logic needs

no further elaboration.

The last line in this section contains two unsupported and completely erroneous

pronouncements. The first one claims that “

there is currently no scientifically valid

evidence in support of the existence of CCSVI in patients with MS

” As has been

demonstrated, there is a very large and robust published data base that CCSVI is

undoubtedly associated with MS and the thousands of CCSVI treatment

procedures that have already been done and the over 100 CCSVI treatment

procedures being done every day only reinforce this inescapable conclusion. Any

claim to the contrary essentially says that fraudulent interventional radiologists

are practicing in the many areas throughout the world, including the Arizona

Heart Institute, which in the past has treated presidents of the United States.

The second unsupported and baseless pronouncement is that “

there is currently

no scientifically valid evidence to support the use of venous angioplasty in the

”. As has been discussed, venous angioplasty is an

extremely safe procedure. Secondly, a pilot trial has indicated that the procedure

may well be of value for MS. Furthermore, the fact that the treatment is already in

use in many countries of the world suggests that the review boards of the clinics

doing such procedures are satisfied there is sufficient scientific evidence to

support the use of venous angioplasty for MS. Finally, it can be argued that the

many hundreds of well documented accounts of improvements following venous

angioplasty represent valid scientific observations. In his testimony Dr Simka

noted that “

But what I can say now about what we are seeing after one or

two months of the treatment is that about 80%, 90%, of the patients