BUFFALO, N.Y. -- A just released study on the relationship
between multiple sclerosis (MS) and chronic cerebrospinal venous
insufficiency (CCSVI), a narrowing of the extracranial veins that
restricts the normal outflow of blood from the brain, found that
CCSVI may be a result of MS, not a cause.
The study, conducted by University at Buffalo researchers,
appears in the current issue of Neurology, the journal of the
American Academy of Neurology.
Robert Zivadinov, MD, PhD, associate professor of neurology in
the UB School of Medicine and Biomedical Sciences and president of
the International Society for Neurovascular Disease, is first
author on the paper.
Zivadinov says of the findings: "Given the intense interest in
the hypothesis that CCSVI is a possible cause of MS, independent
evaluation of CCSVI was identified as an urgent need.
"Our results indicate that only 56.1 percent of MS patients and
38.1 percent of patients with a condition known as clinically
isolated syndrome (CIS), an individual's first neurological
episode, had CCSVI.
"While this may suggest an association between the MS and CCSVI,
association does not imply causality. In fact, 42.3 percent of
participants classified as having other neurological diseases
(OND), as well as 22.7 percent of healthy controls involved in the
study, also presented with CCSVI.
"These findings indicate that CCSVI does not have a primary role
in causing MS," says Zivadinov. "Our findings are consistent with
increased prevalence of CCSVI in MS, but substantially lower than
the sensitivity and specificity rates in MS reported originally by
the Italian investigators."
CCSVI is a complex vascular condition discovered and described
by Paolo Zamboni, MD, from Italy's University of Ferrara. It is
characterized by narrowing of vessels draining blood from the
cranium. Zamboni hypothesized that this narrowing restricts the
normal outflow of blood from the brain, resulting in alterations in
the blood flow patterns within the brain that eventually cause
injury to brain tissue and degeneration of neurons, leading to
Zamboni's original investigation in a group of 65 patients and
235 controls showed that CCSVI appeared to be strongly associated
with MS, increasing the risk of having MS by 43 fold.
The results of the UB study are based on 499 participants in the
Combined Transcranial and Extracranial Venous Doppler Evaluation
(CTEVD) study, which began at the university in April 2009.
The study group consisted of 289 persons with MS, 163 healthy
controls, 26 with OND and 21 with CIS.
MS patients also were defined by disease type:
relapsing-remitting (RR), secondary progressive (SP),
primary-progressive (PP), progressive-relapsing (PR) and MS with
neuromyelitis optical (NMO) -- a type of MS that affects the optic
nerves and spinal cord exclusively.
All patients underwent transcranial and extracranial
echo-Doppler scans of the head and neck. Persons were considered
"CCSVI-positive" if they met two or more of five venous hemodynamic
Prevalence rates were calculated in three groupings: only
subjects with positive and negative CCSVI diagnoses; only
borderline cases included in the negative group; and subjects who
fulfilled any of the five criteria.
When only positive and negative CCSVI cases were considered,
results showed a CCSVI prevalence of 62.5 percent in MS patients,
45.8 percent in those with OND, 42.1 percent in CIS, and 25.5
percent in healthy controls.
When borderline cases were included as negative for CCSVI,
prevalence figures were 56.1 percent in MS patients, 42.3 percent
in those with OND, 38.1 percent with CIS and 22.7 percent in
When all cases that met at least one of the five VH criteria
were included in the analysis, CCSVI prevalence was 81.3 percent in
MS cases, 76.2 percent in CIS patients, 65.4 percent in OND cases
and 55.2 percent in healthy controls.
The highest prevalence was seen in relapsing primary-progressive
MS (89.4 percent), followed by non-relapsing secondary-progressive
MS (67.2 percent), NMO (66.6 percent), primary-progressive MS (54.5
percent) and relapsing-remitting MS (49.2 percent). CCSVI
prevalence was substantially higher in progressive MS than in
non-progressive MS patients. In addition, patients with a
progressive MS disease subtype had higher CCSVI prevalence than
those with non-progressive MS.
"The higher prevalence of CCSVI in progressive MS patients
suggests that CCSVI may be a consequence, rather than a cause, of
MS," says Bianca Weinstock-Guttman, MD, co-principal investigator
of the study and UB professor of neurology. Therefore, the
possibility that CCSVI may be a consequence of MS progression
cannot be excluded and should be further investigated.
"Several studies have reported that patients with progressive MS
show decreased blood flow through the brain's neuronal tissue,
indicating that CCSVI may be secondary to reduced perfusion," says
Weinstock-Guttman. "In addition, we recently showed an association
between the severity of CCSVI and reduced cerebral blood flow in
brain parenchyma of MS patients in an published pilot study."
E. Ann Yeh, MD, UB assistant professor of neurology and a major
collaborator on the study, noted that of the 10 pediatric MS
patients who participated in the study, five presented with CCSVI
(50 percent), yielding prevalence similar to that in adult MS
"Although the sample size was too small to draw any firm
conclusions, these results suggest that CCSVI is also present in
children and is not the result of aging," she says.
Concludes Zivadinov: "The differences between our study, the
original Italian CCSVI study and other recently published studies
also emphasize the need for a multimodal approach for the
assessment of CCSVI. In addition to Doppler sonography, use of
selective venography, magnetic resonance venography and
intraluminal Doppler methods can provide more evidence for the true
prevalence of CCSVI in MS."
Additional UB researchers involved in this research are: Karen
Marr, Murali Ramananthan, PhD, Ralph H. B. Benedict, PhD, Cheryl
Kennedy, MPH, Makki Elfadil, MD, Justine Reuther, Christina Brooks,
Kristin Hunt, Michelle Andrews, Ellen Carl, Michael G. Dwyer and
David Hojnacki, MD. Gary Cutter, PhD, from the Department of
Biostatistics, University at Alabama, Birmingham, also played a
critical role in the research.
The study was supported by the Buffalo Neuroimaging Analysis
Center, Baird MS Center and the Jacobs Neurological Institute, all
from UB, as well as the Direct MS Foundation, the Jacquemin Family
Foundation and more than 500 individual donors.
The University at Buffalo is a premier research-intensive
public university, a flagship institution in the State University
of New York system and its largest and most comprehensive campus.
UB's more than 28,000 students pursue their academic interests
through more than 300 undergraduate, graduate and professional
degree programs. Founded in 1846, the University at Buffalo is a
member of the Association of American Universities.