Chronic Cerebrospinal Venous Insufficiency (CCSVI)

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What is Chronic cerebrospinal venous insufficiency (CCSVI)?

CCSVI Animation (Copyrighted material posted with consent from CCSVI Alliance)

It is caused by a narrowing in the veins (stenosis) that drain the brain and the spine. Blood takes longer to return to the heart, and it can reflux back into the brain and spine or cause oedema and leakage of red blood cells and fluids into the tissues of the brain and spine.

Blood that remains in the brain too long creates a delay in deoxyginated blood leaving the head ("slowed perfusion"). This can cause hypoxia, a lack of oxygen in the brain. Plasma and iron from blood deposited in the brain tissue can also be very damaging leading to iron along with other unwelcome cells crossing the crucial brain-blood barrier.

For more on CCSVI please visit the Chronic Cerebrospinal Venous Insufficiency - CCSVI pages.

The largest study to date testing the venous-obstruction theory of multiple sclerosis failed to support it, leading the Italian Multiple Sclerosis Society to declare the theory dead.

Reported here by leaders of the group, known by its Italian abbreviation AISM, the study of nearly 2,000 individuals with blinded central imaging analysis found the condition in only about 3% of MS patients and in only slightly fewer healthy controls or patients with other neurological conditions.

Key data were released at a press briefing by principal investigator Giancarlo Comi, MD, of the University of Milan, and other study leaders in advance of Comi's formal presentation, scheduled for Saturday at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.

They characterized the study as the largest yet conducted on the so-called chronic cerebrospinal venous insufficiency theory (CCSVI), advanced in 2009 by Paolo Zamboni, MD, of the University of Ferrara in Italy.

The CCSVI theory quickly took the MS community by storm, leading many patients to seek venous angioplasty and stenting procedures in hope of obtaining relief or even a cure, as Zamboni and some other vascular surgeons claimed was possible.

But the theory also drew substantial criticism, especially after numerous other researchers were unable to reproduce Zamboni's original findings of 100% presence of CCSVI in MS patients and 0% in non-MS controls. Some groups were unable to detect CCSVI in more than a small fraction of patients, while others found that it was relatively common but without specificity for MS.

In the new study, sponsored by AISM and called CoSMo, ultrasound analyses were performed on 1,874 individuals at 35 clinics throughout Italy. A total of 107 were subsequently excluded because of technical problems with the images or because participants were found not to meet the specified inclusion criteria (such as age or disease duration).

The analysis included 1,165 patients with MS (including 104 with clinically isolated syndrome), 376 healthy controls, and 226 patients with other neurological diseases.

All participants were evaluated for MS under standard diagnostic criteria.

Initial diagnoses of CCSVI or its absence were made by the sonographers at each clinic, who had received special training in cerebral venous imaging. Some of them had previously trained in Zamboni's clinic. The local sonographers were blinded to participants' diagnoses.

The local clinic diagnoses were then reviewed by one of three blinded central imaging experts: Erwin Stolz, MD, of Justus-Liebig University in Giessen, Germany; Massimo Del Sette, MD, chairman of the Italian Society of Neurosonology and Cerebral Hemodynamics; and Giovanni Malferrari, MD, chairman of the Italian Interdisciplinary Neurovascular Society.

When there was disagreement between the local and central readers, all three of the central readers reviewed the images, with the opinion shared by two counted as the final diagnosis. Analyses in the two-year study were completed last month.

The prevalence of CCSVI as determined under this process was as follows in the three groups of participants:

MS patients: 3.26% (95% CI 2.38% to 4.45%)
Healthy controls: 2.13% (95% CI 1.10% to 4.14%)
Other neurological disorders: 3.10% (95% CI 1.58% to 6.44%)
On the basis of these small values, and the lack of significant (P<0.05) differences between them, the AISM issued a statement declaring that "CCSVI is not a disease connected to multiple sclerosis."

Moreover, it continued, "for people affected by MS, there is no need to carry out additional tests to diagnose CCSVI, nor is vein surgery required."

The AISM is the first national MS society to make such a conclusive determination. In the U.S. and Canada, research on CCSVI commissioned by the major organizations in those countries is still under way, and no similar declaration is likely until those studies are completed.

Comi said that Zamboni had been invited to participate in CoSMo, and did for a time. But he quit before all the sonographers had been trained, objecting to multiple aspects of the study design that he believed would bias the results against finding a relationship between CCSVI and MS.

Stolz said that the sonographers were not trained specifically in Zamboni's method, but that he and others who had conducted the training had extensive experience in cerebrovascular ultrasound imaging.

He noted that this had also been the case with other groups that failed to replicate Zamboni's findings, despite having been trained in his clinic. Stolz added that a diagnostic procedure is only meaningful if it can be taught and used reliably by other experienced practitioners.

"If it is not repeatable, it has no value," he said.

Comi said that other researchers would be permitted to conduct their own evaluations of sonograms collected during the study, as long as the blinding to clinical diagnosis was maintained.

Initial diagnosis of CCSVI in the individual clinics in fact varied widely, Comi said. At one clinic, the condition was found in 60% of participants; in two others, the prevalence was 0%.

Overall, the detection rate at the initial step was considerably higher than after central review: 15.9% among MS patients, 12% in healthy controls, and 15% in patients with non-MS neurological disorders. Comi noted that even at these higher prevalences, there was still no meaningful difference between MS patients and other participants.

He also indicated that central reviewers rarely overruled the local clinic sonographers on negative diagnoses. In only 3% of cases in which the local sonographer found no CCSVI did the central reviewers say it was present.

Agreement was poorer for positive diagnoses. Central reviewers overturned 89% of the CCSVI diagnoses made by local sonographers.

Stolz attributed the lack of concordance on positive findings to the fact that "local sonographers are not on the moon." He suggested that seeing participants, and noting any physical or mental impairments, could have biased them toward diagnosing CCSVI.

Gianluigi Mancardi, MD, head of the AISM's scientific committee and co-principal investigator on the study with Comi, said he hoped the study would put the CCSVI theory permanently to rest.

"In our opinion, this is the final answer," he said.

Noting that the AISM had spent some $2 million to conduct the CoSMo study, he said the group now hoped to direct its attention to more fruitful areas of research in MS and its treatments.

The study was funded by the Italian Multiple Sclerosis Society.

Comi reported consulting fees for participating on advisory boards from Novartis, Teva, sanofi-aventis, Merck Serono, and Bayer Schering; lecture fees from Novartis, Teva, sanofi-aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation. Mancardi reported honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Schering, Biogen Idec, sanofi-aventis, Novartis, and Merck Serono.

Stolz declared that he had no relevant financial interests.

Primary source: European Committee for Treatment and Research in Multiple Sclerosis
Source reference:
Comi G, et al "Chronic cerebro-spinal venous insufficiency (CCSVI) and global venous haemodynamics in multiple sclerosis: the CoSMo study" ECTRIMS 2012; Abstract 167.

Source: Medpage Today © 2012 MedPage Today, LLC (15/10/12)

A Canadian study that tracked 80 multiple sclerosis patients who underwent the controversial “liberation treatment” outside of the country suggests that about half of them saw their symptoms improve after the procedure.
Researchers in British Columbia surveyed 80 people over the phone one year after they received the controversial treatment, which involves opening up blocked veins to improve blood flow from the brain.

“The picture that seems to be coming out is that about half of the patients feel some improvements in MS symptoms. The degree of improvements ranges from mild to significant,” Dr. Anthony Traboulsee, medical director of the UBC Hospital MS Clinic, told CTV News.

“And about half the patients feel exactly the same as before the procedure or worse.”

About 11 per cent of surveyed patients reported complications around the time they received the liberation treatment. Another 13.8 per cent experienced troubles up to one month afterward.

Pain and bleeding were among the complications experienced. One patient suffered a stroke after the procedure while another one reported symptoms similar to those of a heart attack.

Nine patients had difficulties related to the procedure itself. One reported insufficient anesthetic and said they woke up near the end of the procedure.

Lori Batchelor was among those who found the treatment beneficial. She travelled to a U.S. clinic for the procedure after living with MS for over two decades. Before the treatment, she had difficulty walking and standing.

“I felt very strongly that because my results were so good, I wanted it on record that this is a really important procedure to finally have some sort of treatment available for someone like me who was left to just get worse over the years with absolutely nothing available,” she told CTV News.

Fifty-eight women and 22 men were involved in the study. For the respondents, the average age of MS diagnosis was 39 years of age.
The treatment results relayed in the survey are according to reports from the patients themselves, and are not confirmed by a medical assessment.

Traboulsee said the results of the telephone survey underline the need for a formal study of the treatment’s effect on MS patients.
“We have so many unanswered questions, and no shortage of opinion about this situation and a treatment trial is an efficient way to address those concerns," he said.

That’s why Traboulsee and his team will soon begin recruiting people for a broader study in which 100 MS patients will receive the liberation treatment, similar to angioplasty.

The team has received ethics approvals from institutions in B.C. and Québec for the clinical trial.

The controlled study will monitor MS patients over a two-year period to observe any changes in their symptoms. It is a collaborative effort of the Canadian Institutes of Health Research, the MS Society of Canada and the provinces of B.C. and Quebec.
The liberation treatment was developed by Italian doctor Paolo Zamboni, who theorized that MS has vascular symptoms. He posited that narrowed veins in the neck cause a condition he termed Chronic Cerebrospinal Venous Insufficiency, or CCSVI.

Zamboni’s findings have been highly controversial and some experts have dismissed his claims.

Several studies currently underway in North America are looking at whether vein abnormalities and MS are linked.

A recent observational study of people in Newfoundland and Labrador who travelled abroad for the treatment found no measurable benefit from liberation treatment.

Source: CTV News © 2012 (10/10/12)

A long-awaited national trial of a controversial experimental treatment for multiple sclerosis has been given the go-ahead and will soon begin recruiting patients, federal Health Minister Leona Aglukkaq announced Friday.

Aglukkaq, in Halifax for a meeting with provincial and territorial health ministers, said about 100 MS patients will be enrolled in the Phase I and II trial to assess the safety of the procedure to unblock narrowed neck veins and its efficacy in improving MS symptoms.

The condition — dubbed chronic cerebrospinal venous insufficiency, or CCSVI — has been proposed as a possible cause of MS by Italian vascular surgeon Paolo Zamboni.

More than three years ago, Zamboni hypothesized that narrowed and twisted veins in the neck and chest create a backup of blood in the brain, resulting in iron deposits that could cause the brain lesions typical of MS.

The disease causes the destruction of myelin, the protective sheath around nerves throughout the body, leading to progressive physical and cognitive disability. An estimated 55,000 to 75,000 Canadians have MS, and the country has one of the highest rates of the incurable disease in the world.

"We've always said that we needed the science behind the actual procedure," Aglukkaq told reporters. "This area of MS clinical trials is very important to many of our constituents and today is huge progress."

Dr. Anthony Traboulsee, medical director of UBC Hospital's MS Clinic, will lead the $6-million study, which will be conducted initially in Vancouver and Montreal. Medical and ethical approval is also being sought for parts of the trial to be conducted in Quebec City and Winnipeg.

"It's going to be a randomized-control study where patients who have the presence of CCSVI will be randomly selected to either have the venoplasty, which is dilation of the vein, or a sham treatment, which is not an actual dilation, just a pretend dilation," Traboulsee said from Vancouver.

"And after a year, the groups will switch so that everybody eventually gets the dilation of the vein."

A venoplasty to widen veins is the same technique as an angioplasty used to expand coronary arteries; a tiny balloon is fed into the blood vessel, then expanded.

None of the participants will know which treatment they received or during which half of the study, Traboulsee said.

"The patients won't know when they're getting the dilation, the first time or the second time, so it doesn't bias their interpretation of benefit," he said.

Despite criticisms of Zamboni's theory — some neurologists question or even outright dismiss the notion of blocked veins contributing to MS — many patients desperate for relief have embraced the treatment.

Thousands of Canadians with MS have reportedly travelled to clinics outside the country, paying thousands of dollars for the vein-widening procedure since Zamboni's theory first made headlines in late 2009.

Many patients — but by no means all — reported their symptoms had improved following CCSVI treatment, fuelling insistent calls by many MS patients and their advocates to allow doctors to perform the procedure in Canada.

But with several deaths and complications attributed to the surgery, and studies on CCSVI around the world showing mixed results at best, an expert medical panel advised Ottawa to first mount a clinical trial to test Zamboni's theory.

Traboulsee's group, whose study design was chosen from among three proposals, said "safety is really important."

"We've been surveying patients who have gone out of the country for the treatment and we found a complication rate of 11 to 12 per cent. That's what patients are reporting," he said.

"My impression is it's mostly related to stents, and we're not going to be using stents in our study. We don't think the stents are the best idea at this point."

Stents are small mesh cylinders inserted into blood vessels to keep them propped open. Their use in veins is controversial, as the stents can cause blood clots or migrate from their original site. Even Zamboni does not advocate their use in his CCSVI treatment.

"There has been a lot of controversy around it," Traboulsee said of the procedure. "That's why I think it's important to move this forward and get some final answers to it.

"Because so many Canadians are going out of the country to have this procedure done, if we don't bring some resolution to it soon, we won't be able to give people the information they need to make safe, informed decisions."

A spokesman for the CCSVI Coalition, a patient advocacy group that's been pushing to have the treatment performed in Canada, welcomed the announcement of the study.

"It's long overdue," said Dr. Michael Shannon, chair of the group's scientific advisory board. "If the results from this trial come out unequivocally in favour of CCSVI or the other way, either way it's good news — if and only if the trial has been designed properly.

"If it is flawed in any way, you'll be right back to the drawing board and you'll never be able to convince everyone. So this thing has to be so rigorous."

Dr. Alain Beaudet, president of the Canadian Institutes of Health Research (CIHR), said trial subjects will be drawn from the three provinces where the research is being conducted.

Beaudet said the study is among only a handful worldwide that are blinded, randomized-control trials, the gold standard of medical research.

"Which is critical here, because we're wondering if it's a true effect. Is it a placebo effect? Is there really an effect?" he said from Halifax.

Saskatchewan has set aside $5 million for clinical trials of the so-called liberation therapy; $2.2 million of that is funding a trial of the procedure involving 86 patients from the province, being conducted at a clinic in Albany, N.Y.

Provincial Health Minister Dustin Duncan said the rest of the money could go toward a pan-Canadian trial.

"What has been announced today is just the beginnings, I think, of what the federal government is doing," Duncan told The Canadian Press. "We certainly want to be a part of whether it's in trials or whether it's in monitoring ... we want to be a part of trying to answer that question of whether CCSVI is an effective treatment for people with MS."

The national study is funded by the federal government through CIHR, the three provinces where it is taking place, and the MS Society of Canada.

Traboulsee said researchers will use not only standard yardsticks to evaluate patients during the study period, but also some patient-focused measures.

"We've had a lot of patient input into the study, so it's a nice balance of what we consider a classic standard MS clinical trial, with a lot of patient input into the outcome," he said.

"So it's in a sense validated by the patient support groups in that it's addressing questions that they think are important to them as well as to the clinicians."

Source: The Province © 2012 Postmedia Network Inc (01/10/12)

Australian researcher, A/Prof Brian Chambers of the Austin Hospital, Melbourne, has published the results of his MSRA-funded study into the prevalence of chronic cerebrospinal venous insufficiency (CCSVI) in early MS (view the abstract here).

CCSVI is a condition where drainage of blood from the brain and spinal cord is impeded. It is thought CCSVI may contribute to the development or symptoms of MS and was originally described by Dr Zamboni of Italy in 2009. In his sample, all people with MS had CCSVI whereas healthy individuals showed no evidence of CCSVI. Subsequent studies have been unable to replicate this marked difference in CCSVI prevalence. Some studies have found an increased prevalence of CCSVI in MS, but have also shown that it is present in healthy individuals and in people with other neurological diseases (OND). For earlier round-ups of CCSVI news, please type ‘CCSVI’ into the search box of this website.

Australian results
A/Prof Chamber’s study tested whether CCSVI was more prevalent in people with CIS or mild MS, which would imply a role for CCSVI in the development of MS. The study examined 70 people, made up of 94% with relapsing remitting MS with an expanded disability score (EDSS) of 2 or less and 6% with clinically isolated syndrome (CIS – a first attack of MS-like symptoms) and compared them to 70 healthy individuals. Controls were unrelated to the people with MS and were matched for age and sex.

All subjects were examined by ultrasound using the criteria published by Dr Zamboni, with CCSVI defined as the presence of two or more Zamboni criteria. A/Prof Chambers communicated closely with Dr Zamboni to ensure he was interpreting the criteria according to Dr Zamboni’s descriptions. The Australian team also derived their own criteria for venous abnormalities, which were closely related to the Zamboni criteria, but with defined parameters in relation to flow alterations and internal jugular vein narrowing.

The venous flow parameters were studied with subjects lying down on their backs (supine position) and sitting postures. Careful measures were taken to ensure that the sonographer did not know whether participants had MS, including no discussion of clinical status with the subject and the sonographer being absent from the room while subjects were positioned on, and removed from, the couch. A questionnaire conducted with the sonographer after each subject confirmed that blinding was successful.

Only one individual, a person without MS, satisfied the Zamboni definition of CCSVI. However, 19 MS subjects and 13 controls had Zamboni criteria abnormalities, this difference was explained by an increased prevalence of internal jugular vein narrowing, defined as cross-sectional area 0.3cm2 or less. Using the teams’ more clearly defined measure of stenosis, the difference disappeared. This more rigorous method was designed to avoid potential errors introduced by vein compression or normal side to side variation in vein diameter. Further analysis revealed an abnormal internal jugular vein valve in 7 people with MS and one control.

The team concluded that CCSVI does not have a causal role in MS. However, an apparent increase in internal jugular vein abnormalities in people with MS warrants further investigation.

Full Paper

Source: Multiple Sclerosis Research Australia © 2012 Multiple Sclerosis Research Australia (25/09/12)

Seven research projects investigating CCSVI (Chronic Cerebrospinal Venous Insufficiency) and MS — launched with a $2.4 million investment by the National MS Society and the MS Society of Canada — have reached the two-year milepost.

The funded multi-disciplined researchers have been reporting significant progress in their two-year study goals. As of July 2012, most of the investigators are in the process of completing their projects and expect to do so within the next year. Although the work continues for several of the teams, some are already presenting preliminary results at medical meetings, and all have shared technical advice so that the projects can move forward as smoothly and quickly as possible.

The need for continued work beyond the two-year grant funding period is not uncommon, as practical and logistical issues begin impacting on projected timelines, including such items as:

- Getting proper protocols in place;

- Applying for and gaining approvals from the required Institutional Review Boards in the U.S. or the Research Ethics Board in Canada, a requirement established by regulatory authorities to protect humans involved in research projects;

- Getting technicians and other team members trained on how to conduct appropriate screenings; and

- Recruiting study participants.

After the research projects are completed, the data collected in these studies will be analyzed and submitted for publication in one or more scientific journals so that other scientists can evaluate and comment on the findings. Currently it is not known when the full data and results will be available, though updates will continue as appropriate to reflect the ongoing transparency of the work being supported by the MS Society of Canada. Results from the seven projects, as well as other studies underway around the globe, will help guide our planning for future investments in this area of research.

Research project highlights and progress

The teams include an integration of experts drawn from all key relevant disciplines including neuroradiology, neurovascular imaging, MS imaging, vascular surgery, biostatistics, interventional radiology, interventional neuroradiology and MS clinical neurology. Bringing together experts across these areas will help to facilitate understanding of CCSVI in MS as quickly as possible.

The research teams have recruited and scanned 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 to reliably validate the occurrence of CCSVI and understand its implications in the MS disease process.

Already more than 900 people have undergone scanning with various imaging technologies being used by the studies, including the Doppler ultrasound technology 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.

Some of the teams have been trained in, and are using, the ultrasound technique originally published by Dr. Zamboni. Others are using the same methods but are utilizing standard Doppler ultrasound machines rather than purchasing the specific machine used by Dr. Zamboni’s team.

Future Steps – Clinical Trial

Grantee results will help guide future steps, including the development of a clinical trial to test whether treating vein blockages is a safe and effective therapy for people with MS. The Canadian Institutes of Health Research (CIHR) announced in April 2012 that a research team had been chosen to conduct a phase I/II clinical trial to determine the safety of venous angioplasty and obtain evidence on patient outcomes in people with MS. The location of the study has not yet been announced. The clinical trial is a collaborative initiative between the CIHR and the MS Society of Canada.

At this point, no connection has been confirmed between CCSVI and MS, in fact, CCSVI appears to occur in many people who do not have MS. Although some individuals who have MS have undergone surgical procedures for CCSVI, there has not yet been a controlled trial to determine its effectiveness in treating the symptoms or course of the disease. In addition, the U.S. FDA has issued a safety communication about potential risks associated with procedures and devices used to treat CCSVI, encouraging additional research.

The MS Society shares in the public urgency to advance the understanding of CCSVI as quickly as possible, and is urging researchers to complete their studies and to analyze and publish their results as soon as possible.

All Canadians living with MS urgently require answers about the potential risks and benefits of CCSVI treatment. The MS Society honours and respects the decisions Canadians living with MS make for the benefit of their own health. We acknowledge and respect that some Canadians living with MS have travelled abroad to seek CCSVI related procedures and others have decided to wait for more research.

Source: The Multiple Sclerosis Society of Canada (05/09/12)

Purpose
This study proposed to prospectively evaluate safety and clinical changes in outpatient endovascular treatment in patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI).

Materials and Methods
Two hundred fifty-nine patients with MS were followed with the Multiple Sclerosis Impact Scale (MSIS-29) before and for 1and 6 months after treatment of extracranial internal jugular vein and azygos vein stenoses and occlusions using venous angioplasty, as well as stent placement in 2.5% of patients. Before treatment, the patients were tested with magnetic resonance (MR) venography and flow quantification.

Results
We found statistically significant improvements in the MSIS-29 scores (P < .01) at both 1 and 6 months. At 1 and 6 months, 67.9% and 53.6% were improved on the physical scale, respectively, and 53.0% and 44.4% were improved on the psychological scale, respectively. Women showed greater improvement than did men on the physical scale at 6 months (P = .01). Patients with primary progressive MS (PPMS) showed less improvement than did those with relapsing-remitting MS (RRMS) on the psychological scale at 1 month, and venoplasty treatment of more vein sites versus fewer vein sites showed greater improvement on the physical scale at both 1 and 6 months. Fifteen patients (6.3%) reported recurrent symptoms after clinical improvement and were treated again. There was one serious adverse event, a deep venous thrombosis at the catheter insertion site, which resolved with treatment.

Conclusions
Endovascular treatment of CCSVI in patients with MS appears to be a safe procedure resulting in significant clinical improvement.

David Hubbard, MD, Donald Ponec, MD, Justin Gooding, MD, Richard Saxon, MD, Heidi Sauder, PhD, Mark Haacke, PhD

Source: JVIR © 2012 SIR. Published by Elsevier Inc (30/08/12)

New MRI research shows that changes in brain blood flow associated with vein abnormalities are not specific for multiple sclerosis and do not contribute to its severity, despite what some researchers have speculated. Results of the study were published online, August 21, by the Radiological Society of North America in the journal Radiology.

New magnetic resonance imaging (MRI) research shows that changes in brain blood flow associated with vein abnormalities are not specific for multiple sclerosis (MS) and do not contribute to its severity, despite what some researchers have speculated. Results of the research are published online in the journal Radiology.

“MRI allowed an accurate evaluation of cerebral blood flow that was crucial for our results,” said Simone Marziali, M.D., from the Department of Diagnostic Imaging at the University of Rome Tor Vergata in Rome.

MS is a disease of the central nervous system in which the body’s immune system attacks the nerves. There are different types of MS, and symptoms and severity vary widely. Recent reports suggest a highly significant association between MS and chronic cerebrospinal venous insufficiency (CCSVI), a condition characterized by compromised blood flow in the veins that drain blood from the brain. This strong correlation has generated substantial attention from the scientific community and the media in recent years, raising the possibility that MS can be treated with endovascular procedures like stent placement. However, the role of brain blood flow alterations on MS patients is still unclear.

To investigate this further, Italian researchers compared brain blood flow in 39 MS patients and 26 healthy control participants. Twenty-five of the MS patients and 14 of the healthy controls were positive for CCSVI, based on Color-Doppler-Ultrasound (CDU) findings. The researchers used dynamic susceptibility contrast-enhanced (DSC) MRI to assess blood flow in the brains of the study groups. DSC MR imaging offers more accurate assessment of brain blood flow than that of CDU. MRI and CDU were used to assess two different anatomical structures.

While CCSVI-positive patients showed decreased cerebral blood flow and volume compared with their CCSVI-negative counterparts, there was no significant interaction between MS and CCSVI for any of the blood flow parameters. Furthermore, the researchers did not find any correlation between the cerebral blood flow and volume in the brain’s white matter and the severity of disability in MS patients.

The results suggest that CCSVI is not a pathological condition correlated with MS, according to Dr. Marziali, but probably just an epiphenomenon—an accessory process occurring in the course of a disease that is not necessarily related to the disease. This determination is important because, to date, studies of the prevalence of CCSVI in MS patients have provided inconclusive results.

“This study clearly demonstrates the important role of MRI in defining and understanding the causes of MS,” Dr. Marziali said. “I believe that, in the future, it will be necessary to use powerful and advanced diagnostic tools to obtain a better understanding of this and other diseases still under study.”

“Brain Hemodynamic Changes Associated with Chronic Cerebrospinal Venous Insufficiency (CCSVI) Are Not Specific for Multiple Sclerosis (MS) and Do Not Contribute to Its Severity.” Collaborating with Dr. Marziali were Francesco G. Garaci, M.D., Alessandro Meschini, M.D., Maria Fornari, M.D., Silvia Rossi, M.D., Milena Melis, M.D., Sebastiano Fabiano, M.D., Matteo Stefanini, M.D., Giovanni Simonetti, M.D., Diego Centonze, M.D., and Roberto Floris, M.D.

Source: redOrbit © 2002-2012 redOrbit.com (21/08/12)

A Saskatoon man with multiple sclerosis will be the first person sent by the province to the United States to see if he can participate in neck vein therapy clinical trials.

Andrew Dahlen will fly to Albany, N.Y., Monday for a final assessment in order to join a two-year study of the so-called liberation therapy for MS.

The therapy involves using tiny balloons, surgically inserted, to open up constricted veins.

MS is a neurological disease that can seriously affect mobility, vision, speech and bladder function.

Hundreds of people from Canada have gone to the U.S. or overseas for the treatment, and many say it has given them relief from their symptoms.

However, neck vein therapy is controversial, with a number of medical experts saying it doesn't work, or that the relief it provides is temporary or can be explained by the placebo effect.

No Canadian province pays for the procedure for Chronic Cerebrospinal Venous Insufficiency (CCSVI) , which costs thousands of dollars per treatment, so people who leave the country for it must pay out of their own pockets.

Saskatchewan doesn't pay for the procedure either, but it has set aside $2.2 million to have 86 Saskatchewan patients participate in the Albany trials.

Half of the participants will receive the procedure, while the other half will receive a "placebo" operation.

Dahlen, a 28-year-old Saskatoon cook who was diagnosed with MS six years ago, said he's excited to be part of the Saskatchewan effort. He will have to go through a final assessment before he can undergo the procedure, and even then, may not be in the group that receives the real treatment.

After the Albany treatments are complete, a Saskatchewan neurologist will work with the U.S. team with assessments, referrals and ongoing monitoring of Saskatchewan participants, the province says.

Source: CBC.ca Copyright © CBC 2012 (17/08/12)

Abstract
Background

Chronic cerebrospinal venous insufficiency (CCSVI) has been associated to multiple sclerosis (MS).

Objective

To evaluate the possible association between CCSVI and MS, using a population-based control design.

Methods

A random cohort of 148 incident MS patients were enrolled in the study. We have also studied 20 patients with clinically isolated syndrome (CIS), 40 patients with other neurological diseases (OND), and 172 healthy controls. Transcranial (TCC) and Echo Color Doppler (ECD) were carried out in 380 subjects. A subject was considered CCSVI positive if ≥2 venous hemodynamic criteria were fulfilled.

Results

CCSVI was present in 28 (18.9%) of the MS patients, in 2 (10%) of CIS patients, in 11 (6.4%) of the controls, and in 2 (5%) of the OND patients. A significant association between MS and CCSVI was found with an odds ratio of 3.41 (95% confidence interval 1.63–7.13; p=0.001). CCSVI was significantly more frequent among MS subjects with a disease duration longer than 144 months (26.1% versus 12.6% of patients with duration shorter than 144 months; p=0.03) and among patients with secondary progressive (SP) and primary progressive (PP) forms (30.2% and 29.4, respectively) than in patients with relapsing remitting (RR) MS (14.3%). A stronger association was found considering SP and PP forms (age adjusted OR=4.7; 95% CI 1.83–12.0, p=0.001); the association was weaker with the RR patients (age adjusted OR=2.58; 95%CI 1.12–5.92; p=0.02) or not significant in CIS group (age adjusted OR=2.04; 95%CI 0.40–10.3; p=0.4).

Conclusions

A higher frequency of CCSVI has been found in MS patients; it was more evident in patients with advanced MS, suggesting that CCSVI could be related to MS disability.

Full article

Source: PLoS One v.7(8); 2012 PMC3411668 (16/08/12)

Abstract
An open study was conducted with the aim of reporting long-term clinical outcome of endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) in patients with multiple sclerosis (MS).

Twenty-nine patients with clinically definite relapsing-remitting MS underwent percutaneous transluminal angioplasty for CCSVI, outside a clinical relapse.

All the patients were regularly observed over at least two years before the first endovascular treatment and for at least two years after it (mean post-procedure follow up 30.6±6.1 months).

The following clinical outcome measures were used: annual relapse rate and Expanded Disability Status Scale (EDSS) score.

All the patients were observed intensively (mean 6 hours) on the day of the endovascular treatment to monitor for possible complications (bleeding, shock, heart attack, death).

We compared the annual relapse rate before and after treatment (in the two years before and the two years after the first endovascular treatment) and the EDSS score recorded two years before versus two years after the treatment.

Overall, 44 endovascular procedures were performed in the 29 patients, without complications. Thirteen of the 29 patients (45%) underwent more than one treatment session because of venous re-stenosis: 11 and two patients underwent two and three endovascular treatments respectively.

The annual relapse rate of MS was significantly lower post-procedure (0.45±0.62 vs 0.76±0.99; p=0.021), although it increased in four patients.

The EDSS score two years after treatment was significantly lower compared to the EDSS score recorded at the examination two years before treatment (1.98±0.92 vs 2.27±0.93; p=0.037), although it was higher in four patients.

Endovascular treatment of concurrent CCSVI seems to be safe and repeatable and may reduce annual relapse rates and cumulative disability in patients with relapsing-remitting MS. Randomized controlled studies are needed to further assess the clinical effects of endovascular treatment of CCSVI in MS.

Salvi F, Bartolomei I, Buccellato E, Galeotti R, Zamboni P.

Soure: Pubmed PMID: 22687168 (26/06/12)

Percutaneous balloon angioplasty improved flow dynamics in multiple sclerosis patients with chronic cerebrospinal venous insufficiency in a pilot study.

An association has been made recently between multiple sclerosis and chronic cerebrospinal venous insufficiency (CCSVI) that is characterized by stenosis and reflux of the principal extracranial venous drainage, including the internal jugular veins and the azygous veins. But there has been considerable debate about the validity of percutaneous balloon angioplasty in the treatment of this stenosis.

Dr. Manish Mehta of Albany (New York) Medical College and his colleagues conducted the first angiographic study to quantitatively analyze the impact of percutaneous balloon angioplasty on flow dynamics across these lesions. Dr. Mehta shared their results at the Vascular Annual Meeting.

The researchers assessed 50 internal jugular veins (IJVs) from MS patients with CCSVI, as well as 12 IJVs from healthy volunteers, all of whom underwent detailed angiographic evaluation. The technical components of all venograms were standardized.

Quantitative analysis included the contrast time of flight from the mid-IJV to the superior vena cava, and the primary venous emptying time (PVET), quantified as greater than 50% of venous emptying from the IJV. The time of flight and PVET were recorded in patients with CCSVI prior to and subsequent to balloon angioplasty. The same data were recorded in the healthy controls. All data were collected prospectively, and statistical analysis was performed using two-tailed Student’s test.

Of the 50 CCSVI-MS patients who had IJV stenosis greater than 70% and reflux and who underwent balloon angioplasty, technical success (defined as less than 20% residual IJV stenosis) was achieved in 44 (78%). CCSVI patients were observed to have a significant improvement in both the time of flight and PVET following balloon angioplasty that paralleled those of healthy subjects without MS.

“The results of this prospective pilot study suggest an association between MS and CCSVI, which results in abnormally elevated time of flight and PVET through the IJV,” Dr. Mehta said. “Furthermore, balloon angioplasty of these lesions improves the hemodynamic parameters so that they are comparable to” those of healthy non-MS patients.”

Dr. Mehta stressed the need for randomized studies to further investigate this issue and said that this patient population is at high risk for a placebo effect with regard to their reported symptoms. He also stated that this treatment is being provided to many patients around the world and that the U.S. Food and Drug Administration has cautioned against its use outside of well-regulated trials due to lack of safety and efficacy data.

Dr. Mehta reported that he had nothing to disclose.

Source: MedConnect © Copyright 2012 - Elsevier (Australia) Pty Ltd. (14/06/12)

Patients who underwent the so-called liberation treatment for multiple sclerosis experienced no measurable benefit from the procedure, a study commissioned by the government of Newfoundland and Labrador found.

The results of the small, observational study were announced Wednesday in St. John’s by lead investigator William Pryse-Phillips, a professor emeritus of neurology at Newfoundland’s Memorial University.

Pryse-Phillips said he had gone into the study hopeful the treatment might have something to offer his MS patients, but completed it convinced the people who had the vein-opening procedure didn’t experience any gains.

“I am disappointed. I had hoped. I cannot recommend this therapy on the basis of these results at this time,” he said during a news conference, the video of which is posted on the Department of Health and Community Service’s website.

The province spent $400,000 on the study, which compared 30 patients with MS who had travelled outside the province to have the therapy and 10 who did not. Participants were subjected to an array of tests before the treatment and then at intervals of one month, three months, six months and one year post-procedure.

It was an attempt to test a theory that has driven a wedge between MS patients and the neurologists and professionals – including those at the MS Society of Canada – who work to advance the cause of MS sufferers.

The theory hails from Italy. Paolo Zamboni, a vascular surgeon from the University of Ferrara, has hypothesized that MS is not a neurodegenerative disease, as has been thought, but a disease resulting from collapsed veins in the neck and upper chest. He named the condition chronic cerebrospinal venous insufficiency, or CCSVI.

Blockages in the veins of MS patients prevent blood from draining properly from the brain, and the pooled iron-rich blood damages brain tissues, Zamboni suggests. He says opening those blockages with the balloon procedure used to repair clogged arteries – angioplasty – offers substantial benefit to MS patients. (When applied to veins, the procedure is called venoplasty.)

Dr. Zamboni’s theory has taken off, particularly in Canada.

While clinicians here do not do the unproven procedure, scads of MS patients have travelled to the U.S., Eastern Europe, and India to have their veins opened. And enormous pressure has been placed on the federal and provincial governments, both to fund clinical trials and to include the treatment in the items covered by provincial health-care programs.

Newfoundland and Labrador Health Minister Susan Sullivan said based on the findings of Dr. Pryse-Phillips’ trial, her province will not be covering the cost of CCSVI treatment going forward.

Andreas Laupacis, who has been periodically assessing the scientific evidence for and against the CCSVI theory for the Canadian Institutes of Health Research, said the study has some strengths and some weaknesses.

If the patients who didn’t have venoplasty had been given a sham procedure – the equivalent of a placebo in this setting – the results would have been stronger, for instance.

“I think it’s another piece of evidence,” said Dr. Laupacis, who is executive director of the Li Ka Shing Knowledge Institute at St. Michael’s Hospital in Toronto.

“It’s certainly every bit as good a negative bit of evidence as the positive bits of evidence that people on the other side are hauling out.... But I don’t think it’s conclusive.”

Dr. Pryse-Phillips said the study was set up so that he didn’t know which participants had undergone venoplasty and which had not. That is done so any inherent biases a researcher might have cannot influence his or her appraisal of how well an intervention has worked.

The study participants were assessed using a combination of tests – questionnaires which the patients filled out, MRI scans of their brains, and a standardized test used to gauge function in MS patients. Those tests looked at manual dexterity, ability to walk and mental acuity.

Dr. Pryse-Phillips said he saw no differences among the patients, even though those who had received the therapy reported positive results in the questionnaires – things like they felt they had more energy or their balance was better.

He noted, though, that even the self-reported gains seemed to tail off over time, with a drop-off after the three-month check up.

Dr. Laupacis found that interesting.

“It could certainly totally be a placebo effect, the fact that it goes away in three months. On the other hand, without a kind of control group, you can’t be 100 per cent sure.”

Dr. Pryse-Phillips also noted that by the 12-month check up, about a quarter of the patients who had undergone venoplasty had blocked veins – either a clot in or the closure of one or more neck veins. But there was no difference, function-wise, in these patients as compared to the 75 per cent who didn’t have the clots or blockages.

Dr. Pryse-Phillips said under Dr. Zamboni’s theory, those who experienced the closures should have had poorer results than those who didn’t.

Source: The Globe And Mail © Copyright 2012 The Globe and Mail Inc (08/06/12)

Abstract (provisional)

Background

Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of the primary veins outside the skull that has been reported to be associated with MS. In the blinded Combined Transcranial (TCD) and Extracranial Venous Doppler Evaluation (CTEVD) study, we found that prevalence of CCSVI was significantly higher in multiple sclerosis (MS) vs. healthy controls (HC) (56.1% vs. 22.7%, p < 0.001). The objective was to evaluate the clinical correlates of venous anomalies indicative of CCSVI in patients with MS

Methods

The original study enrolled 499 subjects; 163 HC, 289 MS, 21 CIS and 26 subjects with other neurological disorders who underwent a clinical examination and a combined Doppler and TCD scan of the head and neck. This analysis was restricted to adult subjects with MS (RRMS: n = 181, SP-MS: n = 80 and PP-MS: n = 12). Disability status was evaluated by using the Kurtzke Expanded Disability Status Scale (EDSS) and MS severity scale (MSSS).

Results

Disability was not associated with the presence ([greater than or equal to]2 venous hemodynamic criteria) or the severity of CCSVI, as measured with venous hemodynamic insufficiency severity score (VHISS). However, the severity of CCSVI was associated with the increased brainstem functional EDSS sub-score (p = 0.002). In logistic regression analysis, progressive MS (SPMS or PP-MS) vs. non-progressive status (including RR-MS) was associated with CCSVI diagnosis (p = 0.004, OR = 2.34, CI = 1.3-4.2).

Conclusions

The presence and severity of CCVSI in multiple sclerosis correlate with disease status but has no or very limited association with clinical disability.

Full Article

Bianca Weinstock-Guttman, Murali Ramanathan, Karen Marr, David Hojnack, Ralph H.B. Benedict, Charity Morgan, Eluen A Yeh, Ellen Carl, Cheryl Kennedy, Justine Reuther, Christina Brooks, Kristin Hunt, Makki Elfadil, Michelle Andrews and Robert Zivadinov

Source: BMC Neurology 2012, 12:26 doi:10.1186/1471-2377-12-26 © 2012 BioMed Central Ltd (16/05/12)

Abstract
Multiple sclerosis (MS) is a disease with multiple etiologies. The most recent theory of the vascular etiology of MS, Chronic Cerebrospinal Venous Insufficiency (CCSVI), suggests that cerebral venous obstruction could lead to cerebral venous reflux, promoting local inflammatory processes.

This review article offers strong evidence that the route of the observed narrowing of cerebral veins arises from autonomic nervous system dysfunction, particularly cardiovascular autonomic dysfunction.

The dysfunction of this system has two major effects: 1) the reduction of mean arterial blood pressure, which has the potential to reduce the cerebral perfusion pressure and the transmural pressure, and 2) the failure of cerebral autoregulation to maintain constant cerebral blood flow in the face of fluctuations in cerebral perfusion pressure. Alterations in cerebral autoregulation could in turn raise the critical closure pressure, indicated to be the cerebral perfusion pressure at which the transmural pressure will be sub-sufficient to overcome the active tension imparted by the smooth muscle layer of the vessel. These two effects of autonomic nervous system dysfunction (reduction in arterial blood pressure and alterations in cerebral autoregulation), when combined with inflammation-induced high levels of nitric oxide in the brain, will lower transmural pressure sufficiently to the point where the threshold for critical closure pressure is reached, leading to venous closure.

In addition, cerebral vessels fail to overcome the closure as a result of low central venous pressure, which is also regulated by autonomic nervous system function. Furthermore, through their neuroregulatory effects, infectious agents such as the Epstein-Barr virus and vitamin D3 are able to alter the functions of the autonomic nervous system, influencing the rate of CCSVI occurrence.

The absence of CCSVI specificity for MS, observed in recent clinical studies, may stem from a high prevalence of autonomic nervous system dysfunction in control groups which were recruited to these studies. Future studies should investigate CCSVI in relation to cardiovascular autonomic function.

Abbreviations
ANS, autonomic nervous system; BBB, blood brain barrier; BP, blood pressure; CCSVI, chronic cerebrospinal venous insufficiency; CIS, clinically isolated syndrome; CP, chronic progressive; CrCP, critical closure pressure; EBV, Epstein-Barr virus; EDSS, expanded disability status scale; HR, heart rate; IJV, internal jugular vein; MBP, myelin basic protein; PTA, percutaneous transluminal angioplasty; RR, relapsing remitting; SLE, systemic lupus erythematosus; Vit D, 1,25-dihydroxyvitamin D

Zohara Sternberg, Department of Neurology, Baird MS center, Jacobs Neurological Institute, 100 High St. Buffalo, NY 14203, USA

Full Article

Source: Autoimmunity Reviews Copyright © 2012 Published by Elsevier B.V. (08/05/12)

Occlusions in cerebrospinal veins imaged with ultrasound and magnetic resonance venography do not appear to be related to multiple sclerosis, researchers said here.

In two reports from an ongoing study at the University of Texas Health Sciences Center in Houston, a significant proportion of participants -- including MS patients and non-MS controls -- showed abnormalities consistent with chronic cerebrospinal venous insufficiency (CCSVI), but it was not more common in the MS patients relative to controls.

Andrew Barreto, MD, who reported the ultrasound findings at the American Academy of Neurology's annual meeting, acknowledged that the results contrasted markedly with those originally reported by Paolo Zamboni, MD, of the University of Ferrara in Italy.

Zamboni had sparked the flurry of interest in CCSVI with a 2009 paper claiming that every MS patient he examined with ultrasound had CCSVI, whereas it was absent in all the controls.

"We used strict ultrasound criteria definitions," Barreto said. "With these strict definitions, the results are what we found."

Specifically, what he and his colleagues found was that, of 206 patients with some form of MS, only eight met Zamboni's criteria for CCSVI, whereas these criteria were met by five of 59 patients with other neurological diseases, including stroke.

In a companion presentation on magnetic resonance venography (MRV) in a subset of these same patients, Barreto's colleague Staley Brod, MD, said that these results sometimes differed from the ultrasound findings -- but most participants still did not show evidence of CCSVI.

Of 63 individuals included in a matched case-control MRV study, only nine met criteria for CCSVI.

Of those, none had met the Zamboni ultrasound criteria for CCSVI, whereas two of the participants with normal MRV findings had CCSVI according to ultrasound.

"Neither neurosonography nor MRV support the concept of CCSVI," Brod concluded.

In the ultrasound study, the physicians who performed and evaluated the scans were blinded to participants' diagnoses, Barreto said.

About two-thirds of the MS patients had the relapsing-remitting form of the disease. Some 50 had secondary progressive MS, 15 had the primary progressive form, 12 had clinically isolated syndrome, and 3 had a progressive relapsing form.

Overall among the MS patients, the mean time since diagnosis was 10 years (SD 8) and the duration of symptoms averaged 14 years (SD 10). Mean EDSS disability score was 2.6 (SD 2.0).

The study also included 11 healthy volunteers (hospital employees), 22 patients under treatment for stroke or transient ischemic attack, and 37 with other unspecified neurological diseases. These participants were somewhat younger than the MS patients (mean 44 versus 48 years, P<0.007) and included slightly more men (36% versus 29%).

CCSVI diagnoses were made according to the criteria set by Zamboni, in which patients with two out of five abnormalities in deep cerebrospinal veins that can be visualized on ultrasound are considered to have CCSVI.

Three patients with relapsing-remitting MS, four with secondary progressive disease, and one with primary progressive disease had two of the Zamboni criteria. Another 65 of the MS patients met one of the criteria, or 32% of the total.

Nearly as many of the non-MS controls, 24%, also met one CCSVI criterion, Barreto reported.

He also presented detailed results for 10 specific measures of possible CCSVI-related abnormalities, scanned while participants were upright and again while supine.

Of the 20 comparisons between MS and non-MS participants, one showed a significant difference. That was cross-sectional area of the left internal jugular vein (mean 17 cm2 in MS patients versus 22 cm2 in controls, P=0.03).

However, Barreto cautioned that the statistics were not corrected for the large number of comparisons, such that the difference could still easily be due to chance.

More of the participants are slated to undergo MRV scans and eventually some will also have CT venography assessments, Barreto said.

Mark Freedman, MD, of the University of Ottawa in Ontario, pointed out after Barreto's presentation that serial ultrasound scans would have made the findings more reliable, as venous sonography results tend to be variable within patients.

Nevertheless, he told MedPage Today, CCSVI had already been essentially ruled out as a contributor to MS.

"There are just some people who are convinced that neurologists don't know what they're doing. The data [that CCSVI is unrelated] is pretty convincing," Freedman said.

Asked if there was a role for using a series of imaging studies -- ultrasound followed by MR and CT venography, for example, he responded, "You know the expression about a dead horse?"

The studies were supported by the National MS Society.

Barreto reported no potential conflicts of interest. Brod reported personal payments from EMD Serono, Pfizer, Bayer Healthcare, Teva Neuroscience, Questcor, Biogen Idec, and Genzyme, and research support from EMD Serono and Questcor.

Freedman reported personal payments from Bayer Healthcare, Genzyme, EMD Canada, Novartis, sanofi, and Teva, and research support from Bayer Healthcare and Genzyme.

Primary source: American Academy of Neurology
Source reference:
Barreto A, et al "A study of CCSVI with imaging-blinded assessment: neurosonography update" AAN 2012; Abstract S10.005.

Additional source: American Academy of Neurology
Source reference:
Kramer L, et al "Prospective, case-control study of CCSVI with imaging-blinded assessment: Progress report correlating magnetic resonance venography with neurosonography" AAN 2012; Abstract S10.006.

Source: MedPage Today © 2012 Everyday Health, Inc (27/04/12)

Abstract

Objective: Chronic cerebrospinal venous insufficiency (CCSVI) was hypothesized to play a causative role in multiple sclerosis (MS). The assessment of pediatric-onset MS (POMS) may provide a unique window of opportunity to study hypothesized risk factors in close temporal association with the onset of the disease.

Methods: Internal jugular veins, vertebral veins and intracranial veins were evaluated with extracranial and intracranial ultrasound in 15 POMS and 16 healthy controls. Assessor’s blinding was maintained during the study. We considered subjects positive to CCSVI when at least two criteria were fulfilled.

Results: CCSVI frequency was comparable between POMS and controls (p > 0.05). Clinical features were not significantly different between CCSVI-positive and CCSVI-negative patients.

Conclusions: Our findings add to previous data pointing against a causative role of CCSVI in MS.

MP Amato¹, V Saia², B Hakiki¹, M Giannini¹, L Pastò¹, S Zecchino², S Lori², E Portaccio¹, M Marinoni²

¹Department of Neurology, University of Florence, Florence, Italy.
²Department of Neurological Sciences, University of Florence, Florence, Italy.

Full Text

Source: Multiple Sclerosis Journal Copyright © 2012 by SAGE Publications (25/04/12)

OBJECTIVES: Recently an association has been made between Multiple Sclerosis (MS) and Chronic Cerebrospinal Venous Insufficiency (CCSVI) characterized by stenosis and reflux of the principal extracranial venous drainage including the Internal Jugular veins (IJV) and the Azygous veins (AZV). This is the first angiographic study to quantitatively analyze the impact of percutaneous balloon angioplasty (PTA) on flow dynamics across these lesions.

METHODS: 50 IJV form MS patients with CCSVI and 12 IJV from healthy volunteers underwent detailed angiographic evaluation. Technical components of all venograms were standardized. Quantitative analysis included the contrast time of flight (TOF) from the mid IJV to the superior vena cava, and the primary venous emptying time (PVET), quantified as >50% of venous emptying, from the IJV. The TOF and PVET were recorded in patients with CCSVI prior and subsequent to balloon angioplasty, as well in normal healthy subjects. All data was prospectively collected, and statistical analysis was performed using two-tailed Student’s test.

RESULTS: Of the 50 CCSVI-MS patients with IJV stenosis >70% and reflux underwent balloon angioplasty, technical success defined as <20% residual IJV stenosis was achieved in 78% (44/50). Table describes the pre- and post-angioplasty TOF and PVET in patients with CCSVI, as well as in healthy non-MS patients without any treatment. CCSVI patients were noted to have a significant improvement in both the TOF and PVET following balloon angioplasty that paralleled healthy non-MS subjects.

CONCLUSIONS: Results of this prospective pilot study suggest an association between MS and CCSVI, which results in abnormally elevated TOF and PEVT through the IJV. Furthermore, balloon angioplasty these lesions improves the hemodynamic parameters that are comparable to healthy non-MS patients.

AUTHOR DISCLOSURES: R. Darling, Nothing to disclose; P. B. Kreienberg, Nothing to disclose; M. Mehta, Nothing to disclose; K. J. Ozsvath, Nothing to disclose; J. Rey, Nothing to disclose; S. P. Roddy, Nothing to disclose; D. M. Shah, Nothing to disclose; J. B. Taggert, Nothing to disclose.

Manish Mehta, R. Clement Darling, Sean P. Roddy, Paul B. Kreienberg, John B. Taggert, Kathleen J. Ozsvath, Jorge Rey, Dhiraj M. Shah
The Institute for Vascular Health and Disease, Albany Medical College/Albany Medical Center Hospital, Albany, NY.

Source: Vascular Web Copyright © Society for Vascular Surgery® (24/04/12)

The Honourable Leona Aglukkaq, Minister of Health, today announced that a team of researchers was selected through a rigorous peer review process to undertake an interventional Phase I/II clinical trial for Chronic Cerebrospinal Venous Insufficiency (CCSVI) in persons with multiple sclerosis. This announcement was made following a call for research applications launched by the Canadian Institutes of Health Research (CIHR) in November 2011.

"Our Government is committed to advancing research in MS with the goal of improving the health of those who live with this condition," said Minister Aglukkaq. "This clinical trial should provide more insight into the safety and effectiveness of the procedure proposed by Dr. Zamboni."

The main objective of the CCSVI trial, which is to be co-funded by the MS Society of Canada, is to determine the safety of venous angioplasty and obtain better evidence on patient outcomes.

The researchers will need to receive ethics approval from relevant institutional research ethics board(s) (REB) before conducting the trial. The funds will be released and the study will begin if and when ethics approval is granted.

To protect the independence of the REBs, the names of the research team's members and institutions involved will be withheld until REB approval.

"CIHR and the MS Society will continue to collaborate with provincial and territorial partners to ensure implementation of the clinical trial if the team of researchers meets the research ethics boards criteria," said CIHR President, Dr. Alain Beaudet. "In the meantime, the CIHR Scientific Expert Working Group continues to review and analyze any new research evidence on CCSVI."

Source: CNW Canada Newswire © 2012 CNW Group Ltd (19/04/12)

Mice that have their jugular veins ligated to simulate CCSVI do not develop any brain inflammation or demyelination, suggesting yet again that ‘veinous insufficiency’ does not cause multiple sclerosis.

Researchers from Harvard Medical School in the US took 20 mice, ligated both jugular veins and observed them for six months.

Fifteen control mice were given a sham ligation procedure and another eight were induced with experimental autoimmune encephalomyelitis as negative controls.

Despite CT venography confirming the ligation produced hemodynamic changes, MRI demonstrated there were no signs of blood-brain barrier breakdown or neuroinflammation.

In addition, cytometry and histopathology showed ligation didn’t result in any increase in inflammatory cell populations or demyelination.

Moreover, no clinical signs were observed in any of the ligated mice.

Acknowledging that animal models, although good research tools, are imperfect models, the researchers concluded that CCSVI does not cause anything like MS in mice.

To overcome potential differences between mouse and human cerebral venous hemodynamics, the researchers created greater venous insufficiency in the mice than has been reported in humans.

They said the six month follow up should have been "more than sufficient" to observe disease manifestation since it represents a large part of the mice's 400 day lifespan.

Sources: PLoS One, 2012; doi:10.1371/journal.pone.0033671 & Neurology Update (28/03/12)

Eight months ago, on the advice of Canadian Institutes of Health Research (CIHR) president, Alain Beaudet, federal Health Minister Leona Aglukkaq announced funding for an early (phase 1/2) clinical study of venoplasty (the so-called “ liberation treatment ”) for chronic cerebrospinal venous insufficiency ( CCSVI).

This condition, resulting from blockages in neck or chest veins that drain blood from the brain, has been postulated by Dr. Paolo Zamboni to be an underlying cause of multiple sclerosis.

Several months prior to Ms. Aglukkaq’s announcement, Saskatchewan Premier Brad Wall, whose province has one of the world’s highest rates of MS, committed $5 million for a clinical trial of liberation therapy. However, at the time of the federal go-ahead, plans for the Saskatchewan trial remained in limbo after a proposed study was rejected by the premier’s panel of experts.

Then, in early January, with a national Canadian trial still far off, Saskatchewan moved forward, signing a $2.5 million agreement to send patients to participate in a U.S. government-approved clinical CCSVI trial headed by Dr. Gary Siskin, an interventional radiologist at the Albany Medical Center in New York.

Given the already considerable expertise of Siskin and his colleagues in safely performing venoplasties on hundreds of patients with MS, Saskatchewan’s decision appeared to be a savvy one.

Commenting on his province’s commitment, health minister Don McMorris stated, "Patients need answers as soon as possible about the efficacy of the Liberation Therapy as a treatment for MS. We owe it to them to explore every opportunity to advance MS research and find answers about this treatment. This clinical study will enable Saskatchewan patients to be involved quite quickly in a [double-blind] controlled, reputable research process."

In reply, Dr. Siskin stated, "Our research team is very excited about this partnership. We welcome the opportunity to involve Saskatchewan patients in our efforts to gather reliable data that can help determine whether [venoplasty] effectively relieves MS symptoms.”

Now, just three months after signing the agreement with Saskatchewan, Dr. Siskin’s team has reported the results of an earlier phase 2 study that suggest it does.

Here are the findings, presented by Siskin’s colleague, Dr. Ken Mandato, at this weekend’s annual meeting of the Society of Interventional Radiologists in San Francisco.

During a 4-month period, the Albany group performed venoplasties on 192 MS patients (average age 48.5 years; one-third were male and two-thirds were female). The study group included:

96 patients (50%) with relapsing remitting (RR) MS
66 (34%) with secondary progressive (SP) MS
30 (16%) with primary progressive (PP) MS.

In all, 189 patients (98.4%) underwent balloon venoplasty alone; three (1.6%) underwent venoplasty with stent placement. An average of 2.2 blocked veins were treated per procedure.

Both before and after undergoing venoplasty, all patients completed a Multiple Sclerosis Quality of Life (MSQOL-54) questionnaire that scored 14 components of physical health (PH) and mental health (MH). Pre- and post-treatment PH/MH scores were compared to determine the effect of the venoplasty treatment on the quality of life based on each patient’s subtype of MS and the number of years since diagnosis.

The result? A significant improvement in PH/MH scores was observed in approximately 75% of patients with RRMS and PPMS and in approximately 55% of patients with SPMS.

PH and MH improvement was seen in approximately 75% of patients with a diagnosis of MS made less than 10 years previously and in approximately 63% whose diagnosis was made more than 10 years previously.

On average, patients benefited for 3.5 months following venoplasty.

Commenting on his group’s findings, Dr. Mandato, stated:

“Results of the study were quite exciting and promising. We can attest to significant physical improvements…in greater than 75 percent of those with relapsing remitting and primary progressive forms of multiple sclerosis. Additionally, mental health scores improved in greater than 70 percent of individuals studied.

“[We] hope that this work will provide insights into the design of a prospective, randomized trial that is needed to rigorously evaluate the role of this treatment in MS,” he continued. "As we are still early in fully understanding the condition and its relation to treatment of CCSVI, it is our hope that future double-blinded prospective studies will be performed to further assess the durability of these results."

Happily that “future” trial is to start this month (March, 2012) and, thanks to Premier Brad Wall and his government, it will include Saskatchewan residents.

According to the government of Saskatchewan website:

“Applications are now closed for Saskatchewan multiple sclerosis (MS) patients interested in volunteering for a clinical trial in Albany, New York. The two-year, double-blind clinical trial at Albany Medical Centre will accept 86 Saskatchewan MS patients. In total, 682 people submitted applications online or by phone before the February 24 deadline.

"The high interest in this opportunity shows just how committed Saskatchewan people are to finding answers about MS and being part of a possible solution," Highways Minister Jim Reiter said on behalf of Health Minister Don McMorris. "We will be watching the research process unfold with great interest and with the hope that it will help MS patients in the future.”

According to the minister, “The first of the eligible Saskatchewan patients are expected to travel to Albany in March. Half of those participating [in the trial] will receive the Liberation Therapy procedure and half will receive a placebo procedure.”

So there we have it. Less than two years after committing to a clinical trial to test the CCSVI hypothesis, Brad Wall has kept his promise. Hooray for him.

Yet, I would be remiss if I failed to note my disappointment that, in doing so, Premier Wall has had to turn south, to Albany. Then again, what choice did he have? Over the last two years, while doctors and bureaucrats north of the border made a lot of noise (much of it “no-can-do” and anti-CCSVI), the Americans quietly got on with it, developed the necessary procedures, and generated preliminary clinical data, leaving Canadian medicine and scientific know-how far behind.

Will lessons be learned for the future? One can only hope...

Source: CTV © 2012 Bell Media (26/03/12)

Researchers who investigated the connection between chronic cerebrospinal venous insufficiency (a reported condition characterized as a blockage in the veins that drain blood from the brain and spinal cord and returns it to the heart) and multiple sclerosis indicate that a minimally invasive endovascular treatment for CCSVI, is safe and may produce "significant," short-term improvement in physical- and mental health-related quality of life in individuals with MS. These findings were presented at the Society of Interventional Radiology's 37th Annual Scientific Meeting in San Francisco, California.

An estimated 400,000 people in the United States with MS—generally thought of as an incurable, disabling neurologic disease—may find hope that symptom relief is possible. MS is typically treated with disease-modifying drugs, which modulate or suppress the immune response believed to be central in the progression of the disease.

"Traditional theories surrounding treatment for multiple sclerosis in large part focus on autoimmune causes for brain pathology and neurologic symptoms. Based on this, treatment has been predominantly medications by mouth or injection," stated Kenneth Mandato, M.D., an interventional radiologist at Albany Medical Center in Albany, N.Y. "Interventional radiologists, pioneers in the field of minimally invasive therapies, have been performing an endovascular therapy called angioplasty for years, to treat blocked or narrowed arteries and veins. We have been using angioplasty to open jugular and azygos veins in the neck and chest respectively to improve blood flow in people with MS. On follow-up, we have seen many of these individuals report significant symptom relief," he added.

Classifications within a diagnosis of MS include primary progressive, which means a gradually progressive disease without remission; relapsing remitting, which demonstrates acute attacks with intervals of slow improvements in symptoms; secondary progressive, where a disease that was once relapsing remitting is now slowly progressing. MS subtypes within the Albany study group included 96 individuals with relapsing remitting, 66 with secondary progressive and 30 with primary progressive. The study population included those who underwent angioplasty alone and three who underwent angioplasty with a stent (a tiny mesh tube used to hold the vessel open) placement.

"Results of the study were quite exciting and promising," stated Mandato. "We can attest to significant physical improvements reported in greater than 75 percent of those with relapsing remitting and primary progressive forms of multiple sclerosis. Additionally, mental health scores improved in greater than 70 percent of individuals studied. People with secondary progressive multiple sclerosis showed statistically significant improvements in both physical and mental health scores at a rate of 59 percent and 50 percent, respectively," he added.

"During a four-month period, we treated 213 individuals. 192 of these patients (72 men, 141 women; average age 49 years) responded to a standard questionnaire that evaluated key quality of life components including changes in physical abilities, health perception, energy/fatigue, sexual function, emotional well-being, cognition and pain," explained Meridith J. Englander, M.D., also an interventional radiologist at Albany Medical Center and one of the study's co-authors. "We ultimately broke this data down into physical and mental health scores for each person, and found improvement in both components of quality of life," she added. "In addition, we found a trend that patients undergoing this treatment more than 10 years after diagnosis did not respond as well as those with a more recent diagnosis."

"To address the needs and concerns of those with MS who feel they cannot wait until definitive studies are completed, many doctors are currently offering treatments with the hope of helping individuals with hard-to-manage symptoms of MS," said Mandato. "Physicians who perform these treatments hope that this work will provide insights into the design of a prospective, randomized trial that is needed to rigorously evaluate the role of this treatment in MS," he added.

"As we are still early in fully understanding the condition and its relation to treatment of CCSVI, it is our hope that future double-blinded prospective studies will be performed to further assess the durability of these results," said Mandato.

Source: Medical Xpress © Medical Xpress 2011-2012 (26/03/12)

Summary: The authors have designed a study to assess cerebral circulation times (CCTs) in patients with multiple sclerosis (MS) and control subjects by using contrast material-enhanced ultrasonography (US).

The authors have found that the longest and average CCTs were prolonged in patients with MS and that prevalence of CCSVI was higher in patients with MS than in control subjects (77% vs 28%, P < .0001) but no correlation was found between CCTs and clinical status.

The authors conclude that CCT assessment may have a role in the evaluation of cerebral blood flow in patients with MS and that a vascular impairment could be associated with MS but that further evaluation is required, and in particular to determine whether these findings are relevant to neurological outcomes.

Abstract
Purpose: To assess cerebral circulation times (CCTs) in patients with multiple sclerosis (MS) and control subjects by using contrast material-enhanced ultrasonography (US) to determine whether vascular abnormalities can be detected in this disease. Materials and

Methods: This study was approved by the local ethics committee, and informed consent was obtained from all subjects. One hundred three patients with MS and 42 control subjects underwent extracranial and transcranial venous echo-color Doppler ultrasonography (US) and contrast-enhanced US. CCT was defined as the difference in arrival time of the US contrast agent bolus between the carotid artery and the internal jugular vein. The presence of chronic cerebrospinal venous insufficiency (CCSVI) was defined according to previously reported criteria for the extracranial and transcranial US techniques. Nonparametric statistics, including the Mann-Whitney U test and the Kruskal-Wallis analysis of variance, were used to compare contrast-enhanced US parameters between groups.

Results: The longest and average CCTs were substantially prolonged in patients with MS compared with those in control subjects (median longest CCT in patients with MS, 6.47 seconds [range, 3.29-29.24 seconds]; that in control subjects, 5.54 seconds [range, 2.57-7.63 seconds]; P < .001; median average CCT in patients with MS, 5.76 seconds [range, 2.64-17.51 seconds]; that in control subjects, 5.01 seconds [range, 2.57-7.06 seconds]; P < .002). No correlation was found between CCTs and clinical parameters. The prevalence of CCSVI was higher in patients with MS than in control subjects (77% vs 28%, P < .0001). CCT was not significantly different between patients with MS who had CCSVI and patients with MS who did not (P = .182).

Conclusion: These results suggest that contrast-enhanced US with CCT assessment may have a role in the evaluation of cerebral blood flow in patients with MS and that a vascular impairment could be associated with MS. The finding of a prolonged CCT at contrast-enhanced US does not result from outflow impairment. Further studies are required to verify these observations and to clarify if CCT and CCSVI have any physiologic and clinical relevance in MS.

Mancini M, Morra VB, Di Donato O, Maglio V, Lanzillo R, Liuzzi R, Salvatore E, Brunetti A, Iaccarino V, Salvatore M.

Full Article

Source: Radiology. 2012 Mar;262(3):947-55. © RSNA, 2012 & Pubmed PMID: 22357894 (28/02/12)

Saskatchewan multiple sclerosis patients hoping to take part in a clinical trial of a controversial treatment may soon get a call from the ministry of health.

But only around 10 per cent of those who applied will actually get that call.

Deb Jordan, a ministry spokeswoman, said 670 people had signed up as of Thursday.

The deadline to apply for the two-year, double-blind trial of liberation therapy was midnight Friday.

Jordan said names will be randomly drawn starting next week to determine who will fill 86 spots in the test taking place in Albany, N.Y.

A successful candidate must be a Saskatchewan resident, under the age of 60 and not had liberation treatment.

"Once we verify that information, then the applicant will be forwarded to the folks who are involved in the clinical trial," said Jordan.

"I want to also emphasize that the fact that a patient may be drawn does not necessarily mean that they will move on to the clinical trial.

"There's the medical assessment that has to take place by the team and it is the ... clinical team that is operating the clinical trial that will ultimately make the decisions about the patients who will be participating in the trial."

Jordan said the process could take several months.

The treatment is based on a hypothesis by Italian vascular surgeon Dr. Paolo Zamboni that a condition he dubbed chronic cerebrospinal venous insufficiency, or CCSVI, may be linked to multiple sclerosis. The theory suggests that narrowed neck veins create a backup of blood that can lead to lesions in the brain and inflammation.

Liberation therapy involves opening up blocked neck veins.

The idea that the condition might be linked to the progressive neurological disease has divided the medical community.

Some patients have reported substantial improvements in their symptoms after the therapy. Other studies have raised doubts about its effectiveness and questioned the benefits when weighed against the risks of complications from the operation.

The procedure is not offered in Canada and some patients have travelled around the world to seek it out.

At least two Canadians have died after having the treatment.

With a population slightly more than one million, Saskatchewan has some of the highest rates of MS in the country. An estimated 3,500 Saskatchewan residents have the illness. Canada's rate of MS is among the highest in the world at 240 per 100,000 people. On the Prairies, the rate is 340 per 100,000 people.

Saskatchewan was the first province to pledge clinical trials when it put up $5 million and issued a call for proposals in October 2010. The goal was to proceed with clinical trials by the spring of 2011.

But last June, the government said only one proposal had been received and it didn't meet criteria set by an expert panel.

That's when the province looked to New York.

The double-blind aspect of the study means only half of the patients will actually receive the treatment. Patients and physicians who do the followup will not know who got the treatment.

Jordan said the number of applications is in an expected range. Not everyone would be interested, she said.

"People have to take the information and assess it and decide for themselves whether they want to participate in a clinical trial or not," she said.

"Very clearly, while 86 Saskatchewan patients will participate in the trial, half will receive the procedure and half will not, so how that may factor into an individual patient's decision making can only be determined by them."

Source: Global News © Shaw Media Inc 2012 (27/02/12)

Scientists from all over the world came together this week to advance knowledge and collaboration in a critical area of medicine and science – neurovascular disease. Over the past several years, a new avenue of research into the venous involvement in neurovascular conditions ranging from multiple sclerosis to Parkinson’s has grown exponentially. A phenomenon called chronic cerebrospinal venous insufficiency (CCSVI), has attracted global attention for its potential correlation with those and many other diseases.

CCSVI refers to impaired blood flow from the central nervous system to the periphery. It has been hypothesized that this narrowing of veins restricts blood flow from the brain, altering brain drainage, and may contribute to brain tissue injury that is associated with MS and other neurovascular diseases.

Yet, while CCSVI has generated intense interest among MS patients worldwide, and while independent scientific studies, point to an association with MS, work is still being done to determine conclusively that the condition is associated with these diseases, as well as to determine the best methods for diagnosis and treatment. These are among the key topics being discussed at the February Annual Meeting of the International Society for NeuroVascular Disease in Orlando, Fl.

Speakers at the press conference included: ISNVD President Robert Zivadinov, MD, PhD., professor of Neurology at the University at Buffalo; E. Mark Haacke, PhD, global researcher; Michael D. Dake, MD, Chief of Interventional Radiology at Stanford University; Paolo Zamboni, MD, Director of Vascular Diseases Center at the University of Ferrara in Italy and father of CCSVI; Marian Simka, MD, PhD, ISNVD president-elect, administrator of a vascular clinic in Pszczyna, Poland; David Hubbard, MD, Chairman of the Hubbard Foundation for fMRI research.

Some of the key topics included:
Establishing Standards for use of Different Imaging Modalities for Diagnosis of CCSVI: The standards for establishing the best methods for detecting abnormalities in the veins are still largely lacking. The ISNVD is taking a leading role to establish the value of different imaging modalities for the diagnosis of CCSVI. An emphasis is being given to reaching a consensus in non-invasive and invasive imaging of extra- and intra-cranial venous abnormalities. Among others, the following imagining modalities were discussed: ultrasound, magnetic resonance venography, catheter venography and
intraluminal ultrasound. It has been determined that the use of multi-modal imaging is the first big step toward creating a set of standards to be used for screening, as well as for pre- and post-treatment assessment of patients with CCSVI;

A New Device for Rapid Non-Invasive Assessment of Cerebral Venous Return was Presented: An ideal tool to screen for CCSVI among patients affected by neurodegenerative disorders, known as cervical plethysmography was announced. It is also useful and cheaper to monitor the result of endovascular treatment of CCSVI after the operation.

The Effect of Hemodynamics on Endothelium Adhesion and Permeability: The role of abnormal venous flow in neurodegenerative diseases and aging has been widely discussed. Novel information was presented on the effect of hemodynamics on endothelium adhesion and permeability in-vitro and in-vivo models. In particular, a group from Lousiana State Univeristy presented the first CCSVI endothelial model experiments. The role of endothelium damage in MS, Parkinson's disease, Sturge-Weber syndrome, normal pressure hydrocephalus and aging was extensively discussed;

Evaluation of Cerebrospinal Fluid Flow in Multiple Sclerosis Patients Using Phase Contrast MRI: Number of original studies were presented on this topic. It has been reported that it may be possible to be discern the cases with abnormal CSF flow and compare this to the presence of either stenoses or abnormal jugular venous flow. In addition, clinical relevance of abnormal CSF flow has been demonstrated in patients with MS;

MRI Evaluation of Venous Flow Through Internal Jugular Veins: Several studies showed that flow values in subjects affected by several neurologic diseases who present with morphological stenoses are different from those without stenoses and from healthy controls. It has been concluded that evaluation of venous flow by MRI may represent a potential biomarker for diagnosis of venous related abnormalities in neurologic diseases.

Perfusion, Hypoxia, Ischemia And Reperfusion: A number of breakthrough studies on perfusion, hypoxia, ischemia and reperfusion were presented, as well as the physiological role of the capillary bed and what can lead to its malfunction;

Assessing Abnormal Iron Content in Deep Gray Matter of Patients with MS and Other Neurologic Diseases. Increased iron content may serve as a biomarker for the progression of disease. Recent advances in measuring iron with susceptibility weighted imaging (SWI) and other relaxometry based imaging techniques have revealed that there is excessive iron deposition in basal ganglia in MS. The mechanisms leading to abnormal iron deposition were discussed, as well as the first genetic studies of various mutations of single nucleotid polymorphisms of various iron-related genes. It
has been shown that iron is already present at first clinical attack in patients with MS;

Safety and Efficacy Outcomes after Endovascular Treatment for CCSVI in Patients with MS: Careful attention was devoted to describe methodological considerations about performing clinical trials and measuring related treatment outcomes in neurological disorders, with particular emphasis on MS. One of the primary goals of the ISNVD is to encourage safe and ethical approaches in designing new clinical trials that will investigate this important part of the puzzle. It is critically important to assess the recovery of patients post angioplasty. This research addresses that issue and
speaks to the potential benefits offered by treatment of the venous problem.

About ISNVD
The International Society for NeuroVascular Disease is a non-profit professional association founded in 2010 comprised of physicians, scientists, physicists, technologists and researchers worldwide who are devoted to furthering the development of research for neurovascular related diseases - including Chronic Cerebrospinal Venous Insufficiency (CCSVI). The society will hold annual scientific meetings and sponsor educational and scientific workshops. ISNVD is dedicated to promoting communication, research, development, applications, and the availability of information on neurovascular and related neurodegenerative diseases such as multiple sclerosis internationally. CCSVI is a reported abnormality in blood drainage from the brain and spinal cord which may contribute to nervous system damage in MS. This hypothesis has been put forth by Dr. Paolo Zamboni from the University of Ferrara in Italy, an ISNVD past-President and current member, who published his initial findings in June 2009 and continues to be at the forefront of CCSVI research.

Source: ISNVD 2nd Annual Conference (23/02/12)

Reports from seven multi-disciplinary teams investigating CCSVI (chronic cerebrospinal venous insufficiency) in MS indicate that they are making good progress toward providing essential data and critical analysis as these two-year projects move toward their completion.

The 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 ongoing work by the seven teams will help inform the design of an early-phase clinical trial that is expected to launch in late spring 2012 with funding from the MS Society of Canada and the Canadian Institutes of Health Research (CIHR).

The research teams have recruited and scanned 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 to reliably validate the occurrence of CCSVI and understand its implications in the MS disease process. All of the seven teams are working under approvals 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.

Already more than 800 people have undergone scanning with various imaging technologies being used by the studies, including the Doppler ultrasound technology 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.

Representatives of each of the seven funded teams are part of the CIHR's Scientific Expert Working Group. In November 2011, the Canadian Institutes of Health Research (CIHR) announced the release of a Request for Proposals seeking grant applications from researchers to conduct an early-phase clinical trial in Canada to test the ability of a surgical procedure called balloon venoplasty to improve blood drainage in individuals with MS who have been identified as having CCSVI. The request for research proposals is a collaborative initiative between the CIHR and the MS Society of Canada. The working group will provide leadership and advice concerning the clinical trial, and will continue to monitor and analyze the data from the seven studies and other studies related to CCSVI and MS around the world.

Several teams have presented, or are planning to present, preliminary results at medical meetings. 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 1,300 people representing a spectrum of MS types, severities and durations, as well as individuals with other disease types and healthy controls.

"The research underway is significantly advancing our understanding of CCSVI and what its relationship might be to MS disease process," notes Dr. Tim Coetzee, chief research officer at the National MS Society. Dr. Karen Lee, Vice President Research at the Canada MS Society, concurs, "We are pleased that our collaborations with the National MS Society and CIHR are moving us closer to the answers that people with MS need about CCSVI and MS."

Details of Progress
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.

Dr. Brenda Banwell, The Hospital for Sick Children, Toronto, Ontario:
Dr. Banwell's team is seeking confirmation for findings that Cerebrospinal Venous Insufficiency is a cause for Multiple Sclerosis (MS). If impaired venous drainage occurs as a key part of the beginnings of the MS process, then venous abnormalities should be present even in the youngest MS patients. The team is now studying children and teenagers with MS to determine whether the venous system is abnormal in a population where the disease process is at a very early stage.

Unlike adult MS patients, children are very unlikely to have any age-related changes in blood vessels, and do not have any of the adult-onset health conditions (such as high blood pressure, heart disease, use of medications) that might complicate the ability to determine whether blood flow patterns are due to MS or other causes. Their ultrasound team has received training from Dr. Zivadinov's group in Buffalo, and has created ultrasound and brain imaging procedures suited to explore venous drainage in children. They plan to assess 30 children with MS, 30 healthy children of the same age, and 30 "graduates" (young adults who experienced the onset of MS during childhood and who received care and prior brain imaging studies at the Hospital for Sick Children).

Enrollment began in December 2010 and Dr. Banwell's team has reported that it is going well. To ensure the highest standards of scientific accuracy, they intend to analyze their findings once all 90 participants have undergone the testing; which will help to determine whether impaired venous drainage is indeed a core component of MS.

Dr. Fiona Costello, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta:
The University of Calgary team has initiated a prospective cross-sectional study to determine the association between ultrasonography (US) and magnetic resonance venography (MRV) measures of venous outflow in MS patients. This study will evaluate 120 people with MS (including 65 with relapsing-remitting MS, 20 with secondary-progressive MS, 10 with primary-progressive MS, 10 with neuromyelitis optica, and 15 with pediatric MS) and 60 age- and sex-matched healthy control subjects. To date, 98 participants have been recruited. The main outcome measure will be the proportion of cases and controls with US and MRV evidence of extracranial venous outflow obstruction. Secondary outcomes will include MRI measures of brain inflammation, Expanded Disability Status Scale (EDSS) scores, and extracranial US measures of venous wall thickening and jugular valve competence.

The team published a paper based on the cases of five people who had experienced medical complications after undergoing procedures focused on treatment of venous abnormalities: "Complications in MS Patients after CCSVI Procedures Abroad." Burton JM, Alikhani K, Goyal M, Costello F, White C, Patry D, Bell R, Hill M. (Calgary, AB) Can J Neurol Sci 2011 Sep;38(5):741-6.)

Dr. Aaron Field, University of Wisconsin School of Medicine and Public Health, Madison:
Official approval of this study protocol was issued on June 28, 2011. The team continues to actively recruit study subjects from a database of approximately 100 MS patients who had contacted them since the study was first announced, as well as from the patient population seen regularly in their MS clinic. Thus far, 17 people with MS and 12 healthy controls have undergone both MRI/MRV and ultrasound imaging. No results are yet available as the study is blinded.

Since the previous progress report, Dr. Field was awarded a $27,000 grant from his institution to further investigate the novel MRI components of this study in healthy controls, particularly with regard to reliability and reproducibility. Specifically, they investigated (1) the use of a novel method to adjust venous flow measurements for variations related to breathing and heartbeat, (2) the use of a novel MRI method for measuring the iron content in brain tissue, and (3) the use of a relatively new, FDA-approved MRI contrast agent (a drug administered intravenously to enhance the visibility of blood vessels on MRI) that can enhance the visibility of head/neck veins and enable the measurement of blood flow through brain tissue. Ten healthy subjects underwent these components of the team's CCSVI protocol twice, on separate days. Progress made in these studies includes:

The team's novel approach to measuring venous flow with MRI is able to detect clear differences in venous flow between inspiration and expiration, and demonstrates evidence of expiration-related reflux (backwards flow) in the jugular veins of healthy subjects.
The team's system of rating the degree of venous narrowing on MR images of the azygous and jugular veins yields comparable results when performed by different individuals.

Their novel MRI method for measuring iron content in brain tissue provides reproducible results that are comparable to previously described methods of iron measurement, with fewer technical pitfalls.

A single dose of a relatively new MRI contrast agent is sufficient to enhance the visibility of head/neck veins and generate reproducible maps of blood flow through the brain. (It would normally require two separate doses of a conventional contrast agent to accomplish both of these objectives.)

These investigations have yielded two abstracts presented or to be presented at national/international imaging meetings: "Comprehensive assessment of cerebral venous return with MRA: preliminary results." Wieben O, Johnson K, Schrauben E, Reeder S, Field A. 23rd annual meeting of the "MRA Club" (International Magnetic Resonance Angiography Workshop), Calgary, Alberta, Canada, September 25-28, 2011.

"The importance of the sonographer in the investigation of chronic cerebrospinal venous insufficiency." Kohn S, Kliewer K, Field AS. American Institute of Ultrasound in Medicine (AIUM) Annual Convention, Phoenix, AZ, March 29-April 1, 2012.

In addition, three abstracts have been submitted for consideration for the American Society of Neuroradiology (ASNR) 50th Annual Meeting, New York, NY, April 21-26, 2012, and two have been submitted for the International Society of Magnetic Resonance in Medicine (ISMRM) 20th Annual Meeting & Exhibition, Melbourne, Victoria, Australia, May 5-11, 2012.

Dr. Robert Fox, Cleveland Clinic Foundation, Cleveland:
Dr. Fox's team continues to use MR venography, ultrasound, MRI and clinical measures in people with MS or who are at risk for MS (CIS) and comparison groups to evaluate vein drainage. 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.

Early on they identified 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) might impact results of several of the criteria used to determine CCSVI.

The team reported at the international ECTRIMS/ACTRIMS congress in October 2011 preliminary results of ultrasound assessments. Pooling the results of the ongoing, blinded study of CCSVI in MS and non-MS controls, they reported results from the first 20 subjects, finding that 6 (30%) met criteria for CCSVI, four subjects met no criteria, and none met criteria for reverted postural control of cerebral venous outflow. Nine subjects (45%) had a flap and/or septum/abnormal valve. Identifi­cation of deep cerebral vein reflux depended upon the ultrasound technique. They noted that this finding highlights the importance of ultrasound methodology in performing and interpreting deep cerebral vein assessments. (P1104 – "Ultrasound assessment of chronic cerebrospinal venous insufficiency." R. Fox, L. Baus, C. Diaconu, A. Grattan, I. Katzan, S. Kim, M. Lu, L. Raber, A. Rae-Grant)

At the same ECTRIMS/ACTRIMS meeting, the team shared preliminary results from an ongoing study of vein structure in autopsy specimens from seven people who had MS in their lifetimes, compared to six people who did not have MS. In this unblinded study, they identified abnormalities inside the vein tubes (lumen) that drain the brain and found a variety of structural abnormalities and anatomic variations in both groups. However, they reported higher frequency of abnormalities in those who had MS (2 abnormalities in 2 out of 6 controls versus 9 abnormalities in 6 out of 7 MS patients). They noted that MR venography may be less effective than ultrasound for identifying these venous abnormalities, and that ultrasound that examines only vein wall circumference may miss some intraluminal abnormalities. (Abstract 134 – "Anatomical and histological analysis of venous structures associated with chronic cerebro-spinal venous insufficiency." C. Diaconu, S. Staugaitis, J. McBride, C. Schwanger, A. Rae-Grant, R. Fox )

Dr. Carlos Torres, The Ottawa Hospital, University of Ottawa, Ontario:
The team began phase 1 of their project which consists of imaging with MRI the veins of the head and neck of 100 people without MS. MR venography is also being performed to obtain normative data that will allow the team to better understand the normal anatomy and variants of the veins before they begin to examine the veins of the subjects and controls.

So far, they have performed this additional sequence in 85 people and expect to complete the target of 100 within the next 2 weeks. Further, they have gathered MRI studies of 30 people with a specific sequence that allows them to measure the amount of iron in the brain. The iron deposits are being quantified by an MR Physicist.

In order to perform the ultrasound studies of the veins in the head and neck the same way they were done as described by Dr. Zamboni, the team received training in Vancouver from an experienced group who received training in Italy. Two sonographers and a radiologist traveled to Vancouver and received appropriate training on the technique in mid-May.

In early September, the team reported that they successfully started phase 2 of the study recruiting subjects and controls through the Ottawa Hospital MS Research Unit. Since then, they have recruited a total of 30 people with MS (with relapsing-remitting, primary-progressive or secondary-progressive MS) and 30 controls (60 total), who have undergone both a contrast enhanced MRI and an ultrasound of the veins of the head and neck. The team is currently scanning approximately 4 people with MS and 4 controls per week. They expect to complete recruitment and begin analysis of the data by mid February 2012.

Dr. Anthony Traboulsee, UBC Hospital MS Clinic, UBC Faculty of Medicine and Dr. Katherine Knox, Saskatoon MS Clinic, University of Saskatchewan:
This team is conducting their study at two centers (UBC Hospital, Vancouver, BC and Saskatoon City Hospital, Saskatoon, Sask.) and the goal is to recruit up to 200 subjects. Imaging protocols have been both developed and tested and the group is very satisfied with the quality of their results. Their ultrasound technologists were trained by Dr. Zamboni to perform the ultrasound testing in a similar way. There is no previous standardized venography protocol for looking at neck veins.

Recruitment is now closed at the University of British Columbia site, and will be closing soon at the Saskatoon site. All investigations are expected to be completed in March 2012. The team plans to do the preliminary analysis by April 2012. Analysis will occur in stages, starting with the catheter venography and ultrasound data, then the MR venography results will be reviewed.

The team reported that the level of interest and response rate remained high throughout recruitment. The UBC site recruited 110. At the Saskatoon site, 70 subjects have been recruited and are at various stages of the protocol. All investigators remain blinded to the status of the subjects and do not have any preliminary results to report at this time.

Dr. Jerry Wolinsky, University of Texas Health Science Center at Houston:
The team reports that they have recruited about 82% of the expected study cohort. The cumulative number of volunteers recruited from study inception includes: 10 Healthy Volunteers; 34 Other Neurological Diseases; 22 Stroke/TIA; 12 CIS; 112 relapsing-remitting MS; 44 secondary-progressive MS; 1 progressive-relapsing MS; 15 primary-progressive MS. Of people with MS or CIS, 45 have undergone MR venography with advance MRI. In addition, to date 10 people with MS have consented to transluminal venography, 2 are scheduled for study and 4 have completed the procedure without complications. No therapeutic interventions are considered in these investigations.

Dr. Wolinsky and the team's MR vascular expert, Dr. Larry Kramer, are members of the MS Scientific Expert Working Group established by the Canadian Institutes of Health Research (CIHR), in collaboration with the Multiple Sclerosis (MS) Society of Canada, and additional team members have participated in the meetings and provided advice to the CIHR as requested.

A summary of the team's preliminary work was presented as a poster at the international ECTRIMS/ACTRIMS congress in October 2011. They used Doppler technology to evaluate venous drainage in a blinded fashion. They reported that of all participants, 48/162 fulfilled at least one of five criteria for anomalous venous outflow proposed by Dr. Zamboni; 10/48 fulfilled two criteria consistent with CCSVI; none fulfilled more than 2 criteria. There was no significant difference between people with MS and non-MS, or within MS subgroups. They also found no significant differences between MS and non-MS subjects for measures of cross-sectional areas of the internal jugular veins or for venous flow rates. The team concluded that thus far they find less CCSVI than previously reported by other groups. They are now focusing on whether ultrasound can be complemented or supplanted by MRV and/or transluminal venography. (P1108 -- "Prospective, case‐control study of CCSVI with imaging‐blinded assessment: progress report focused on neurosonography." Barreto AD, Brod SA, Bui T, Jamelka J, Kramer LA, Ton K, Cohen AM, Lindsey JW, Nelson F, Narayana PA, Wolinsky JS (2011). MSJ 17(S10):S511‐2.)

In addition, two abstracts have been submitted for consideration for the 64th Annual Meeting of the American Academy of Neurology to be held in late April 2012.

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 18-month milepost, the investigators are making significant progress on their overall two-year study goals. Some of the teams are presenting preliminary results at medical meetings, and all have shared technical advice so that the projects can move forward as smoothly and quickly as possible. Their results will help guide the development of an early-phase clinical trial to test whether treating vein blockages may be safe and effective in treating people with MS. The trial should launch in late spring 2012 with funding from the MS Society of Canada and the Canadian Institutes of Health Research (CIHR).

The next update on the work of the seven grantees will be reported in six months.

Source: The Business Journals © 2012 American City Business Journals, Inc. (30/01/12)

The two-year study out of Albany Medical Center in New York is about to get the go-ahead from the U.S. Food and Drug Administration. It's being called the largest trial of its kind into so-called liberation therapy — a treatment not available in Canada.

MS patients in Saskatchewan can apply to participate in the study until Feb. 24. Prospective candidates will be randomly selected from the applications and will be screened for eligibility.

"We're keeping our promise to help find answers for patients," Wall said in a statement."We owe that to the 3,500 people in Saskatchewan with MS."

The prevalence of multiple sclerosis in this country is among the highest in the world, with approximately three new cases diagnosed each day, according to the MS Society of Canada.

Source: Canoe Copyright © 2011, Canoe Inc. (13/01/12)

Materials and Methods
Two hundred subjects with MS from two sites (n = 100 each) were evaluated with magnetic resonance (MR) imaging at 3 T. Contrast-enhanced time-resolved MR angiography and time-of-flight MR venography were used to assess vascular anatomy. Two-dimensional phase-contrast MR imaging was used to quantify blood flow. The MS population was divided into two groups: those with evident internal jugular vein (IJV) stenoses (stenotic group) and those without (nonstenotic group).

Results
Of the 200 patients, 136 (68%) showed IJV structural abnormalities, including unilateral or bilateral stenoses at different levels in the neck (n = 101; 50.5%) and atresia (n = 35; 17.5%). The total IJV flow normalized to the total arterial flow of the stenotic group (56% ± 22) was significantly lower than that of the nonstenotic group (77% ± 14; P < .001). The arterial/venous flow mismatch in the stenotic group (12% ± 15) was significantly greater than that in the nonstenotic group (6% ± 12; P < .001). The ratio of subdominant venous flow rate (Fsd) to dominant venous flow rate (Fd) for the stenotic group (0.38 ± 0.27) was significantly lower than for the nonstenotic group (0.59 ± 0.23; P < .001). The majority of the stenotic group (67%) also had an Fsd of less than 3 mL/s, a Fd/Fsd ratio greater than 3:1, and/or a total IJV flow rate of less than 8 mL/s.

Conclusions
MR imaging provides a noninvasive means to separate stenotic from nonstenotic MS cases. The former group was more prevalent in the present MS population and carried significantly less flow in the IJVs than the latter.

E. Mark Haacke, PhD, Wei Feng, PhD, David Utriainen, BS, Gabriela Trifan, MD, Zhen Wu, MD, Zahid Latif, RT, Yashwanth Katkuri, MS, Joseph Hewett, MD, David Hubbard, MD

Full Article

Source: Journal ofVascular and Interventional Radiology © 2012 SIR. Published by Elsevier Inc (04/01/12)

The University at Buffalo study investigated associations between CCSVI and demographic, clinical and environmental risk factors in a large control group of volunteers who did not have known central nervous system disease.

"Our results suggest that risk factors for CCSVI in this group of volunteers are remarkably similar to those of possible or confirmed importance to MS, but we do not yet understand the whole story," says Robert Zivadinov, MD, PhD, FAAN, professor of neurology at the UB School of Medicine and Biomedical Sciences, and senior author on the study.

Published today (Nov. 30) in PLoS One, the current study of 252 volunteers "was designed to help provide scientists and the MS patient community with new information that, combined with the results of studies that are still ongoing at UB, will ultimately help explain CCSVI and its relationship to MS," according to Kresimir Dolic, a lead author on the study. Dolic, a radiologist from the Department of Radiology, University Hospital, Split, Croatia, was a visiting fellow at the Buffalo Neuroimaging Analysis Center, part of UB's Department of Neurology, where the study was conducted.

CCSVI refers to impaired blood flow from the central nervous system to the periphery. It has been hypothesized that this narrowing of veins restricts blood flow from the brain, altering brain drainage, and may contribute to brain tissue injury that is associated with MS.

Yet, while CCSVI has generated intense interest among MS patients worldwide, and while independent scientific studies, including one of the largest to date being conducted by Zivadinov and UB colleagues, have suggested an association with MS, none have found conclusively that the condition is associated with MS.

For this reason, the UB team decided that it was critical to proceed with this prospective study to determine the risk factors for CCSVI in individuals without neurological disease.

The study found that CCSVI risk factors occurred more frequently in 1) those with a history of mononucleosis, i.e. infected with Epstein-Barrvirus; 2) those with irritable bowel syndrome; 3) those who smoke or have a history of smoking.

"All three are confirmed risk factors for MS," said Bianca Weinstock-Guttman, MD, second author on the study and professor of neurology at UB. According to the results, individuals with CCSVI were 2.7 times more likely than individuals without CCSVI to have infectious mononucleosis, 3.9 times more likely to have irritable bowel syndrome and 1.98 times more likely to have a history of smoking.

"Our finding that a risk factor that is highly significant for MS - Epstein-Barr virus, indicated by a history of infectious mononucleosis - is strongly associated with CCSVI, is important," says Zivadinov.

"This is the first time a connection has been found between Epstein-Barr virus and CCSVI.

"We know that Epstein-Barr virus is associated with an increased risk for MS," he explains. "We also know that having mononucleosis when you are young increases the MS risk several-fold. So our finding that Epstein-Barr virus is also correlated with CCSVI is a novel finding that must be explored in future studies."

In addition, individuals with heart disease -- which is not a known MS risk factor -- were 2.7 times more likely to have CCSVI, and those with heart murmurs, in particular, were 4.9 times more likely to have CCSVI. Zivadinov added that the study's finding of a weak, protective effect from the use of dietary supplements was also noted and has to be further explored.

The UB team cautions that the study was preliminary and that these findings must be expanded upon and confirmed in further studies.

The volunteer subjects were all part of the prospective Combined Transcranial and Extracranial Venous Doppler Evaluation study at UB. They were either independent individuals, or spouses or relatives of MS patients. The controls were purposely selected from different sources of recruitment, Zivadinov explains.

"Spouses had no genetic similarity but may have shared environmental risk factors with MS patients, while relatives of MS patients had shared both genetic and environmental background," he says."However, no differences in risk factors or frequency of CCSVI were found according to the various sources of recruitment."

All volunteers were screened for medical histories and underwent physical exams and Doppler sonography examinations of the neck; they also responded to an extensive environmental questionnaire. Individuals were considered to have CCSVI if they had at least two positive venous hemodynamic criteria on Doppler sonography. Additional co-authors on the paper are Karen Marr, Vesela Valnarov, Ellen Carl, Jesper Hagemeier, Christina Brooks and Colleen Kilanowski all of UB's Buffalo Neuroimaging Analysis Center; Bianca Weinstock-Guttman, MD, UB professor of neurology; David Hojnacki of the Jacobs Neurological Institute of UB and Kaleida Health and Murali Ramanathan, PhD, professor of pharmaceutical science at the UB School of Pharmacy and Pharmaceutical Sciences.

The research was funded by the Buffalo Neuroimaging Analysis Center, Baird MS Center and the Jacobs Neurological Institute, all of UB, as well as the Direct MS Foundation and the Jacquemin Family Foundation. 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.

Source: Medical News Today MediLexicon International Ltd © 2004-2011 (01/12/11)