The first-year progress reports from seven multi-disciplinary teams investigating CCSVI (chronic cerebrospinal venous insufficiency) in MS indicate that they are on track to provide essential data and critical analysis as these two-year projects move toward their completion. These studies were launched on July 1, 2010 with a more than $ 2.4 million commitment from the MS Society of Canada and the National MS Society (USA).
The research teams have already recruited a broad spectrum of people with MS and others to build understanding of who may be affected by CCSVI. In addition they are refining CCSVI imaging methods for accuracy and consistency in order to reliably validate the occurrence of CCSVI and understand its implications in the MS disease process.
Representatives of each of the seven funded teams are part of the
Canadian Institutes of Health Research (CIHR)’s Scientific Expert
Working Group.
Following a meeting of the working group in June 2011, the
Canadian Federal Minister of Health, the Honourable Leona
Aglukkaq, announced a Phase I/II interventional clinical
trial on CCSVI. The working group will provide leadership and
advice in the drafting of the terms of reference for the Phase
I/II clinical trial in Canada, and will continue to monitor and
analyze the data from the seven studies and other studies related
to CCSVI and MS around the world.
Regarding the seven funded teams, all have received approval for
their studies from the required Institutional Review Boards in
the U.S. or the Research Ethics Board in Canada, a first step
established by regulatory authorities to protect human subjects
involved in research projects. Read more on steps involved in conducting clinical research.
Already more than 486 people have undergone scanning with various imaging technologies being used by the studies, including the Doppler ultrasound technology originally used by Dr. Paolo Zamboni and his collaborators, as well as magnetic resonance studies of the veins (MR venography), catheter venography, MRI scans of the brain, and clinical measures.
Because the studies employ rigorous blinding and controls designed to collect objective and comprehensive data, the full results of the ongoing research will be available only after completion of the studies which will involve more than 1300 people representing a spectrum of MS types, severities and durations, as well as individuals with other disease types and healthy controls. In the meantime, several teams are planning to present preliminary results at medical meetings later this year.
“We are pleased that this important work investigating the link between CCSVI and MS is advancing quickly,” notes Dr. Tim Coetzee, chief research officer at the National MS Society. “Results from these comprehensive studies will help inform important next steps.”
Yves Savoie, President and chief executive officer of the MS Society of Canada concurs, “The CIHR’s Scientific Expert Working Group, who will provide leadership and advice in the drafting of the terms of reference for the Phase I/II clinical trial in Canada, will continue to monitor and analyze the data from these studies and other studies related to CCSVI and MS around the world. We are heartened to be moving closer to more definitive answers about CCSVI and MS.”
Details: The funded investigators, who are drawn
from a broad range of disciplines ranging from MS neurology,
vascular surgery and interventional radiology, report progress in
establishing standardized protocols, recruiting and scanning
participants and in the development of plans for sharing their
findings, as summarized below.
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Dr. Brenda Banwell, The Hospital for
Sick Children, Toronto, Ontario: To determine
whether signs of impaired vein drainage might be present
early in the MS disease course, Dr. Banwell’s team received
approval from the Research Ethics Board and then began
enrolling children and teenagers who have MS, and healthy
controls of the same age. They are seeking venous
abnormalities using non-invasive MRI measures of vein anatomy
and novel measures of venous flow, as well as ultrasound.
Unlike adults with MS, children are unlikely to have
age-related changes in blood vessels, and are less likely to
have adult health conditions such as high blood pressure or
heart disease, which might otherwise complicate findings. The
team’s ultrasound team received training in Dr. Zamboni’s
original techniques from the Buffalo Neuroimaging Analysis
Center, and they have created ultrasound and brain imaging
procedures suited to explore venous drainage in children. Dr.
Banwell’s team reports that recruitment is going well, and
that they plan to analyze findings only after all 90
participants have undergoing the testing.
Read details of Dr. Banwell’s original study plans.
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Dr. Fiona Costello, Hotchkiss Brain
Institute, University of Calgary, Calgary, Alberta:
Once her team received Research Ethics Board approval, they
began recruiting a cross-section of people with MS who would
be compared with those affected by other neurological
diseases or healthy volunteers. They have three dedicated
ultrasound technologists who have been trained to do scanning
as originally done by Dr. Zamboni, and they have refined
their scanning protocol. The team is planning to repeat scans
on a subset of participants who had been scanned before they
made method changes, which will allow them to compare the
sensitivity of results pre- and post-training. Dr. Costello’s
team slowed recruitment briefly to upgrade to a new 3 Tesla
(3T) MRI scanner (twice as strong as standard clinical MRI),
and they have expanded their MRI team to include two
additional, experienced members. The 3T machine went online
in March 2011 and it is now being used to perform MR
venography scans to compare against the ultrasound tests.
Read details of this team’s original study plans.
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Dr. Aaron Field, University of Wisconsin School of
Medicine and Public Health, Madison: His team is now
actively recruiting participants to undergo MR venography and
ultrasound techniques originally used by Dr. Zamboni to
investigate CCSVI in people with early and later stages of
MS, controls with other conditions and healthy volunteers,
now that they have received approval of the study from the
Institutional Review Board. Their ultrasound expert has
received training in the Zamboni techniques. The team has
refined its MR venography protocol to account for variations
in blood flow that occur with breathing and heartbeats. They
have determined that they will use a relatively new contrast
agent or dye that will permit high-quality images of the
veins in the head and neck and for measuring blood flow in
the brain. This will enable the entire MRI/MRV exam to be
completed with one time-saving injection instead of two. They
have also standardized locations along the length of veins
where they take blood flow measurements because they have
found large differences in both anatomy and size of head and
neck veins. The team has submitted a meeting abstract
reporting on their protocol development for consideration at
the International Magnetic Resonance Angiography Workshop to
be held September 25-28, 2011 in Calgary, Alberta, Canada.
Read details of this team’s original study plans.
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Dr. Robert Fox, Cleveland Clinic Foundation,
Cleveland: After his team received IRB approval for
using MR venography, ultrasound, MRI and clinical measures in
people with MS or who are at risk for MS (CIS) and comparison
groups, they began recruiting and scanning participants. The
ultrasound team, which underwent training in the technique
originally used by Dr. Zamboni, found several aspects of the
published methodology ambiguous, and they have standardized
the protocol and analysis to achieve consistent results.
They shared their solutions to these methodological
challenges in a poster presented at the American Academy of
Neurology’s annual meeting in April 2011 (Abstract P01.263).
The poster outlined physiological and technical factors that
can complicate screening for vein blockages using ultrasound,
including that heartbeat irregularities, stages of breathing,
head position and pressure applied by the operator could
alter results; and that the state of hydration of the subject
(whether they drank adequate amounts of fluids) could impact
results of several of the criteria used to determine CCSVI.
They concluded that these complications may help explain the
mixed results reported thus far related to CCSVI and MS, and
they have added to their aims a study designed to evaluate
the impact of hydration on CCSVI assessments.
Dr. Fox’s team has also gathered autopsy specimens of venous
tissue from 9 MS tissue donors and 6 donors who did not have
MS. The team first had to develop and standardize techniques
for studying these specimens for signs of CCSVI. They are
analyzing their data and have submitted abstracts reporting
preliminary findings related to this pathology study and
their scanning results for consideration at the international
ECTRIMS (European Committee for Treatment and Research in MS)
meeting in October 2011.
Read details of this team’s original study plans.
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Dr. Carlos Torres, The Ottawa Hospital, University of
Ottawa, Ontario: His team obtained Research Ethics
Board approval after negotiating details over elements of the
informed consent form used to explain the study’s procedures
and potential outcomes to participants. The team has been
conducting the first phase of scanning, using MRI and MR
venography, in people without MS, which will be used to
compare with various scans in people with MS. Three team
members have been trained using the ultrasound techniques
originally used by Dr. Zamboni, and they are on track
recruiting more participants for the study. Dr. Torres
expects to finalize phase 1 of the study by the end of the
summer and then will move on to phase 2, which involves
people with MS and other controls.
Read details of this team’s original study plans.
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Dr. Anthony Traboulsee, UBC Hospital MS Clinic, UBC
Faculty of Medicine and Dr. Katherine Knox, Saskatoon MS
Clinic, University of Saskatchewan: After both sites
received Research Ethics Board approval they began to
recruit, they have scanned a significant number of
participants, and the level of interest in the MS community
remains high. Their ultrasound technologists were trained by
Dr. Zamboni, and they are also using catheter venography and
MR venography to investigate the prevalence of CCSVI in
people with MS and controls without MS. After the
radiologists at both sites met in February 2011 to ensure the
consistency of their protocols, they did a second wave of
recruitment and hope to finish all testing before the end of
2011.
Read details of their original study plans.
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Dr. Jerry Wolinsky, University of Texas Health
Science Center at Houston: After receiving IRB
approval, the team began recruiting participants, and their
neurosonographer received intensive training for intracranial
and extracranial ultrasound scanning techniques. The team has
already scanned a significant number of participants, which
include people with different types of MS, people with other
conditions, and people with no known health problems. The
team is testing whether other imaging methods can confirm the
ultrasound findings, while identifying the most reliable
technique to screen for CCSVI. Dr. Wolinsky’s team continues
to encounter difficulty in recruiting non-MS control subjects
who don’t have a personal interest in the purpose of the
trial. The executive committee that oversees this study has
agreed with the team’s plan to continue aggressively recruit
other controls, while at the same time increasing the number
of MS participants. In some cases they have also found that
some participants who were contacted to go into the next
phase of scanning informed the investigators that they had
gotten the venoplasty procedure, which made them ineligible
to continue in the study.
Read details of this team’s original study plans.
Going Forward: These seven teams were chosen by an international panel of experts that included specialists drawn from all key relevant disciplines including radiology, vascular surgery and neurology. The projects were selected for having the greatest potential to quickly and comprehensively determine the significance of CCSVI in the MS disease process.
At this one-year milepost the investigators are making significant progress on their overall two-year study goals. The teams are making plans for sharing preliminary results at upcoming medical meetings, and have demonstrated a clear willingness to share technical advice so that the projects can move forward as smoothly and quickly as possible. Their results will help guide the development of a phase I/II clinical trial recently announced by the Canadian Federal Minister of Health to test whether treating vein blockages may be safe and effective in treating people with MS.
The next update on the work of the seven grantees will be reported in six months.