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Study finds CCSVI theory not viable (Lancet)

 
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PostPosted: Wed Oct 09, 2013 10:24 pm    Post subject: Study finds CCSVI theory not viable (Lancet) Reply with quote

From MedPage Today, October 9, 2013:

Quote:
Another Study Slams Vascular Theory of MS


By John Gever, Deputy Managing Editor, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

The embattled theory that multiple sclerosis is caused by obstructed cerebrospinal veins took another hit, as a much anticipated imaging study found no differences between patients and healthy individuals.

An assessor-blinded analysis of catheter venography images in 65 patients with MS, 46 of their siblings, and 32 unrelated healthy individuals identified just one person in each group as meeting criteria for "chronic cerebrospinal venous insufficiency" (CCSVI), according to Anthony L. Traboulsee, MD, of the University of British Columbia in Vancouver, and colleagues.

Using broader definitions of cerebrospinal venous narrowing or stenosis, most people in each group qualified, whether imaged with catheter venography or ultrasound, the researchers reported online in The Lancet.

Traboulsee and colleagues concluded that CCSVI as proposed by Paolo Zamboni, MD, of the University of Ferrara in Italy, is a "rare finding" and that venous imaging results "do not distinguish patients with multiple sclerosis from healthy controls."

The researchers added that catheter venography is "the gold standard for the assessment of venous stenosis because it details the venous anatomy with high spatial and temporal resolution."

The study had been closely watched by proponents of CCSVI, who hoped it would support the Zamboni theory. (Skeptics, on the other hand, had already considered it dead after a series of negative studies.)

Zamboni -- himself a vascular surgeon -- and colleagues set off a firestorm with a 2009 report that CCSVI, as they defined it, was present in every one of 65 MS patients examined versus none of 235 controls. In a subsequent paper, he reported that endovascular treatment (venoplasty plus stenting in some cases) dramatically relieved MS symptoms in most cases.

The CCSVI hypothesis holds that MS results from, or is exacerbated by, occlusions in the veins that drain blood from the brain. The resulting backup of blood in the brain is proposed to cause inflammation and, in turn, the destruction of nerve fibers characteristic of MS.

Vascular theories of MS have been around for decades but had faded into the background in recent years as research pointed to autoimmune processes as the cause of MS, bolstered by the success of drugs targeting immune components in delaying, if not preventing, disease progression and disability.

Although Zamboni's papers were seized upon by many in the MS community as the new way forward, his early studies were not blinded, and attempts by neurologists and radiologists to replicate them have consistently failed.

Most recently, in 2012, a group of Italian researchers reported that blinded analysis of nearly 2,000 patients and controls found CCSVI in only a tiny minority of both groups. Another study from Canada published 2 months ago came to a similar conclusion.

Some other studies yielded results more like those reported Tuesday by Traboulsee and colleagues, with cerebrospinal venous abnormalities found to be relatively common in both MS patients and in controls, with no difference in rates.

Traboulsee and colleagues performed venography and/or ultrasound imaging in a total of 177 MS patients, siblings, and controls at two Canadian centers. Venography data were available for 149 of these individuals. Data were analyzed according to Zamboni's criteria, which gave a diagnosis of CCSVI if any two of five different findings were present, or if there were areas in the internal jugular or azygous veins of more than 50% narrowing seen either on venography or in measurements of venous blood flow.

The ultrasound results were CCSVI-positive by Zamboni's criteria for 44% of the MS patients, 31% of their healthy siblings, and 45% of the unrelated controls, the researchers found.

More than 50% venous narrowing according to venography was found in 74% of MS patients, 66% of siblings, and 70% of controls. When identified by reductions in venous blood flow, narrowing was present in 51% of patients, 45% of siblings, and 54% of controls.

Ultrasound studies disclosed no abnormalities in half the MS patients as well as in half of the non-MS participants. Rates of absent valves, asynchronous valves, immobile valves, and valves that did not close fully were also nearly identical in patients versus controls.

Traboulsee and colleagues also found that ultrasound and venography findings often disagreed. Using the venography results as the standard, they calculated a sensitivity of 40.6% (95% CI 31.1%-50.8%) for ultrasound in detecting 50% venous narrowing and a specificity of 64.3% (95% CI 48.0%-78.0%).

"Our results ... challenge both the validity of ultrasound for the purpose of detecting chronic cerebrospinal venous insufficiency and its existence as a disorder," the researchers wrote -- a direct slap at Zamboni and his supporters, who have relied on ultrasound as the principal method for diagnosing CCSVI.

And, noting the high prevalence of venous narrowing in both patients and controls, they argued that their study "supports the contention that venous narrowing is a common anatomical variant."

Traboulsee is currently leading a randomized, sham-controlled study of venoplasty intended to recruit 100 MS patients. Results are expected in 2015. A similar but much smaller trial reported earlier this year failed to find any benefit for the procedure.

At the recently concluded annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis, Traboulsee's group reported that about half of individuals who had undergone endovascular treatments on their own initiative reported symptomatic improvements when interviewed shortly after the procedure.

But 6 months later, fewer than 20% indicated that their mobility, fatigue level, or general health were improved from their presurgical baseline.

___________________

The study was funded by the MS Society of Canada, Saskatoon City Hospital Foundation, the Lotte and John Hecht Memorial Foundation, Vancouver Coastal Health Foundation, and the Wolridge Foundation.

Traboulsee reported relationships with Bayer, Roche, Biogen Idec, Merck Serono, and Chugai. Other authors reported relationships with these firms and others including Angiotech, Teva, Centocor, BioMS, Daiichi Sankyo, Nuron, Genzyme-Sanofi, Schering-Plough, Nuron, Genentech, Cook, Boston Scientific, Perceptives, and Berlex.


Primary source: The Lancet

Source reference: Traboulsee A, et al "Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study" Lancet 2013.


The article can be seen here.
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PostPosted: Wed Oct 09, 2013 10:45 pm    Post subject: (ECTRIMS) BC CCSVI Registry--self-reporting Reply with quote

This study is still going on but the first two interviews have been done. The initial interview took place 15.5 months after the CCSVI procedure. The second interview was 6 months after the first.

Presented at the annual ECTRIMS conference in Copenhagen, October 2-5, 2013:

Quote:
Chronic cerebro-spinal venous insufficiency (CCVI)

Thursday, October 03, 2013, 15:45 - 17:00

British Columbia chronic cerebrospinal venous insufficiency (CCSVI) registry: early self-reported benefits are not sustained at follow-up interview

L. Kipp, I. Yee, A. D. Sadovnick, T. Greenwood, M. de Lemos, G. Keyes, L. Machan, A. Traboulsee (Vancouver, CA)

Background:

Venoplasty with or without intravascular stents (the “liberation” treatment) has been proposed as a treatment for multiple sclerosis (MS) patients with radiologic findings suggestive of chronic cerebrospinal venous insufficiency (CCSVI). The purpose of the British Columbia (BC) CCSVI Registry is to gather information on safety and efficacy from MS patients in BC, Canada who have received the “liberation” treatment abroad.

Methods:

A standardized telephone survey is used to interview volunteer MS patients up to 4 times - initial, 6-month, 12-month and 24-month follow-up.

Participants are asked to rate their general health (GH), fatigue level (FL), mobility (M), exercise level (EL) and procedure rating (PR) on a scale of 5 (1= much better, 2= somewhat better, 3= same, 4= somewhat worse and 5= much worse).

Results:

As of April 23, 2013, 76 patients completed the first 2 interviews. Patient-reported outcomes at initial interview (average 15.5 months post-treatment) and 6-month follow-up (average 21.5 months post-treatment) are:

• GH [General Health]

o initial interview - 50% “1+2”; 29% “3”; 21% “4+5”

o 6-month follow-up - 16% “1+2”; 57% “3”; 26% “4+5”

• FL [Fatigue Level]

o initial interview – 66% “1+2”; 57% “3”; 8% “4+5”

o 6-month follow-up - 16% “1+2”; 26% “3”; 26% “4+5”

• M [Mobility]

o initial interview - 40% “1+2”; 45% “3”; 16% “4+5”

o 6-month follow-up - 13% “1+2”; 53% “3”; 34% “4+5”

• EL [Exercise Level]

o initial interview - 53% “1+2”; 30% “3”; 17% “4+5”

o 6-month follow-up - 36% “1+2”; 45% “3”; 20% “4+5”

• PR [Procedure Rating]

initial interview - 50% “1+2”; 20% “3”; 30% “4+5”

o 6-month follow-up - 46% “1+2”; 18% “3”; 36% “4+5”

Conclusions:

The majority of participants’ self-reported benefits in general health, fatigue level, mobility and exercise level following CCSVI “liberation” treatment are short term and decline the longer the time period from treatment. Interestingly, while this self perception of impact of the therapy declines over time, this perception is less true when patients are asked to rate the overall procedure (PR). This may reflect psychosocial and interpersonal issues rather than be a true measure of treatment outcome.

Data collection is ongoing.
_______________________________

L. Kipp, I.M. Yee, T. Greenwood, M. deLemos, L. Machan, G. Keyes – nothing to disclose

A.D. Sadovnick - Grant support from MS Society of Canada Scientific Research Foundation, CIHR, Alzheimer Society of Canada. Travel support and honoraria from BiogenIdec, Teva Neuroscience, Merck-Serono, consultant for Novartis

A. Traboulsee- received grant funding from the MS Society of Canada, Canadian Institute for Health Research, Lotte and John Hecht Foundation, Vancouver Hospital Foundation, Bayer, Roche, Biogen. He has served on data safety monitoring board for Merck Serono and clinical trial steering committee for Roche. He received honoraria or travel grants from Biogen, Teva Canada Innovation, Roche, Merck/EMD Serono, Chugai Pharmaceuticals.
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PostPosted: Sat Oct 12, 2013 6:04 pm    Post subject: (Abst.) Extracranial venous narrowing in PwMS... Reply with quote

From The Lancet, 0ctober 11, 2013:

Quote:
Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study


Dr Anthony L Traboulsee MD a Corresponding Author, Katherine B Knox MD d, Lindsay Machan MD b, Yinshan Zhao PhD a, Irene Yee MSc c, Alexander Rauscher PhD b, Darren Klass MD b, Peter Szkup MD e, Robert Otani MD e, David Kopriva MD f, Shanti Lala MD f, Prof David K Li MD b, Prof Dessa Sadovnick PhD a c


Background

Chronic cerebrospinal venous insufficiency has been proposed as a unique combination of extracranial venous blockages and haemodynamic flow abnormalities that occurs only in patients with multiple sclerosis and not in healthy people. Initial reports indicated that all patients with multiple sclerosis had chronic cerebrospinal venous insufficiency. We aimed to establish the prevalence of venous narrowing in people with multiple sclerosis, unaffected full siblings, and unrelated healthy volunteers.

Methods

We did an assessor-blinded, case-control, multicentre study of people with multiple sclerosis, unaffected siblings, and unrelated healthy volunteers. We enrolled the study participants between January, 2011 and March, 2012, and they comprised 177 adults: 79 with multiple sclerosis, 55 siblings, and 43 unrelated controls, from three centres in Canada. We assessed narrowing of the internal jugular and azygous veins with catheter venography and ultrasound criteria for chronic cerebrospinal venous insufficiency proposed by Zamboni and colleagues.

Catheter venography data were available for 149 participants and ultrasound data for 171 participants.

Findings

Catheter venography criteria for chronic cerebrospinal venous insufficiency were positive for one of 65 (2%) people with multiple sclerosis, one of 46 (2%) siblings, and one of 32 (3%) unrelated controls (p=1·0 for all comparisons). Greater than 50% narrowing of any major vein was present in 48 of 65 (74%) people with multiple sclerosis, 31 of 47 (66%) siblings (p=0·41 for comparison with patients with multiple sclerosis), and 26 of 37 (70%) unrelated controls (p=0·82). The ultrasound criteria for chronic cerebrospinal venous insufficiency were fulfilled in 35 of 79 (44%) participants with multiple sclerosis, 17 of 54 (31%) siblings (p=0·15 for comparison with patients with multiple sclerosis) and 17 of 38 (45%) unrelated controls (p=0·98). The sensitivity of the ultrasound criteria for detection of greater than 50% narrowing on catheter venography was 0·406 (95% CI 0·311—0·508), and specificity was 0·643 (0·480—0·780).

Interpretation

This study shows that chronic cerebrospinal venous insufficiency occurs rarely in both patients with multiple sclerosis and in healthy people. Extracranial venous narrowing of greater than 50% is a frequent finding in patients with multiple sclerosis, unaffected siblings, and unrelated controls. The ultrasound criteria are neither sensitive nor specific for narrowing on catheter venography. The significance of venous narrowing to multiple sclerosis symptomatology remains unknown.

_______________
Funding

MS Society of Canada, Saskatoon City Hospital Foundation, Lotte and John Hecht Memorial Foundation, Vancouver Coastal Health Foundation, and the Wolridge Foundation.

_________________
a Department of Medicine, University of British Columbia, Vancouver, BC, Canada
b Department of Radiology, University of British Columbia, Vancouver, BC, Canada
c Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
d Department of Physical Medicine and Rehabilitation, College of Medicine, University of Saskatchewan, Saskatoon, Canada
e Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, Canada
f Department of Surgery, University of Saskatchewan, Regina, Saskatchewan, Canada

Corresponding Author Information Correspondence to: Dr Anthony L Traboulsee, University of British Columbia Hospital, University of British Columbia, 2211 Wesbrook Mall, Room s199, Vancouver, BC, V6T 2B5, Canada
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