What does this mean?

[1eye]

Investigating Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis 1

Issue 15  December 2010
Context and Policy Issues
Multiple sclerosis (MS) is a neurological
disease common in young adults.
1
The
Multiple Sclerosis Society of Canada
estimates that there are 55,000 to 75,000
people living with MS in Canada.
2
This is one
of the highest prevalence rates of MS in the
world. MS causes disability because of
mobility and vision problems, fatigue,
incontinence, and cognitive impairment.
1

The Public Health Agency of Canada
estimated that the total costs associated
with MS in 2000 to 2001 for hospitalization,
treatment, and lost productivity due to
morbidity and premature mortality was
$950.5 million.
1


There is currently no cure for MS. First-line
therapies for MS, such as interferon beta
and glatiramer acetate, have not been
shown to consistently suppress disease
progression.
3
Immunosuppressive therapies
(such as, cyclosporine, methotrexate,
mitoxantrone, and azathioprine) also play a
role in MS therapy, but tolerability of them
and their adverse effects limit their use.
3

Natalizumab is the first monoclonal
antibody approved by Health Canada for the
management of MS;
4
however, its use may
be limited by the risk of progressive
multifocal leukoencephalopathy (a serious
viral infection of the brain that is often life-
threatening).

Although MS is commonly believed to be an
autoimmune disease, the evidence to
support this concept has been questioned.
5

An alternative hypothesis has been put forth
by Dr. Paolo Zamboni, a former vascular
surgeon and professor at the University of
Ferrara in northern Italy.

Dr. Zamboni believes a phenomenon termed
chronic cerebrospinal venous insufficiency
(CCSVI), an abnormality in blood drainage
from the brain and spinal cord, may cause
the build-up of iron deposits and contribute
to inflammation and nervous system
damage.
6
Initial findings that CCSVI may be
associated with MS were published in 2008
from a study of 65 patients with MS.
7

Results from a second study suggested that
treating CCSVI with endovascular
angioplasty (the insertion of a tiny balloon
or stent into blocked veins to improve blood
flow), also referred to as the liberation
procedure, is feasible and safe.
8


However, results from other studies have
not supported the hypothesis that CCSVI is
present in patients with MS.
9,10
In March
2010, Stanford University halted
endovascular treatments for CCSVI after
two people experienced serious
complications after the stenting of the
jugular veins.
11


As is it not known if or how CCSVI
contributes to MS, rigorous large-scale
clinical trials have been recommended to
determine if CCSVI is a clinically important
factor in the development or progression of
MS.
12,13


In light of the high prevalence of MS in
Canada, the validity of the liberation
procedure for MS has generated
considerable interest in the medical and
scientific communities and politicians have
faced pressure from the public to provide
funding for clinical trials.
Environmental Scan
Investigating Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis 2
Objectives
The purpose of this report is to provide
information regarding the investigation of
the liberation procedure for the treatment
of MS. The following questions will be
addressed:
Which clinical trials in North America
are currently studying the association
of CCSVI with MS?
What is the status of funding for CCSVI
research in Canada?

Ongoing Clinical Trials
The findings of this environmental scan are
not intended to provide a comprehensive
review of the topic. The results of this
report are based on a limited literature
search. This report is based on information
gathered as of November 15, 2010.

In June 2010, the National MS Society in
the US and the Multiple Sclerosis Society of
Canada committed more than $2.4 million
to support seven new research projects
focused on the role of CCSVI in MS
(Appendix 1).
14
The two-year grants began
in July 2010. The seven research leads
have been asked to provide interim
updates every six months to the Canadian
and US MS societies on their grant
progress.

The structure and function of veins
draining the brain and spinal cord will be
studied in individuals representing a
spectrum of MS types, severities, and
durations of disease. People with other
diseases and healthy volunteers will be
used for comparison. These diagnostic
studies are not designed to treat CCSVI
but, rather, to confirm whether CCSVI
contributes to MS disease activity, to
identify the best imaging technology to
evaluate it, and to resolve conflicting data
from previous studies. These studies may
also be used to design protocols for
possible exploratory therapeutic trials that
may be undertaken if blockages are found.
In addition to the clinical trials funded by
the MS societies, researchers at the
University of Buffalo in New York are
currently studying the prevalence of CCSVI
in people with MS15
and the safety and
efficacy of endovascular angioplasty16

(Appendix 1). Two other trials have also
been registered for the evaluation of
endovascular angioplasty in the treatment
of MS.
17,18


Investigators at McMaster University and
St. Joseph’s Healthcare in Hamilton, who
were not funded by the Multiple Sclerosis
Society of Canada, are currently raising
funds through public donations for CCSVI
research.
19


Government Funding for
CCSVI Research
In August 2010, the Canadian Institutes for
Health Research (CIHR), the Multiple
Sclerosis Society of Canada, and federal
and provincial representatives met to
review evidence related to the etiology
and treatment of MS and to identify
clinical research priorities.
20
There was
unanimous agreement from the scientific
experts that a pan-Canadian interventional
trial should not be initiated because of a
lack of scientific evidence. The following
recommendations were made to the
Minister of Health:
To establish a scientific expert working
group made up of the principal
investigators of the seven MS society-
sponsored studies, scientific leadership
from CIHR and the MS societies, and a
representative from the provinces and
territories to monitor and analyze the
results of ongoing studies.
Based on the outcomes of the studies,
the scientific expert working group
should make recommendations on
further studies including, if appropriate,
a pan-Canadian interventional clinical
trial that would evaluate the safety and
efficacy of the liberation procedure in
patients with MS. Environmental Scan
Investigating Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis 3
On September 1, 2010, Federal Health
Minister Leona Aglukkaq accepted the
recommendations presented by CIHR and
announced that the federal government
would await the results of studies currently
underway and guidance from the scientific
expert working group before funding a pan-
Canadian clinical trial.
21


Provincial Ministries of Health in Manitoba,
Quebec, Nova Scotia, and Prince Edward
Island have all expressed interest in
supporting a pan-Canadian clinical trial,
provided that the evidence from ongoing
studies is positive.
22-25
Manitoba has set
aside $500,000 to allow the province to
move quickly if evidence from ongoing
studies supports the move to clinical
trials.
22


In October 2010, Saskatchewan invested $5
million to fund province-based clinical
trials, which are expected to begin in April
2011.
26
The Saskatchewan Health Research
Foundation will develop the call for clinical
trials and provide the scientific, ethical,
and financial expertise to manage this
initiative on behalf of the government.
27

This decision was made despite a
statement from Manitoba Health Minister
Theresa Oswald that a “patchwork”
approach of small provincial trials may
lead to conflicting results.
28
Saskatchewan
Health Minister Don McMorris commented
that he is skeptical that the federal,
provincial, and territorial governments will
commit to CCSVI research in the near
future, prompting the provincial
initiative.
29


Similarly, Newfoundland and Labrador has
devoted $320,000 to fund a provincially
based observational study to track the
progress of patients who travel overseas at
their own expense to have the liberation
procedure.
30
Participants will receive a
magnetic resonance imaging exam before
the procedure and will be followed-up by
local neurologists to collect data on their
condition.

On November 24, 2010, New Brunswick
Premier-elect David Alward, announced
during his throne speech, to create a
$500,000 fund to help MS patients receive
the liberation procedure.
31
How the fund
will be dispersed is still being worked out,
but the intent is for the money to be
matched by contributions from the public.

Ontario is waiting for more scientific
research and consensus in the scientific
community before proceeding with funding
for clinical trials.
32


Alberta’s Health Minister Gene Zwozdesky
has established a working group to improve
coordination of programs and services to
patients with MS. Minister Zwozdesky has
also held a meeting with researchers, MS
advocates, patients, and medical experts
to discuss what Alberta can do to help
accelerate research in the area of MS and
possible treatments, including the
liberation procedure. In August 2010,
Alberta Health Services issued a position
paper challenging the validity of findings
published by Dr. Zamboni and cautioning
MS patients about seeking the liberation
procedure.

A statement from Health Minister Glenn
Hart in October 2010 indicated that the
Yukon territorial government will not be
providing financial support for clinical
trials.
33


Since the CIHR recommendation, the
Multiple Sclerosis Society of Canada has
announced it is reserving $1 million for a
pan-Canadian therapeutic clinical trial if
preliminary results indicate that such a
trial is warranted.
33
The organization hopes
to work with the provinces and federal
government to secure the remaining funds
if the trial is approved.

Environmental Scan
Investigating Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis 4
Other Emerging Technologies
In September 2010, fingolimod (a
sphingosine-1-phosphate analog) was
approved by the Food and Drug
Administration as the first oral disease-
modifying therapy for MS.
34
Cladribine (a
purine nucleoside analog) was granted a
priority review designation by the Food and
Drug Administration in July 2010.
35


Health technologies currently being studied
in clinical trials for MS include monoclonal
antibodies (such as rituximab, daclizumab,
alemtuzumab, ocrelizumab, and
ofatumumab), statins (such as atorvastatin
and simvastatin), laquinimod, oral
fumarate, teriflunomide, firategrast, and
autologous hematopoietic stem cell
transplantation.
3,36,37


Conclusions
It is not yet established whether CCSVI
contributes to MS disease activity, and
there have been conflicting data as to the
frequency of this condition in people with
MS. It is hoped that findings from ongoing
studies will provide clarity regarding the
need for pan-Canadian therapeutic clinical
trials. Scientific and medical organizations
and experts across Canada have uniformly
urged caution and rigorous study before
the liberation procedure is recommended
for use, particularly considering the other
emerging health technologies that are
currently in the pipeline for the
management of MS.

Complementing this environmental scan,
CADTH prepared, in December 2009, a
rapid response on surgical procedures
targeting CCSVI for the treatment of MS.
This is available free of charge on the
CADTH website.
38






North American Guidelines and
Recommendations
Canadian Institutes of Health Research and
Multiple Sclerosis Society of Canada. Joint
Invitational Meeting on Multiple Sclerosis
Research- Summary Report, August 2010.
http://www.cihr-irsc.gc.ca/e/42381.html
Interventional Endovascular Management
of Chronic Cerebrospinal Venous
Insufficiency in Patients with Multiple
Sclerosis: A Position Statement by the
Society of Interventional Radiology,
Endorsed by the Canadian Interventional
Radiology Association, August 2010.
http://www.sirweb.org/news/newsPDF/SI
R_MSstatement_JVIR.pdf
Ontario Ministry of Health and Long-Term
Care for the Ontario Health Technology
Advisory Committee. Multiple Sclerosis and
Chronic Cerebrospinal Venous
Insufficiency, May 2010.
http://www.health.gov.on.ca/english/pro
viders/program/ohtac/tech/recommend/r
ec_ccsvi_20100611.pdf

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Environmental Scan
Investigating Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis 9
Appendix 1: Ongoing CCSVI Clinical Trials in North America
Investigator, Location Study Information Funding
Canada
Dr. Brenda Banwell, Hospital
for Sick Children, Toronto.
39


The study will use MRI and novel measures of
venous flow to determine if CCSVI occurs in the
veins of children and teenagers with MS. A total
of 60 participants, both healthy and with MS,
will be enrolled. This population will allow an
examination of disease process at an early stage
where other health conditions that might affect
blood flow do not exist.
Multiple Sclerosis
Society of
Canada and the
National Multiple
Sclerosis Society
Dr. Fiona Costello, Hotchkiss
Brain Institute, University of
Calgary.
40

This controlled study will examine vein drainage
in a cross-section of people with MS compared
with healthy volunteers. The team will assess if
linkages exist between venous abnormalities and
different aspects and measures of MS activity
and tissue damage. A total of 180 participants
will be enrolled. Ultrasound, as originally used
by Dr. Zamboni, and magnetic resonance studies
of the veins will be used.
Multiple Sclerosis
Society of
Canada and the
National Multiple
Sclerosis Society
Dr. Carlos Torres, Ottawa
Hospital, University of
Ottawa.
41

The study will use 3-Tesla MRI and Doppler
ultrasound technology to explore differences in
the anatomy of veins in the neck, chest, and
spine and to assess iron deposits in the brain.
The study will include 50 people with MS and 50
age-matched healthy volunteers.
Multiple Sclerosis
Society of
Canada and the
National Multiple
Sclerosis Society
Dr. Anthony Traboulsee,
MS Clinic at UBC Hospital,
Vancouver Coastal Health
and University of British
Columbia, Vancouver.

Dr. Katherine Knox,
Saskatoon MS Clinic,
University of Saskatchewan,
Saskatoon.
42

The prevalence of CCSVI in 200 people with and
without MS will be studied using catheter
venography, ultrasound, and magnetic resonance
venography. The study allows the inclusion of
family members of the MS patient, such as
identical twins, in the control group. The
research aims to determine the reliability and
accuracy of different imaging techniques for
screening of CCSVI.
Multiple Sclerosis
Society of
Canada and the
National Multiple
Sclerosis Society
United States
Dr. Aaron Field, University of
Wisconsin School of Medicine
and Public Health
Madison, Wisconsin.
43


The study will use MRI scans to generate detailed
images of veins in the head and neck in 112
people with MS, 56 controls without MS, and 56
people with other neurological conditions. These
images will be compared with results obtained
from the ultrasound techniques used by Dr.
Zamboni.
Multiple Sclerosis
Society of
Canada and the
National Multiple
Sclerosis Society
Dr. Robert Fox, Cleveland
Clinic Foundation
Cleveland.
44

The study will compare 90 people with MS to 80
healthy volunteers. The team will use the
ultrasound techniques used by Dr. Zamboni, as
well as magnetic resonance studies of the veins,
MRI scans of the brain, and clinical measures to
determine MS activity. To distinguish if vein
abnormalities are from atrophy (brain-tissue
Multiple Sclerosis
Society of
Canada and the
National Multiple
Sclerosis Society Environmental Scan
Investigating Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis 10
Investigator, Location Study Information Funding
volume loss) and not specifically MS, the study is
also comparing the MS group to people with
atrophy from Alzheimer disease. Neck and spinal
cord tissue from MS patients obtained through
autopsy will be used for tissue-based evaluation
of CCSVI and its possible relationship to MS.
Dr. Jerry Wolinsky,
University of Texas Health
Science Center, Houston.
45


This study will replicate the ultrasound methods
used by Dr. Zamboni to investigate the
association of CCSVI with major clinical types of
MS using non-MS control groups. A total of 275
people will be recruited. The team will also
assess whether other imaging methods can
confirm the ultrasound findings and which
technique is the most reliable to screen for
CCSVI.
Multiple Sclerosis
Society of
Canada and the
National Multiple
Sclerosis Society
Buffalo Neuroimaging
Analysis Center, University of
Buffalo, New York.
46

This blinded randomized controlled trial is
investigating the prevalence of CCSVI in patients
with MS when compared with healthy controls or
controls with other neurological disorders.
Preliminary results of the first 500 of 1,000
participants were released in February 2010 and
show that 56.4% of participants with MS
exhibited evidence of CCSVI compared with
22.4% of healthy controls.
47
Complete data from
the first 500 participants will be presented at
the American Academy of Neurology in April
2011.
University of
Buffalo
Neuroimaging
Analysis Center
of the Jacobs
Neurological
Institute
Dr. Adnan Siddiqui,
University of Buffalo,
Department of Neurosurgery,
New York.
16

This randomized, double-blind study will test the
safety and efficacy of interventional
endovascular therapy. In the first phase, 10 MS
patients exhibiting CCSVI will undergo minimally
invasive venous angioplasties to determine if the
procedure can be performed safely. The second
phase will randomize 20 MS patients to undergo
either venous angioplasty or a “sham
angioplasty” (i.e., catheter is inserted, but there
is no inflation of the balloon). If the results are
positive, the researchers will approach the
University of Buffalo Institutional Review Board
for an extension of the protocol to study a larger
group of patients.
Not stated
Dr. Gary Siskin, Albany
Medical Center, New York.
17

This double blind, randomized controlled trial
will determine if venous angioplasty is an
effective treatment for CCSVI and it is expected
that the study will enrol approximately 130
patients. The outcomes of two groups of patients
will be compared. The first group will have
CCSVI diagnosed on a venogram and treated with
angioplasty and the second group will have CCSVI
diagnosed on a venogram and treated with a
sham procedure. Several outcomes will be
evaluated over 24 months, including safety,
efficacy, and quality of life.
Community Care
Physicians, P.C. Environmental Scan
Investigating Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis 11
Investigator, Location Study Information Funding
Dr. Manish Mehta, The
Vascular Group, PLLC; and
The Vascular Health Pavilion
Albany, New York.
18

The study is a randomized, double-blind (sham
procedure), placebo-controlled, feasibility
clinical trial with an expected enrolment of 600
patients. The purpose is to evaluate the safety,
feasibility, and efficacy of percutaneous
transluminal angioplasty in treating extracranial
venous obstructive lesions, and its influence on
the clinical outcomes of MS patients who have
been found to have CCSVI. Outcome measures
evaluated over 24 months include adverse
events, neurological assessment, MRI evaluation
of MS lesions, and mortality.
The Vascular
Group, PLLC
CCSVI = chronic cerebrospinal insufficiency; MRI = magnetic resonance imaging; MS = multiple sclerosis.






Cite as: Ndegwa, S. Investigating Chronic Cerebrospinal Venous Insufficiency for the Treatment of
Multiple Sclerosis [Environmental Scan, Issue 15]. Ottawa: Canadian Agency for Drugs and
Technologies in Health; 2010.

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***************
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[Cece]

The following questions will be
addressed:
Which clinical trials in North America
are currently studying the association
of CCSVI with MS?
What is the status of funding for CCSVI
research in Canada?

Those are good questions which seem to have been thoroughly answered!