RESEARCH TOWARD RESTORING FUNCTION
-- CCSVI and MS
Two platform presentations and 14 posters focused on issues surrounding CCSVI (chronic
cerebrospinal venous insufficiency) and multiple sclerosis, presenting
mixed or conflicting results. In addition, the Charcot Foundation
convened a Satellite Symposium focused on CCSVI before the official
start of ECTRIMS, for which abstracts are not available.
The symposium featured formal short presentations by Drs. Paolo Zamboni
(Ferrara, Italy), Robert Zivadinov (Buffalo, New York), Florian Doepp
(Berlin, Germany), Omar Khan (Detroit, Michigan) and several others.
Among the issues raised were conflicting results from different groups,
the lack of “gold standards” for methodology or validated guidelines for
what constitutes vein abnormalities, disagreement about which imaging
technologies are optimum for evaluating variations in vein flow and
structure, and inconclusive results in terms of how or whether vein
abnormalities contribute to MS pathology. There was general agreement
from those on stage that invasive procedures to correct narrowing of the
veins should only be done in the context of controlled clinical trials.
The ECTRIMS presentations related to CCSVI are summarized here:
• In a platform presentation, Dr. Claudio Baracchini presented results
of a study at the University of Padua to investigate the prevalence of
CCSVI at the time of clinical onset of MS. The study involved 50
consecutive people who had clinically isolated syndrome (CIS, meaning
they had experienced a single neurological episode and had brain lesions
on MRI suggestive of MS, but for which there was insufficient evidence
to diagnose definite MS). Also included as controls were 50 age-matched
healthy controls, 50 people who had transient global amnesia (TGA), and
50 controls age-matched to those with transient global amnesia. All
underwent sonography of the veins in the brain (transcranial color-coded
venous sonography- TCCvS) and outside (extracranial color-coded venous
sonography - ECCVS) of the brain, and those who showed abnormalities in
sonography underwent venography. TCCvS was normal in all with CIS, and
abnormal ECCvS findings were found in 52% of CIS, in 32% of healthy
controls, and in 68% of TGA. Eight out of 50 CIS, or 16%, met CCSVI
criteria. Of those, venography was normal in 6, one had a hypoplasia
(incomplete development) of the right internal jugular vein, and one
developed tachycardia (rapid heart beat) and the exam was stopped.
(Abstract 81)
• In a platform presentation, Dr. Robert Zivadinov described a study at
the University of Buffalo using powerful 3T MRI
(“susceptibility-weighted imaging or SWI) of brain tissues (parenchyma)
and veins of 59 people with MS and 33 age and sex-matched healthy
controls to investigate the relationship between CCSVI and altered
visibility of the venous vasculature of the brain. Using Doppler
sonography, the team also determined that 79.7% of those with MS
fulfilled criteria for CCSVI, as did 18.2% of healthy controls. They
measured absolute venous volume (AVV) for total vein vasculature, and
relative venous intracranial fraction (VIF) to correct for head size and
brain atrophy. They also measured the size of individual veins, and
calculated “distance from vein maps,” with the higher distance
indicating lower density or fewer veins. They found that compared to
healthy controls, people with MS had lower AVV, lower volume of veins
with a diameter less than 0.3mm, higher distance from the veins, and
lower VIF. They found that this loss of smaller veins was related to
lower venous vasculature visibility and was linked with subjects that
fulfilled their criteria for CCSVI. They also found (perhaps
paradoxically, see Abstract P265 below) that the relationship between
altered vasculature and CCSVI was stronger for relapsing-remitting MS
than for secondary-progressive MS. (Abstract 82)
• Reporting in a poster (Abstract P321) on the same group of 59
patients and 33 age-matched controls, the Buffalo team found that
reduced venous vasculature visibility seen in people with MS was related
to changes in spinal fluid flow and hypoperfusion, or lower blood flow,
in the brain. In another poster related to the same group of 59
patients and controls, (Abstract P775), the team used conventional brain
MRI scans (with a 3T magnet) and found that reduced venous vasculature
visibility in MS was related to higher volume of T1-type lesions (these
types of MS plaques are thought to represent “black holes” or areas of
tissue destruction).
• In a study described in a poster (Abstract P324), Dr. M. P. Wattjes
and colleagues at the VU University Medical Center in Amsterdam examined
20 people with MS and 20 healthy controls using 3T magnetic resonance
venography (3D phase contrast angiography and multi-phase 3D
contrast-enhanced MR angiography) in an attempt to evaluate venous
obstructions using a technology that, unlike Doppler sonography,
provides consistent results which do not vary according to the
individual operator. Phase contrast MRI was used to quantify flow of the
internal cerebral veins and straight sinus. Images were analyzed by two
neuroradiologists who were blinded as to the status of the patients.
They found intracranial venous stenosis (narrowing) in 4 people with MS
and 1 healthy control. Extracranial stenosis was found in 8 MS patients
and 7 healthy controls, and no venous backflow was found in any patients
or controls.
• In several posters, more data was shared from a large-scale
prevalence study at the University of Buffalo involving 499 people,
including 289 people with MS, 21 people with CIS, 26 people with other
neurological disorders (OND) and 163 healthy controls. The team
reiterated previously released results suggesting that 54.8% of people
with MS fulfilled criteria for CCSVI, compared to 25.4% of the combined
controls. Further, they noted that CCSVI was more frequent in people
with progressive MS (69.6%) versus non-progressive MS (48.6%). For this
poster (Abstract P265), they evaluated whether there was any
relationship between a gene variation associated with increased MS
progression (HLA 1501) and the presence of CCSVI. They reported no
significant association between HLA 1501 and people with MS and CCSVI.
• In 70.3% of the same group of 499 people, the Buffalo team used
conventional MRI scans to evaluate differences in those meeting the
criteria for CCSVI and those who did not meet those criteria. Those
considered to have CCSVI were found to have a higher average number of
classic MS brain lesions (T2, thought to detect established, scarred
plaques) and also a higher average volume of T2 lesions than those
classified as not having CCSVI. Those with CCSVI also had signs of
having more brain atrophy, as measured by ventricle volume, parenchymal
volume and cortical volume, than those without CCSVI. (Abstract P318)
The team also evaluated clinical characteristics of the same group of
499 people (Abstract P653), reporting that CCSVI was more prevalent in
people with more advanced MS, ranging from 89.5% of those with relapsing
secondary-progressive MS to 49.2% in relapsing-remitting MS and 38.1%
of those with CIS. The team also reported that those meeting CCSVI
criteria tended to have more severe motor, cerebellar and brainstem
involvement.
• The Buffalo team presented a poster (Abstract P774) investigating the
presence of iron concentrations in the brain in 93 consecutive people
with MS and 51 age- and sex-matched healthy controls. Using Doppler
sonography they found that 66.7% of people with MS met criteria for
CCSVI, and 27.5% of healthy controls. They used MRI imaging to assess
venous insufficiency and susceptibility-weighted imaging of the deep
gray matter and found that those with CCSVI and MS who had the greatest
signs of venous insufficiency also had the highest concentrations of
iron in specific areas of the brain.
• Dr. Florian Doepp of Humboldt University in Berlin presented a poster
that expanded on his recently published findings in which the team was
unable to find evidence of CCSVI in MS in 56 people with MS and 20
controls, using extra- and transcranial Doppler sonography of veins and
blood flow. Expanding the study to 59 people with MS, the team confirmed
previous results, including that blood flow in the internal jugular
veins and vertebral veins was normal in all those tested except for one
patient. The team found that turning from the supine to the upright
position resulted in less pronounced decrease of total jugular blood
volume flow in people with MS, and suggested that future studies should
elucidate this difference seen in blood flow regulation. (Abstract P579)
• Dr. B. Yamout and colleagues at the American University of Beirut
reported in a poster (Abstract P663) a study using selective
extracranial venous angiography in 42 people with MS of varying duration
of disease; no controls were noted. Stenosis (narrowing) of at least
one vein was detected 24% of people classified as having early MS, and
in 92% of those classified as having late MS, with 7%, all in the late
MS group, having two veins blocked. They report that disease duration
was the strongest predictor of stenosis.
• Drs. K. Alikhani and M.C. Kremenchutzky presented a poster from the
MS Clinic in London, Ontario, studying the frequency of abnormal
magnetic resonance venography (MRV) of the great cervical veins in 46
people (21 with MS, 6 with CIS, 5 with possible MS, and 14 with non-MS).
They identified MRV abnormalities in 5 (23.8%) of those with MS, 3
(21.4%) of those with non-MS, in 1 with CIS, and none with possible MS.
The feature that most distinguished people with MS who had MRV
abnormalities was older age (average age of 54.8 years in those with
abnormal MRV, versus 44.14 years in those with normal MRV.) (Abstract
P778)
• In a poster presentation, Dr. Marian Simka and colleagues of
Katowice, Poland presented findings from 331 people with MS who had
previously been determined to meet criteria for CCSVI, who were
evaluated for duration and severity of MS, fatigue and other factors.
They found no correlation between the severity of venous obstacles and
age or duration of disease. They reported that those with narrowed
azygous veins tended to have the most aggressive clinical course. No
controls were noted. (Abstract P641)
• In another poster, Dr. Simka and colleagues reported on safety and
complications of endovascular procedures (balloon angioplasty and
stenting) in 347 people with MS and CCSVI whom they had treated. The
amount of followup time after the procedures was not provided. They
conducted 414 balloon angioplasties and 173 stent implantations during
361 interventions in 347 people with MS and CCSVI. Complications noted
included 2 cases of stent thrombosis, 1 case of surgical removal of a
balloon, 4 cases of bleeding from the groin, 1 case of minor
gastrointestinal bleeding, 2 cases of transient cardiac arrhythmia, 4
cases of difficulty removing balloon or its delivery system, 4 problems
with placement of stents, and 4 unsuccessful catheterization of the
stenosed internal jugular vein. (Abstract P914)
• Dr. Zamboni of the University of Ferrara, and colleagues from Italy
and the U.S., including the University of Buffalo, presented a poster
related to safety and tolerability of endovascular treatment
(percutaneous transluminal angioplasty, without stenting) for people
with MS meeting criteria for CCSVI. In this pilot study, 15 people who
remained on disease-modifying therapy were randomly assigned to two
treatment groups: 8 people received immediate treatment, and 7 received
treatment after a delay of 6 months. The treatment consisted of
selective venography and balloon dilation when stenoses (narrowing) were
detected, with followup imaging and clinical exams for 12 months. They
report that the treatment was well tolerated, and that no serious
adverse events occurred except one transitory vasovagal syndrome
(irregular heartbeat or faintness) one hour after treatment. Restenosis
occurred at a rate of 26.7%, exclusively in the jugular vein. They
conclude that further and larger studies are needed to determine the
effect of endovascular treatment for CCSVI in MS. (Abstract P508)
• Related to this treatment study, team members presented a poster
(Abstract P773) focusing on their use of different imaging techniques to
evaluate blood flow and narrowing of the internal jugular veins in 10
of the people treated as noted above and followed over 12 months, plus 6
healthy controls. They reported poor agreement of findings of stenosis
and flow between Doppler sonography and magnetic resonance venography.
http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=4057