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    You are here : Home » MS Research News » New Discoveries » Chronic Cerebrospinal Venous Insufficiency (CCSVI)

    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)

    Chronic cerebrospinal venous insufficiency is described as a chronic  problem (ongoing) where blood from the brain and spine has trouble getting back to the heart.

    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.

    Further Information

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


    MSRC Statement on CCSVI and Dr Paolo Zamboni’s work.

    "MSRC is very encouraged by the early results of Dr Paolo Zamboni’s work. There is no doubt that this area warrants a great deal more study. This could represent a completely novel approach to MS research which, if proven to be relevant, could be a “sea change” in the understanding of the mechanisms involved in the condition. There has already been a huge amount of interest about this study and MSRC will continue to report on any and all developments in this very important area. MSRC looks forward to the results of the further trials that are taking place and hopes that these studies are able to reproduce the findings of Dr Zamboni.” - Helen Yates MSRC Chief Executive

    Venous angioplasty in MS: neurological outcome at two years in a cohort of RRMS patients

    CCSVI VenogramAbstract
    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)

    Balloon angioplasty improved venous flow in MS patients

    Balloon  AngioplastyPercutaneous 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. (114/06/12)

    'No measurable change’ in MS symptoms from liberation treatment: study

    CCSVI VenogramPatients 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)

    Clinical correlates of chronic cerebrospinal venous insufficiency in multiple sclerosis

    CCSVI Venogram 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)

    Autonomic dysfunction: A unifying MS theory, linking CCSVI, vitamin D3, and Epstein-Barr virus

    MS MRIAbstract
    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)

    More negative results for vein blockage in MS

    CCSVI VenogramOcclusions 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)

    No association between chronic cerebrospinal venous insufficiency and pediatric-onset MS

    CCSVI VenogramAbstract

    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)

    The hemodynamic impact of balloon angioplasty in MS patients with CCSVI

    CCSVI Venogram 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.

    <><>< />
    Table
    MS patients with CCSVI
    Healthy Non-MS
    p-Value
    Pre-Angioplasty
    Post-Angioplasty
    No Treatment
    TOF
    PVET
    TOF
    PEVT
    TOF
    PEVT
    Mean Time (sec.)
    5.28
    12.45
    2.45
    6.44
    2.33
    6.10
    <0.001
    St. Dev.
    2.52
    10.0
    0.79
    2.05
    0.42
    0.58

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

    Canada announces successful research proposal for CCSVI and MS clinical trial

    CCSVI Venogram 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)

    Study indicates CCSVI does not cause 'MS' in mice

    MouseMice 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)

    Unblocking veins in multiple sclerosis: New U.S. study supports Zamboni’s CCSVI theory

    CCSVI VenogramEight 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)

    Interventional radiologists see 'significant' symptom relief in MS patients

    CCSVI VenogramResearchers 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)

    Multiple sclerosis: cerebral circulation time

    CCSVI VenogramSummary: 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 starts to fill trial spots for controversial MS liberation therapy

    CCSVI VenogramSaskatchewan 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)

    Newest neurovascular breakthroughs announced at ISNVD 2nd annual conference

    CCSVI VenogramScientists 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)

    Research teams report on 18 months of progress from initial studies on CCSVI and MS

    CCSVI VenogramReports 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)

    Saskatchewan sending MS patients to U.S. to test new treatment

    CCSVI VenogramSaskatchewan Premier Brad Wall announced Thursday his government will spend $2.2 million to have 86 multiple sclerosis patients from the province participate in a huge U.S. clinical trial of a controversial treatment.

    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)

    Some MS patients exhibit an abnormal flow distribution of the internal jugular veins

    CCSVI VenogramAbstract
    Purpose
    To evaluate extracranial venous structural and flow characteristics in patients with multiple sclerosis (MS).

    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)

    Risk factors for CCSVI are similar to those for developing MS

    CCSVI VenogramThe first study to investigate risk factors for the vascular condition called CCSVI (chronic cerebrospinal venous insufficiency) in volunteers without neurological disease has identified what the researchers call a remarkable similarity between this condition and possible or confirmed risk factors for multiple sclerosis (MS).

    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-Barr virus; 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)

    Canadian government requests proposals for clinical trial on CCSVI and MS

    CCSVI VenogramThe Honourable Leona Aglukkaq, Minister of Health, and Dr. Alain Beaudet, President of the Canadian Institutes of Health Research (CIHR), today announced that CIHR is ready to accept research proposals for the Phase I/II clinical trial on Chronic Cerebrospinal Venous Insufficiency (CCSVI).

    "Our Government is committed to helping Canadians with multiple sclerosis," said Minister Aglukkaq. "This next step will help identify a proposed clinical trial which can then undergo ethical review. At every step of this process, patient safety must be first and foremost."

    The request for research proposals will be available on CIHR's website on November 30, 2011. This announcement was made today at the Federal, Provincial and Territorial Health Ministers Meeting in Halifax, Nova Scotia. The request for research proposals is a collaborative initiative between the CIHR and the MS Society of Canada. CIHR will also continue to work with the provinces and territories as it moves forward with this initiative.

    "Multiple sclerosis (MS) affects thousands of Canadians and their families. It is imperative given the uncertainties related to CCSVI and its potential relationship to MS that CIHR support ethical research based on international standards of excellence to help us better understand what impact venous angioplasty procedures have on the clinical outcomes and quality of life of MS patients," said Dr. Beaudet. "The research evidence to-date is so mixed that the only way to get to the bottom of this is to conduct a well-designed clinical trial with appropriate stringent patient safety considerations factored in."

    "We are excited to collaborate with CIHR in bringing the MS community closer to definitive answers on CCSVI and MS," said Yves Savoie, President and CEO of the MS Society. "People with MS deserve clarity about the hope that CCSVI offers as a potential treatment for MS. It is only through rigorous research that we can get these answers."

    On June 29, 2011, the Government of Canada accepted the recommendation of CIHR's Scientific Expert Working Group on CCSVI and MS to undertake a small scale Phase I/II clinical trial on CCSVI.

    The main objective of the trial is to determine the safety of venous angioplasty and better evidence on patient outcomes. CIHR will announce the successful research team in March 2012. The applications received will undergo rigorous review by an international peer review committee that will be established over the coming weeks. The selected team will then need to obtain ethics approval from relevant institutional research ethics board(s) before conducting the trial.

    The Canadian Institutes of Health Research (CIHR) is the Government of Canada's health research investment agency. CIHR's mission is to create new scientific knowledge and to enable its translation into improved health, more effective health services and products, and a strengthened Canadian health care system. Composed of 13 Institutes, CIHR provides leadership and support to more than 14,100 health researchers and trainees across Canada.

    Source: Digital Journal © 1998-2011 digitaljournal.com (28/11/11)

    Safety of endovascular treatment of CCSVI: A report of 240 patients with MS

    CCSVI VenogramPurpose
    To evaluate the safety of outpatient endovascular treatment in patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI).

    Materials and Methods
    A retrospective analysis was performed to assess complications occurring within 30 days of endovascular treatment of CCSVI. The study population comprised 240 patients; 257 procedures were performed over 8 months. The indication for treatment in all patients was symptomatic MS. Of the procedures, 49.0% (126 of 257) were performed in a hospital, and 51.0% (131 of 257) were performed in the office. Primary procedures accounted for 93.0% (239 of 257) of procedures, and repeat interventions accounted for 7% (18 of 257). For patients treated primarily, 87% (208 of 239) had angioplasty, and 11% (26 of 239) had stent placement; 5 patients were not treated. Of patients with restenosis, 50% (9 of 18) had angioplasty, and 50% (9 of 18) had stent placement.

    Results
    After the procedure, all but three patients were discharged within 3 hours. Headache after the procedure was reported in 8.2% (21 of 257) of patients; headache persisted > 30 days in 1 patient. Neck pain was reported in 15.6% (40 of 257); 52.5% (21 of 40) of these patients underwent stent placement. Three patients experienced venous thrombosis requiring retreatment within 30 days. Sustained intraprocedural arrhythmias were observed in three patients, and two required hospital admission. One of these patients, who was being retreated for stent thrombosis, was hospitalized because of a stress-induced cardiomyopathy.

    Conclusions
    Endovascular treatment of CCSVI is a safe procedure; there is a 1.6% risk of major complications. Cardiac monitoring is essential to detect intraprocedural arrhythmias. Ultrasonography after the procedure is recommended to confirm venous patency and to identify patients experiencing acute venous thrombosis.

    Kenneth D. Mandato, MD, Paul F. Hegener, MD, Gary P. Siskin, MD, Ziv J Haskal, MD, Meridith J. Englander, MD, Sreenivas Garla, MD, Nancy Mitchell, NP, Laura Reutzel, NP, Christopher Doti, NP

    Full Article

    Source: JVIR © 2011 SIR. Published by Elsevier Inc. (21/11/11)

    Study concludes venous drainage not related to MS

    CCSVI VenogramNo causal relationship between obstructed blood flow caused by venous narrowing and multiple sclerosis (MS) was found in a combined MRI and ultrasound study, German researchers reported.

    Chronic cerebrospinal venous insufficiency has been proposed as the causal trigger for MS development. However, there is no gold standard for venous flow assessment, and current data are contradictory, said Florian Doepp, MD, of Charité University Medicine Berlin and colleagues in the Nov. 8 issue of Neurology.

    Doepp's group enrolled 40 patients (44 ±10 years) with MS who underwent contrast-enhanced MR venography to assess narrowing in the internal jugular vein and the azygos vein. The patients were graded into three groups based on vessel narrowing:

    Group 1: 0% to 50%
    Group 2: 51% to 80%
    Group 3: >80%
    Dynamic extracranial color-coded duplex sonography was used to analyze blood flow direction, cross-sectional area, and blood volume in both the internal jugular vein and the vertebral veins. Imaging was done with the patient in supine and upright body positions.

    One azygos vein narrowing was identified on MR venography. Analysis of the internal jugular vein yielded 12 patients in group 1 (30%), 19 patients in group 2 (48%), and nine patients in group 3 (22%). By ultrasound criteria, four patients (10%) presented with venous drainage abnormalities.

    Jugular blood flow velocity was different only between groups 1 and 3 (616 ± 133 versus 381 ± 213 mL/min, P=0.02), the researchers reported.

    No other parameters in the supine position, and none of the parameters in the upright body position were different, apart from the internal jugular vein narrowing and its decreased blood flow in groups 1 and 3 (479± 172 versus 231 ± 144 mL/min, P =0.01).

    The sonography data contradicted the postulated 100% prevalence of chronic cerebrospinal venous insufficiency criteria in MS, the researchers stated. A measurable hemodynamic effect existed only in vessel narrowing of 80% or more. MR venography seemed more sensitive in detecting internal jugular vein narrowing compared with sonography, they added.

    Study limitations were:

    MR and sonographic data were obtained on different days.

    A control group was not included, although one was not needed for comparison of the two imaging techniques.

    The sample size may have been too small to give clear evidence for some of the observed "plausible" trends.

    In comparing MRI and ultrasound, these data favoured MR venography for pinpointing narrowing as its visual field exceeds that of ultrasound, the researchers wrote.

    Furthermore, "comparison of jugular blood flow volume demonstrates that a jugular venous narrowing up to 80% does not lead to measurable venous flow alterations, seriously questioning the use of the term 'stenosis,'" the group wrote.

    The combined data argue against a causal relationship between venous narrowing and MS. These results favour rejecting the hypothesis that an obstruction in venous outflow leads to a consecutive decrease in cerebral blood flow, the group wrote, and "underline the plea to all clinicians to omit any intervention to remove 'stenoses' by dilatation or stent implantation."

    The study was funded by the German Research Foundation.

    Doepp and co-author J.T. Würfel reported no disclosures. Disclosures for some other authors included research support or honoraria from institutions including Teva Pharmaceutical Industries, Sanofi-Aventis, Novartis, Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, the German Research Foundation, and the Arthur Arnstein Foundation, Berlin.

    Primary source: Neurology
    Source reference:
    Doepp F, et al "Venous drainage in multiple sclerosis: A combined MRI and ultrasound study"Neurology 2011; 77: 1745–1751.

    Source: MedPage Today © 2011 Everyday Health, Inc. (09/11/11)

    Venous drainage in MS - a combined MRI and ultrasound study

    CCSVI VenogramABSTRACT

    Background: Chronic cerebrospinal venous insufficiency (CCSVI) was proposed as the causal trigger for developing multiple sclerosis (MS). However, current data are contradictory and a gold standard for venous flow assessment is missing.

    Objective: To compare structural magnetic resonance venography (MRV) and dynamic extracranial color-coded duplex sonography (ECCS) in a cohort of patients with MS.

    Methods: We enrolled 40 patients (44 ± 10 years). All underwent contrast-enhanced MRV for assessment of internal jugular vein (IJV) and azygos vein (AV) narrowing, graded into 3 groups: 0%–50%, 51%–80%, and >80%. ECCS analysis of blood flow direction, cross-sectional area (CSA), and blood volume flow (BVF) in both IJV and vertebral veins (VV) occurred in the supine and upright body position.

    Results: MRV identified 1 AV narrowing. IJV analysis yielded 12 patients for group 1 (30%), 19 patients for group 2 (48%), and 9 patients for group 3 (22%). By ECCS criteria, 4 patients (10%) presented with venous drainage abnormalities. Jugular BVF was different only between groups 1 and 3 (616 ± 133 vs 381 ± 213 mL/min, p = 0.02). No other parameters in supine position and none of the parameters in the upright body position, apart from the IJV-BVF decrease in groups 1 and 3 (479 ± 172 vs 231 ± 144 mL/min, p = 0.01), were different.

    Conclusions: Our ECCS data contradict the postulated 100% prevalence of CCSVI criteria in MS. MRV seems more sensitive to detect IJV narrowing compared to ECCS. A measurable hemodynamic effect only exists in vessel narrowings >80%. Our combined data argue against a causal relationship of venous narrowing and MS, favoring the rejection of the CCSVI hypothesis.

    F. Doepp, MD, J.T. Würfel, MD, C.F. Pfueller, MD, J.M. Valdueza, MD, D. Petersen, MD, F. Paul, MD and S.J. Schreiber, MD

    Source: Neurology Copyright © 2011 by AAN Enterprises, Inc. (31/10/11)

    Little support found for vascular MS theory at ECTRIMS

    CCSVI VenogramOf more than a dozen studies presented here on the chronic cerebrospinal venous insufficiency (CCSVI) theory of multiple sclerosis, most failed to find any support for it.

    One study presented at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, found that eight of 15 children with pediatric MS had venous abnormalities when examined with magnetic resonance venography.

    Another, conducted in 45 healthy controls and 133 adult MS patients, found signs of CCSVI in about half the patients -- but also in one-third of the controls.

    The other studies all either failed to find CCSVI at all in their participant groups, or it was equally distributed between patients and controls.

    The latter included one of the largest studies reported so far, with 160 MS patients and 160 healthy controls. Transcranial echo-color Doppler sonography indicated possible CCSVI in 16 patients, but venography found stenoses in only two patients.

    The authors, from the University Hospital of Padova in Italy, declared in their poster that "CCSVI is definitely not the cause of MS."

    They titled it "No Need for 'Liberation' in MS Patients," a direct slap at their countryman Paolo Zamboni, MD, of the University of Ferrara.

    Zamboni had launched the CCSVI craze in 2009 by claiming to find the condition in all the MS patients he evaluated but never in healthy controls. He advocated a venoplasty-based therapy that he dubbed the "liberation procedure."

    Yet some of the negative studies may still provide ammunition for the CCSVI theory's backers.

    What Is Normal?

    For example, a study by Robert Fox, MD, and other researchers at the Cleveland Clinic found that CCSVI-like sonography findings were exquisitely dependent on how the evaluation is carried out.

    Interim findings on 42 individuals (including unstated numbers of MS patients and controls) found that 26% had venous reflux when examined with Quality Doppler Profiles technology, but traditional transcranial Doppler scans did not show reflux.

    Also, scanning people when seated rather than lying down made a big difference in findings. The study also found that 60% of participants had some type of structural venous abnormality, such as a flap or septum.

    The same Cleveland Clinic group also has begun examining cerebrospinal veins from cadavers of MS patients and controls.

    Some results from the first 13 cadavers were presented during a platform session at ECTRIMS by Case Western University medical student Claudiu Diaconu. He confirmed that venous structures in the brain and brainstem appear to be far more complicated and variable than previously thought.

    In fact, the postmortem study revealed the presence of a novel venous valve that had not been described in anatomy textbooks.

    Perhaps the most important finding was that most of the stenoses identified in the study were not associated with vessel wall thickness or circumference.

    As a result, Diaconu said, cerebrospinal vein scans in live patients "should focus on identifying intraluminal abnormalities, not just vessel wall narrowing or thickening."

    Alexander Rae-Grant, MD, of the Cleveland Clinic, told MedPage Today that these studies demonstrated that medical science does not "know what normal is" for the cranial venous system.

    Probably the least negative study reported here came from researchers at the University of Turin, represented by Paola Cavalla, MD.

    Using transcranial echo Doppler sonography, and trained at Zamboni's Ferrara lab in his technique, Cavalla and colleagues found that 53% of their 133 MS patients met Zamboni's criteria for CCSVI, compared with 33% of the 45 controls.

    Individuals who meet any two of the following qualify for a CCSVI diagnosis under Zamboni's scheme:

    Reflux in the internal jugular or vertebral veins
    Reflux in deep cerebral veins
    Internal jugular vein stenosis seen in high-resolution B-mode sonography
    Absence of flow in internal jugular or vertebral veins on sonography
    Abnormal postural control of venous outflow
    Cavalla and colleagues found no differences between their MS patients with CCSVI versus those without -- age, gender ratio, disease duration, type of disease (relapsing-remitting versus primary or secondary progressive), level of disability, and other factors were all nearly identical.

    "Our findings are consistent with increased prevalence of CCSVI in MS," the researchers indicated in their poster, but they added that it is "quite different" from what Zamboni's initial reports suggested.

    Overwhelmingly Negative

    Other studies reported at ECTRIMS from separate groups in Israel, Hungary, Australia, Germany, and the U.S. were overwhelmingly negative.

    For example, researchers from Heinrich Heine University in Duesseldorf, Germany, evaluated one implication of the CCSVI theory -- that if cerebrospinal venous outflow is low or reversed, then pressure within those veins should be increased.

    But ophthalmodynamometry showed that intracranial venous pressure was equal in 30 MS patients and 30 controls.

    Still another poster reported on a major safety issue related to venoplasty procedures.

    Doctors at Mutua Terrassa University Hospital near Barcelona described a patient who suffered femoral venous thrombosis and pulmonary embolism three days after having a bilateral balloon angioplasty of the jugular veins in another country.

    The patient survived but suffered brain damage that "continues deteriorating," the authors indicated.

    The attacks on CCSVI also came from the podium at ECTRIMS. In separate presentations, two researchers from Germany and the U.S. blasted Zamboni's research methods and reports.

    Florian Doepp, MD, of Humboldt University in Berlin, took the first shot, outlining what he said were the methodological flaws in Zamboni's initial reports -- such as lack of evaluator blinding -- and the failure to replicate Zamboni's results in multiple independent attempts.

    "There is no evidence for CCSVI in MS [and] no evidence for venous angioplasty or stent implantation in MS," he declared.

    Social Media Fan the Flames

    Aaron Miller, MS, of Mount Sinai School of Medicine in New York City, followed Doepp to the podium and said Zamboni's initial results were too clearcut to be believable.

    He noted that Zamboni was claiming his diagnostic technique had 100% sensitivity and 100% specificity, which most people working in medicine would find "100% incredible," Miller said.

    He suggested that the subsequent failures by others to replicate the findings might have put the theory quickly to rest, but the consumer press had already given glowing coverage to Zamboni's reports and patients began demanding evaluation and then treatment.

    Miller also identified online chatrooms and blogs as keys to fueling popular support for the CCSVI theory.

    Canada became a hotbed of CCSVI fever as patients and major newspapers pressured the government to pay for the "liberation procedure."

    In August 2010, the Canadian Institute for Health Research indicated that it would not fund a trial of venoplasty in MS patients at that time, "in the absence of clear and convincing evidence for CCSVI."

    But then a meta-analysis appeared earlier this month in CMAJ, which pooled data from eight studies -- including Zamboni's -- and found that CCSVI was apparently much more common in MS patients.

    The authors noted that the findings in the individual studies "were incredibly inconsistent" and that no conclusions about a causal relationship were justified.

    Nevertheless, Miller said, the Canadian government changed course and has indicated it will now support a venoplasty trial.

    Proponents of CCSVI and therapies based on it were not much in evidence at ECTRIMS. During the question and answer session following Doepp's presentation, one audience member said it was unbalanced and had given short shrift to other studies that tended to support the CCSVI concept.

    But Miller's equally harsh assessment of Zamboni and CCSVI drew no protests, and Zamboni himself was not in attendance.

    In fact, Zamboni is a vascular surgeon, whereas ECTRIMS is run and attended mainly by neurologists, who have generally been skeptical of CCSVI. Many of the published reports on CCSVI and its associated therapies have appeared in the Journal of Endovascular Therapy and similar titles.

    None of the CCSVI-related studies had industry funding. The studies at the Cleveland Clinic were supported by the National MS Society.

    Diaconu, Cavalla, and Doepp said they had no disclosures.

    Rae-Grant reported lecture fees from Teva and Biogen Idec. Miller reported relationships with these firms and Acorda, EMD Serono, Medimmune, Nuron Biotech, Novartis, ONO, and sanofi-aventis.

    Primary source: ECTRIMS/ACTRIMS Triennial Meeting
    Source reference:
    Cavalla P, et al "CCSVI prevalence in a northern Italian population of MS patients and controls" ECTRIMS/ACTRIMS 2011; Abstract P631.

    Additional source: ECTRIMS/ACTRIMS Triennial Meeting
    Source reference:
    Diaconu C, et al "Anatomical and histological analysis of venous structures associated with chronic cerebro-spinal venous insufficiency" ECTRIMS/ACTRIMS 2011; Abstract 134.

    Additional source: ECTRIMS/ACTRIMS Triennial Meeting
    Source reference:
    Fox R, et al "Ultrasound assessment of chronic cerebrospinal venous insufficiency" ECTRIMS/ACTRIMS 2011; Abstract P1104.

    Source: MedPage Today © 2011 Everyday Health, Inc. (26/10/11)

    Decreased brain venous vasculature visibility in MS patients related to CCSVI

    CCSVI VenogramAbstract (provisional)

    Background
    The potential pathogenesis between the presence and severity of chronic cerebrospinal venous insufficiency (CCSVI) and its relation to clinical and imaging outcomes in brain parenchyma of multiple sclerosis (MS) patients has not yet been elucidated. The aim of the study was to investigate the relationship between CCSVI, and altered brain parenchyma venous vasculature visibility (VVV) on susceptibility-weighted imaging (SWI) in patients with MS and in sex- and age-matched healthy controls (HC).

    Methods
    59 MS patients, 41 relapsing-remitting and 18 secondary-progressive, and 33 HC were imaged on a 3T GE scanner using pre- and post-contrast SWI venography. The presence and severity of CCSVI was determined using extra-cranial and trans-cranial Doppler criteria. Apparent total venous volume (ATVV), venous intracranial fraction (VIF) and average distance-from-vein (DFV) were calculated for various vein mean diameter categories: <.3 mm, .3-.6 mm, .6-.9 mm and >.9 mm.

    Results
    CCSVI criteria were fulfilled in 79.7% of MS patients and 18.2% of HC (p<.0001). Patients with MS showed decreased overall ATVV, ATVV of veins with a diameter <.3mm, and increased DFV compared to HC (all p<.0001). Subjects diagnosed with CCSVI had significantly increased DFV (p<.0001), decreased overall ATVV and ATVV of veins with a diameter <.3mm (p<.003) compared to subjects without CCSVI. The severity of CCSVI was significantly related to decreased VVV in MS (p<.0001) on pre- and post-contrast SWI, but not in HC.

    Conclusions
    MS patients with higher number of venous stenoses, indicative of CCSVI severity, showed significantly decreased venous vasculature in the brain parenchyma. The pathogenesis of these findings has to be further investigated, but they suggest that reduced metabolism and morphological changes of venous vasculature may be taking place in patients with MS.

    Robert Zivadinov, Guy U Poloni, Karen Marr, Claudiu V Schirda, Christopher R Magnano, Ellen Carl, Niels Bergsland, David Hojnacki, Cheryl Kennedy, Clive B Beggs, Michael G Dwyer and Bianca Weinstock-Guttman

    Full Article.

    Source: BMC Neurology 2011, 11:128doi:10.1186/1471-2377-11-128 (20/10/11)

    Canadian study to track MS patients after vein-opening treatments abroad

    CCSVI VenogramA Canadian doctor is beginning his own before-and-after study of MS patients who are opting for the so-called liberation treatment.

    Dr. Sandy McDonald, a cardiovascular surgeon in Barrie, Ont., hopes to recruit 250 MS patients for the study, which is aimed at assessing the results of the procedure to unblock neck veins.

    The study will involve ultrasound imaging of the patient's neck veins and quality-of-life testing before and after patients undergo the procedure, which is not approved in Canada for treating multiple sclerosis.

    Thousands of Canadians have travelled to centres in the United States, Europe, India and elsewhere that provide the unproven treatment, based on a theory by Italian vascular surgeon Dr. Paolo Zamboni that MS is linked to impaired blood flow from the brain due to blocked or twisted jugular and other neck veins.

    The technique to correct the condition — which Zamboni calls chronic cerebro-spinal venous insufficiency, or CCSVI — involves unclogging the veins with balloon angioplasty, the same technique used to clear blocked coronary arteries.

    McDonald, who was trained by Zamboni in his specific ultrasound technique to detect CCSVI, provides the diagnostic testing at his clinic in Barrie.

    When MS patients seek the vein-clearing procedure at clinics outside Canada, there is little or no formal followup after they return home — so information about the condition of their neck veins, possible adverse effects and measures of whether the procedure alleviated symptoms are all lost, McDonald said.

    "And what I'm trying to do is capture some of the data so that data isn't lost."

    As part of the study, McDonald's clinic will repeat the ultrasound imaging to see if vein abnormalities have been corrected and to identify any complications, such as a blood clot that could result in a reblocking of the vein.

    "Unless you do a followup study, you don't know if a patient has that," said McDonald. "And if the patient has that, the question is: should it be treated as a standard DVT (deep vein thrombosis)? And my thought is it probably should."

    McDonald is conducting his study in association with the U.S.-based Hubbard Foundation, which has international ethics approval for such research.

    The foundation, begun by Dr. David Hubbard in San Diego, Calif., has undertaken research aimed at validating the existence of CCSVI and determining any link it may have to MS.

    "We're not going to know the answer unless we do the research," said McDonald.

    Zamboni's theory remains controversial and polarizing, with some patients and their advocates fully embracing the treatment, while others in the MS community take a wait-and-see attitude and doctors debate its scientific validity.

    Results from a number of studies have so far varied widely in their results, although a recent pooling of findings suggested there is enough of an apparent link between CCSVI prevalence and people with MS to warrant further investigation.

    "And clearly it needs to be done," said McDonald, noting that it is unclear whether CCSVI may cause MS or if the abnormal veins are a result of the progressively debilitating neurological condition.

    While his study won't resolve that issue, he said "it may say if you have CCSVI and MS, if the CCSVI is treated, then your MS symptoms may improve."

    McDonald said he is not receiving funding for his study, and patients will have to pay for their ultrasound assessment.

    Source: Winnipeg Free Press © 2011 Winnipeg Free Press. (18/10/11)

    Research into controversial MS treatment still too conflicting, study finds

    CCSVI VenogramA new study attempting to evaluate the validity of research into the prevalence of blocked veins in multiple sclerosis patients has concluded the evidence is too conflicting and inconsistent to draw any concrete conclusions.

    The study, published Monday in the Canadian Medical Association Journal, adds another layer of uncertainty to the controversy surrounding the contentious issue, which has been brewing for about two years following media reports of the possible link between blocked veins and MS.

    “I think it’s really hard to come to any conclusion, any definitive conclusion,” said Andreas Laupacis, lead author of the study and executive director of the Li Ka Shing Knowledge Institute at St. Michael’s Hospital in Toronto. “We won’t know for a few years the full story.”

    Italian doctor Paolo Zamboni popularized a theory that blocked or malformed neck veins cause or somehow contribute to MS, and that a relatively minor procedure to open them can treat symptoms.

    Clinics around the world, many of them charging high fees, began offering the procedure and patients flocked to them from countries such as Canada, which doesn’t cover the treatment due to a lack of solid evidence.

    Over the past two years, thousands of patients and advocates have used political rallies and social media campaigns to pressure governments to bring the treatment to Canada. They have had some success, with provinces such as Saskatchewan pledging last week to pay for patients to get the treatment in the U.S. and participate in a study there.

    The federal government announced earlier this year it would fund a clinical trial to investigate the vein-widening procedure, referred to by proponents of the theory as “liberation treatment.”

    But the findings of the new study indicate it’s still too early to know whether blocked veins, a condition described by Dr. Zamboni as chronic cerebrospinal venous insufficiency (CCSVI), plays a role in multiple sclerosis, according to the researchers. And even if it does, researchers have no way of knowing if blocked veins cause the disease or are a byproduct of it.

    The new study was funded by the Canadian Institutes of Health Research and was used by an expert panel earlier this year to help determine whether the federal government should pay for clinical trials investigating the safety and efficacy of the vein-widening procedure. The panel ruled there was enough evidence to warrant clinical trials, which the government has pledged to fund.

    Dr. Laupacis and his colleagues analyzed eight previously-conducted studies looking into the presence of venous abnormalities in various MS patients, their relatives and healthy controls.

    The studies were all different and some have been criticized for using flawed methods, such as failing to “blind,” meaning researchers knew which study participants had MS and which didn’t, which could lead to biased results.

    The analysis of the eight studies shows a high degree of variability with little consensus, said Anthony Traboulsee, director of the University of British Columbia Hospital MS Clinic.

    “It does not give us any new insight into the role of CCSVI in causing MS or the relationship between CCSVI and MS symptoms,” he wrote in an e-mail.

    Several new studies investigating the prevalence of venous abnormalities in MS patients and control groups are under way, including one by Dr. Traboulsee and colleagues. The publication of the results, expected in coming months, should help shed light on the issue and clarify the role blocked veins play in MS, if any.

    Until more solid, credible research emerges, questions about the future of this controversial MS theory will remain up in the air, according to an editorial published with the new CMAJ study. While the new study is a good start, wrote Robert Fox,medical director at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, “much work remains to be done before we can be certain whether [CCSVI] is a paradigm shift…or just another fad.”

    Source: The Globe and Mail © Copyright 2011 The Globe and Mail Inc. (04/10/11)

    Saskatchewan to enter partnership with U.S. on MS research

    CCSVI VenogramSaskatchewan says it will pay for some provincial patients to participate in a multiple sclerosis clinical trial of the so-called "liberation" therapy in Albany, N.Y.

    Health Minister Don McMorris said in a news release Friday that the province is finalizing a partnership with U.S researchers led by Dr. Gary Siskin, a vascular and interventional radiologist at Albany Medical Centre.

    "Patients need answers as soon as possible about the efficacy of the liberation therapy as a treatment for MS," McMorris said in a statement. "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 controlled, reputable research process."

    Saskatchewan MS patients will be advised how and when they can apply to participate after the partnership is finalized. The news release did not include an anticipated timeline.

    It is anticipated that between 80 and 90 Saskatchewan MS patients would be involved in the clinical trial. The province is setting aside approximately $2 million to cover costs and patient expenses.

    The procedure involves angioplasty to open veins in the neck to increase blood flow from the brain and spinal cord. It's based on a theory that links MS with the vein blockages, a condition referred to as chronic cerebrospinal venous insufficiency, or CCSVI.

    The Saskatchewan Party government took the unusual step last summer of announcing it would commit $5 million to fund provincial trials of the potential multiple sclerosis therapy. But that plan suffered a scientific setback in June when the Saskatchewan Health Research Foundation said the single research proposal that it received didn't meet the criteria set out by the foundation's expert panel.

    Some in the medical community have urged caution, noting more scientific research on the liberation treatment is required. But many MS patients have been urging provincial governments to move faster to offer the procedure.

    The provincial government said it still intends to support a pan-Canadian research effort into liberation therapy once that gets underway.

    Source: The Regina Leader-Post © Copyright (c) Postmedia News (27/09/11)

    Saskatchewan to detail MS trials

    CCSVI VenogramSaskatchewan's Health Minister Don McMorris says his government will announce details this week of how $5 million in provincial funding will be used to help advance clinical trials of the controversial "liberation" procedure to treat multiple sclerosis.

    The Saskatchewan Party government's initial plan to fund provincial trials of the potential treatment for the disease suffered a scientific setback in June, when the Saskatchewan Health Research Foundation said the single research proposal it received didn't meet the criteria set out by the foundation's expert panel.

    But McMorris said the government has been working ever since to determine how the funding can still be used to further clinical trials, and is close to making an announcement.

    "The point that I continue to stress is that we're still committed. The $5 million is still committed to Saskatchewan residents getting into some trials that will further the science. We're not backing away from that whatsoever," the minister said.

    The procedure involves angioplasty to open veins in the neck to increase blood flow from the brain and spinal cord. It is based on a theory that links MS with the vein blockages, a condition referred to as chronic cerebrospinal venous insufficiency, or CCSVI.

    Premier Brad Wall took the unusual step more than a year ago of announcing the province would fund clinical trials if a research proposal came forward, a decision that was at first met with skepticism from other provincial leaders. However, some premiers have since announced they are willing to fund trials.

    In June, Ottawa also reversed course and announced plans for a trial, a two-phase approach of a smaller scale than what had been proposed by Saskatchewan.

    But untold numbers of MS sufferers have rejected the prospect of waiting for the outcome of research and are seeking out the treatment at clinics in the U.S. and abroad where they can pay to get the procedure done.

    McMorris said the province has not been dissuaded by some recent scientific literature that casts doubt on whether the liberation treatment is as promising as was initially hoped. He said he regularly hears from Saskatchewan people who feel the procedure has provided some level of relief from MS symptoms, and that warrants further study of the theory.

    But the province won't be rushed into providing the procedure as an insured service, either, he said.

    "Until procedures such as this are proven in the medical community through proper research, it's tough for us to do that. But having said that, we want to move that science ahead as quickly as possible."

    Source: The Edmonton Journal © Copyright (c) The Edmonton Journal (19/09/11)

    Morphological and haemodynamic abnormalities in the jugular veins of patients with MS

    CCSVI VenogramAbstract
    OBJECTIVES:
    Multiple areas of stenosis and different levels of obstruction of internal jugular and azygous veins (a condition known as cronic cerebrospinal venous insufficiency) recently emerged as an additional theory to the well-known autoimmune concept, explaining etiology of multiple sclerosis (MS).

    The aim of our study was to evaluate internal jugular vein (IJV) morphology and haemodynamic characteristics in patients with MS and compare it with well-matched healthy individuals and to evaluate the prevalence of venous flow abnormalities in both groups.

    METHODS:
    Sixty-four patients with clinically proven MS and 37 healthy individuals were included in our study. In all patients, IJV morphology and haemodynamic characteristics were evaluated by colour Doppler sonography as well as venous flow disorder. The patients were classified into four groups according to MS clinical form presentation. The prevalence of morphological and haemodynamic abnormalities in the IJV were assessed.

    RESULTS:
    The presence of stenosing lesion, mostly intraluminal defects like abnormal IJV valves, were observed in 28 patients (43%) in the MS group, and in 17 patients (45.9%) in the control group (P = NS). By adding haemodynamic Doppler information in the IJV venous outflow was significantly different in 42% of MS patients showing flow abnormalities (27/64), as compared with 8.1% of the controls (3/37), P < 0.001.

    CONCLUSION:
    In our group of patients, patients suffering from MS had significantly more IJV morphological changes and haemodynamic abnormalities when compared with healthy individuals not suffering from MS. These findings can be well demonstrated by non-invasive and cost-effective Doppler ultrasound.

    Radak D, Kolar J, Tanaskovic S, Sagic D, Antonic Z, Mitrasinovic A, Babic S, Nenezic D, Ilijevski N.
    Source

    New research into MS gets go-ahead

    CCSVI VenogramThe go-ahead has been given for further research into a procedure which could relieve symptoms for some people who have multiple sclerosis.

    The procedure, called percutaneous venoplasty, aims to improve blood flow from the brain by using a small inflatable balloon or stent to widen narrowed veins in the neck which carry oxygen-depleted blood.

    Multiple sclerosis is the most common disabling neurological condition affecting young adults. Around 100,000 people in the UK have MS.

    The National Institute for Health and Clinical Excellence (Nice) is proposing in its draft guidance that the procedure should be used in the context of research only, so further evidence on its safety and clinical efficacy can be developed.

    It has been suggested that there could be a link between narrowed veins - called chronic cerebrospinal venous insufficiency, or CCSVI - and the progression of MS.

    Professor Bruce Campbell, chairman of the independent committee that develops Nice's interventional procedures guidance, said: "Multiple sclerosis can be a distressing and disabling condition with a lack of effective treatments.

    "This means that it is really important to find out whether percutaneous venoplasty is clinically effective and safe for use in the NHS.

    "Based on the existing evidence, we believe that clinicians should only consider offering percutaneous venoplasty as a treatment option for people with MS who fit the diagnostic criteria for CCSVI, as part of structured clinical trials.

    "In particular, we would welcome controlled research comparing percutaneous venoplasty against 'sham venoplasty', in the same way that drug treatments are compared to a placebo.

    "This is so that we can learn more about whether venoplasty works and for how long. Further research could also improve the understanding of the relationship between MS and CCSVI, as this is very unclear at present."

    Source: The Press Association © 2011 The Press Association (25/08/11)

    University of Calgary records serious health complications in MS patients

    CCSVI VenogramResearchers at the University of Calgary have documented some serious complications suffered by multiple sclerosis patients who travelled outside of Canada to undergo a controversial treatment for their disease.

    Many MS patients have travelled overseas to find clinics willing to provide chronic cerebrospinal venous insufficiency treatment, which uses balloon angioplasty to open blocked veins in the neck. Italian physician Paolo Zamboni was the first to suggest that blocked neck veins may be linked to MS and use venous angioplasty to unblock them.

    Some patients have reported that the procedure has drastically improved their symptoms, but some studies have called into question its effectiveness.

    The Calgary study followed five patients who had the so-called liberation therapy and were treated in Calgary hospitals in October and November of last year after complications from the procedure.

    The complications included clot formation within stents, stent migration, significant hemorrhage, cranial nerve damage and cerebral vein thrombosis, which is clots in the veins of the brain. Zamboni has always warned against the use of stents.

    The lead author of the paper, Dr. Jodie Burton, admits it's that it is difficult to draw conclusions since there were only five patients involved and it's not known how many Canadians have travelled to locations such as Mexico, India, the United States and Poland to have the procedure done.

    "Every pro has a con. I think the issue is informed consent so you fully understand what the risks are when you undertake something," said Burton, a clinical assistant professor in the department of clinical neurosciences.

    "It's important to make sure when we expose patients to potential risks we're aware of what those are as best we can up front and those are tempered by the potential gains."

    The information was published this week in the Canadian Journal of Neurological Sciences.

    Last month, a Calgary man revealed that his wife died after having the treatment at a California clinic.

    The federal government plans to fund a preliminary clinical trial of liberation therapy, but has warned it could be years before it would be widely available in Canada.

    Alberta is conducting its own web-based study which will consult with MS patients as a precursor to clinical trials.

    Burton said the seriousness of the complications should serve as a "cautionary tale" to anyone considering having the procedure done and for physicians who may be required to provide medical care to future patients.

    "I understand this is a group of people who have not the greatest set of options and are in desperate need. I totally understand that and I can appreciate the interest and the attention to the topic," said Burton.

    "I'm still worried. I think the issue is people are going for procedures that we know are not benign. They're not having the procedures done in this country so it's hard to know exactly what's being done."

    Source: Wiinepeg Free Press © 2011 Winnipeg Free Press (25/08/11)

    Study looks at early CCSVI 'liberation therapy' in MS patients

    CCSVI VenogramA small study of 15 patients with multiple sclerosis suggests those who get balloon angioplasty treatment earlier have fewer disease relapses, and may have decreased brain volume that could indicate a lessening of inflammation in their brains.

    The study, conducted jointly at the University of Buffalo and the University of Ferrara, was based on a sample of MS patients from Italy and the U.S.

    The results were published Friday in the European Journal of Vascular Endovascular surgery.

    Patients receiving the experimental treatment registered smaller brain volumes, which led researchers to conclude that they may have experienced less inflammation of the brain.

    All 15 patients had the relapsing-remitting form of MS, and all were found to have abnormal blood drainage from their brains -- a condition known as Chronic Cerebrospinal Venous Insufficiency (CCSVI).

    They were divided into two groups. Eight patients were given immediate balloon angioplasty to open blocked veins. Seven others did not receive the treatment for six months. All remained on their medications.

    After one year, researchers found that the patients who were treated first had fewer lapses. Two of the eight patients in the immediate-treatment group had relapses over the one-year study. In the delayed-treatment group, five of the seven patients had relapses.

    One of the researchers, Dr. Robert Zivadinov a neurologist at the University of Buffalo, told CTV News in a phone interview that "the results should be viewed with caution" because it was a small study with no placebo group.

    "While we can't recommend this type of therapy based on this small study, surely it is encouraging to look more carefully in bigger and larger studies, whether this kind of treatment can be beneficial," Zivadinov said.

    MRI scans also showed that patients had fewer brain lesions over the first six months, with a 10 per cent drop in the early treatment group compared to a 23 per cent increase in those treated later.

    The other change was a decrease in brain volume in the early treatment group, which may be due to decreased inflammation, or a normalization of blood flow in the brain, Dr. Zivadinov said.

    There were no complications from the procedure. However, researchers did find that 27 per cent of the patients saw their veins re-narrow during the one-year study.

    Source: CTV News.ca © 2011CTV Bell Media (15/08/11)

    No link between MS, narrow blood vessels: study

    CCSVI VenogramA new study provides more evidence that multiple sclerosis (MS) is not caused by a blood vessel condition, as some research has suggested.

    The new findings follow a study last month in which Dr. Ellen Marder from the Dallas Veterans Affairs Medical Center and her colleagues reviewed the current literature on the condition, called chronic cerebrospinal venous insufficiency, or CCSVI. They couldn't find any convincing data to suggest that narrowing blood vessels in CCSVI are behind MS.

    Based on those findings, Marder's group said MS patients should not undergo surgery to open up those blood vessels.

    Now they've reported on another study, in which they found that people with MS are no more likely to have signs of CCSVI on ultrasound tests than people without MS.

    The researchers say the results -- and recent reports from other investigators -- "call into question" whether CCSVI actually does play a role in causing MS, and whether there's really any point in trying to treat the blood vessel condition.

    In Archives of Neurology, they summarize the history of the suggested link between MS and CCSVI. In 2009, Italian researchers first suggested that people with MS were more likely to have narrowing of the veins that run from the brain and spine to the heart -- which could cause some blood to leak back into the brain.

    Doctors then proposed that correcting the situation through surgery might ease MS symptoms, such as movement and balance problems.

    But more recent studies haven't shown clearly whether people with MS are more likely than others to have CCSVI, or whether an invasive vessel-opening surgery could have any benefit.

    In their current study, Marder's team took ultrasound images inside and outside the brains of 18 people with MS -- all U.S. veterans -- and another 11 people of the same age and gender without MS. On those scans, they looked for the proposed signs of CCSVI, including a lack of blood flow -- or backward blood flow -- in veins in the head and neck, as well as narrowing of those veins.

    Four MS patients had one of those signs show up on their ultrasounds -- but so did four people in the comparison group.

    "We don't think (CCSVI) is the cause of multiple sclerosis," Marder recently told Reuters Health. "We would not advise our patients to be tested for this or act on any recommendations based on this sort of testing."

    Still, some researchers have continued pushing for a link between MS and CCSVI, and a few doctors have started offering procedures to MS patients to open their veins -- surgeries typically given to people at risk of heart attack that carry bleeding and infection risks.

    Timothy Coetzee, chief research officer at the National Multiple Sclerosis Society, said there are still conflicting opinions about what role CCSVI might play in the disease -- and that while this study adds evidence to that debate, it doesn't shut the door on it.

    "In my mind the jury's still somewhat out on what it means for MS," he told Reuters Health.

    His organization has handed out over $2 million to fund research on CCSVI, and Coetzee said he hopes those studies will help "draw some conclusions" on what the condition might mean for MS care. "We need to be sure that ideas are tested and validated because of the impact that has on people" with MS, he said.

    In the end, he added, what matters most is that people with MS talk with their own doctors about the best treatment for their condition.

    Abstract: Archives of Neurology, online August 8, 2011.

    Sources: YAHOO! News Copyright © 2011 Yahoo! Inc. (09/08/11)

    Endovascular therapy for chronic cerebrospinal venous insufficiency in MS

    CCSVI VenogramRecent reports have emerged suggesting that multiple sclerosis (MS) may be due to abnormal venous outflow from the central nervous system, termed chronic cerebrospinal venous insufficiency (CCSVI).

    These reports have generated strong interest and controversy over the prospect of a treatable cause of this chronic debilitating disease. This review aims to describe the proposed association between CCSVI and MS, summarize the current data, and discuss the role of endovascular therapy and the need for rigorous randomized clinical trials to evaluate this association and treatment.

    Marc A. Lazzaro1, Osama O. Zaidat1,2,3, Nils Mueller-Kronast4, Muhammad A. Taqi1 and Douglas Woo1
    1 Department of Neurology, Froedtert Hospital and Medical College of Wisconsin, Milwaukee, WI, USA
    2 Department of Neurosurgery, Froedtert Hospital and Medical College of Wisconsin, Milwaukee, WI, USA
    3 Department of Radiology, Froedtert Hospital and Medical College of Wisconsin, Milwaukee, WI, USA
    4 Department of Neurology, Delray Medical Center, Delray Beach, FL, USA

    Full Article

    Source: Frontiers IN Endovascular and Interventional Neurology © 2007 - 2011 Frontiers Media S.A. (04/08/11)

    Alberta launches web-based Multiple Sclerosis study

    MS SurveyThe Alberta government has launched an online questionnaire to study the experiences of Albertans with multiple sclerosis, especially those who have undergone controversial out-of-country Zamboni treatments.

    Health Minister Gene Zwozdesky said he’s heard of the procedure leading to adverse effects, including death.

    But he’s also listened to stories of the vein procedure — also called liberation treatment — giving people with the neurological disease less pain and a much-improved quality of life.

    “It’s compelling enough for us to do something,” the minister said at a press conference in Calgary on Wednesday.

    Wednesday’s announcement adds meat to the bones of a push outlined by Zwozdesky last December, when he said $1 million would be put toward studying the treatment. The Alberta Multiple Sclerosis Initiative (TAMSI) will gather information from MS sufferers through a series of questions posted on a secure website. The results will be used to design clinical trials, likely to proceed a year or two from now, the minister said.

    MS, a chronic disease, causes physical symptoms ranging form numbness, fatigue and pain to difficulty speaking and inability to control bodily functions.

    The treatment was developed by Italian Dr. Pablo Zamboni and involves opening blocked veins in the neck with balloon catheters similar to those used in coronary angioplasty. The treatment is not approved in Canada and hasn’t been scientifically proven.

    Dr. Luanne Metz, Calgary MS Clinic Director, said officials will ensure that only MS sufferers participate by asking each online visitor for their Alberta health care number, and matching it with medical records. This will help with the legitimacy of the study, and ensure no one person is able to fill out multiple questionnaires.

    Metz notes she wants every Albertan with MS and related conditions to participate, whether they have undergone the treatment or not. The province believes there are 11,000-13,000 MS sufferers in the province, with about 700 new cases diagnosed every year.

    Officials want to study the impact of MS in a broad sense. Metz said nobody knows for sure how many Albertans have undergone the vein treatment.

    On Wednesday, some MS sufferers in Calgary were supportive of both the government’s survey, and its cautious approach.

    “There’s so much unknown,” said Kathy Collins, 60.

    After hearing of the positive results, she’s considering undergoing the treatment. But her MS symptoms are not debilitating, and Collins said she’s going to wait for “safe, ethical studies” before making a decision about the invasive procedure.

    “It does scare me, absolutely.”

    However Calgarian Linda Zack, 58, who paid to have the treatment in Poland last year, said she will not participate in the government’s survey. She said it’s a waste of time.

    “They have blinders on. They don’t want to hear the good things,” she said.

    Zack, who says she’s suffered from MS for 35 years, said there’s no doubt the treatment works. Feeling in her lower body has returned, she said, and muscle spasms that kept her awake all night are gone.

    The Alberta government’s study can be found at http://www.tamsi.ca

    Source: The Calgary Herald © Copyright (c) The Calgary Herald (28/07/11)

    CCSVI treatment unethical, even in trials - commentary

    CCSVI VenogramInvasive treatment of CCSVI is unethical, even in clinical trials, because of “egregious” methodological problems with the single study that supports it, experts argue.

    Recent independent studies “not only cast doubt on whether CCSVI is the cause of MS, they call into question whether CCSVI exists at all”, according to a critical analysis published in the Archives of Neurology.

    The greatest problem with the results of the controversial study by Pablo Zamboni and colleagues was the apparent confounding of CCSVI treatment with the initiation of disease-modifying therapy, the authors said.

    Sixty-five patients were reported to have significantly few relapses and decreased rate of lesions on MRI following percutaneous transluminal angioplasty (PTA).

    But the critical analysis showed there was very good reason to think most of these patients (67%) began disease modifying treatment at the start of the treatment trial.

    In addition, there was no control group and therefore no blinding of the neurologists or accounting for the placebo effect
    .
    Zamboni’s earlier paper reporting that CCSVI provided negative and positive predictive values for MS of 100% had no description of how the investigators were blinded.

    It appeared that the main interpreting physician in the study was Zamboni himself, raising doubts regarding the objectivity of his interpretations.

    Three independent studies conducted through 2010 and 2011 were unable to replicate Zamboni’s prevalence findings, the results of which suggested the venous anomalies were “simply anatomical variants and not pathological”, the review authors said.

    Finally there was little reason to think CCSVI would cause MS based on the famous Bradford-Hill criteria for determining causality in biology, they said. The theory failed to satisfy the important criteria of biological plausibility, coherence (with other known data) and analogy (with other disease models).

    “Invasive research investigations into treatment of CCSVI are inappropriate until the question of whether CCSVI exists in MS is settled,” they concluded.

    Dr Bill Carroll, scientific chairman of MS Research Australia would not say whether or not he agreed with the opinion in the critical review.

    Michael Slezak

    Source: Neurology Update © Reed Business Information 2011 (26/07/11)

    Symptom improvement observed after venoplasty in MS patients

    VenoplastyPreliminary data from a series of multiple sclerosis patients who underwent percutaneous transluminal venoplasty to treat chronic cerebrospinal venous insufficiency suggest that the treatment was safe and offered significant disease-specific and quality of life improvements.

    The results of the controversial treatment on 125 patients in the series will need to be validated with future randomized, blinded, controlled trials that evaluate endovascular and surgical options, Dr. Manish Mehta said at the Vascular Annual Meeting.

    The patient series follows Dr. Paolo Zamboni’s identification in 2009 of stenoses in the internal jugular veins and azygous vein of patients with MS (J. Neurol. Neurosurg. Psychiatry 2009;80:392-9).

    "Dr. Zamboni’s theory has been that stasis of blood can cause reflux, and reflux can cause propagation and [can] break down the blood-brain barrier," Dr. Mehta said. The resulting microbleeds can allow red blood cells to escape into the brain matter, leading to hemosiderin deposits that can act as the inflammatory mediators of an autoimmune response, he said.

    Although Dr. Zamboni, a vascular surgeon and professor of surgery at the University of Ferrara (Italy), observed a strong association between chronic cerebrospinal venous insufficiency (CCSVI) and MS, it is unclear if the relationship between CCSVI and MS is causative, or if CCSVI might play a role in the etiology of the disease.

    In 2009, Dr. Zamboni also reported on a series of 65 patients who had significant improvements in functional composite scores and quality of life at 1 year (J. Vasc. Surg. 2009;50;1348-58.e1-3).

    The preliminary data that Dr. Mehta presented at the meeting came from the LIBERATION study, which is designed to assess the utility of percutaneous transluminal venoplasty for individuals with CCSVI and MS. It’s a prospective, randomized, double-blind study that is currently enrolling 600 patients.

    Because there is a learning curve involved with the assessment and technique, the researchers included a prospective longitudinal arm as part of the study. Dr. Mehta of the Albany (N.Y.) Medical College and the director of endovascular services for the Vascular Group PLLC, presented preliminary results on this group of patients.

    In the study, investigators performed venograms to identify stenoses of 50% or greater in internal jugular and azygous veins in the patients, all of whom underwent venoplasty. Neurologists and other clinicians evaluated the patients at baseline, and then at 1 month, 3 months, and every 6 months thereafter.

    The 125 patients included in the study had a mean age of 47 years, and 62% were female. Relapsing-remitting MS accounted for 54% of the patients, followed by secondary-progressive MS in 34% and primary-progressive MS in 12%.

    The patients had a total of 230 lesions altogether, 90% of which involved the internal jugular veins; the majority of these were at the origin. The remaining 10% of patients had stenoses in their azygous veins.

    The mean degree of occlusion was about 80%, with approximately 1.8 lesions per patient. Immediate success (defined as less than 20% residual stenosis) occurred in 82%. The remaining patients underwent a second venoplasty without stenting.

    In all, 79 patients were available for follow-up at a mean of 4.5 years. Restenosis of 50% occurred in eight of these patients, occlusions occurred in two patients, and one patient had new-onset atrial fibrillation.

    The investigators reassessed 48 patients with the EDSS (Extended Disability Status Scale) following initial baseline testing. From before to after the procedure, "there was a statistical improvement. Improvements occurred in each of the MS types, except in primary progressive MS," Dr. Mehta said.

    Reevaluations of 79 patients who performed a timed 25-foot walk at baseline showed a significant improvement in walking speed. In terms of MS quality of life, from before to after the procedure "there were significant improvements in physical and mental ability. There clearly seems to be a trend. In the modified fatigue impact score, there also seems to be a clear improvement," he said.

    Dr. Mehta also said that there was a trend toward improvement in balance, lower-extremity weakness, incontinence, coordination, and vertigo in more than 80% of patients.

    Dr. Mehta and his colleagues reported that they each had several significant financial relationships with device manufacturers.

    Source: Internal Medicine News Copyright © 2011 International Medical News Group, LLC (19/07/11)

    Research teams report first year’s progress in initial studies on CCSVI and MS

    CCSVI VenogramThe first-year progress reports from seven multi-disciplinary teams investigating CCSVI (chronic cerebrospinal venous insufficiency) in MS indicate that they are on track to provide essential data and critical analysis as these two-year projects move toward their completion. These studies were launched on July 1, 2010 with a more than $ 2.4 million commitment from the MS Society of Canada and the National MS Society (USA).

    The research teams have already recruited a broad spectrum of people with MS and others to build understanding of who may be affected by CCSVI. In addition they are refining CCSVI imaging methods for accuracy and consistency in order to reliably validate the occurrence of CCSVI and understand its implications in the MS disease process.

    Representatives of each of the seven funded teams are part of the Canadian Institutes of Health Research (CIHR)’s Scientific Expert Working Group. Following a meeting of the working group in June 2011, the Canadian Federal Minister of Health, the Honourable Leona Aglukkaq, announced a Phase I/II interventional clinical trial on CCSVI. The working group will provide leadership and advice in the drafting of the terms of reference for the Phase I/II clinical trials in Canada, and will continue to monitor and analyze the data from the seven studies and other studies related to CCSVI and MS around the world.

    Regarding the seven funded teams, all have received approval for their studies from the required Institutional Review Boards in the U.S. or the Research Ethics Board in Canada, a first step established by regulatory authorities to protect human subjects involved in research projects.

    Already more than 486 people have undergone scanning with various imaging technologies being used by the studies, including the Doppler ultrasound technology originally used by Dr. Paolo Zamboni and his collaborators, as well as magnetic resonance studies of the veins (MR venography), catheter venography, MRI scans of the brain, and clinical measures.

    Because the studies employ rigorous blinding and controls designed to collect objective and comprehensive data, the full results of the ongoing research will be available only after completion of the studies which will involve more than 1300 people representing a spectrum of MS types, severities and durations, as well as individuals with other disease types and healthy controls. In the meantime, several teams are planning to present preliminary results at medical meetings later this year.

    “We are pleased that this important work investigating the link between CCSVI and MS is advancing quickly,” notes Dr. Tim Coetzee, chief research officer at the National MS Society. “Results from these comprehensive studies will help inform important next steps.”

    Yves Savoie, President and chief executive officer of the MS Society of Canada concurs, “The CIHR’s Scientific Expert Working Group, who will provide leadership and advice in the drafting of the terms of reference for the Phase I/II clinical trials in Canada, will continue to monitor and analyze the data from these studies and other studies related to CCSVI and MS around the world. We are heartened to be moving closer to more definitive answers about CCSVI and MS.”

    Details: The funded investigators, who are drawn from a broad range of disciplines ranging from MS neurology, vascular surgery and interventional radiology, report progress in establishing standardized protocols, recruiting and scanning participants and in the development of plans for sharing their findings, as summarized below.

    • Dr. Brenda Banwell, The Hospital for Sick Children, Toronto, Ontario:
    To determine whether signs of impaired vein drainage might be present early in the MS disease course, Dr. Banwell’s team received approval from the Research Ethics Board and then began enrolling children and teenagers who have MS, and healthy controls of the same age. They are seeking venous abnormalities using non-invasive MRI measures of vein anatomy and novel measures of venous flow, as well as ultrasound. Unlike adults with MS, children are unlikely to have age-related changes in blood vessels, and are less likely to have adult health conditions such as high blood pressure or heart disease, which might otherwise complicate findings. The team’s ultrasound team received training in Dr. Zamboni’s original techniques from the Buffalo Neuroimaging Analysis Center, and they have created ultrasound and brain imaging procedures suited to explore venous drainage in children. Dr. Banwell’s team reports that recruitment is going well, and that they plan to analyze findings only after all 90 participants have undergoing the testing.

    • Dr. Fiona Costello, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta:
    Once her team received Research Ethics Board approval, they began recruiting a cross-section of people with MS who would be compared with those affected by other neurological diseases or healthy volunteers. They have three dedicated ultrasound technologists who have been trained to do scanning as originally done by Dr. Zamboni, and they have refined their scanning protocol. The team is planning to repeat scans on a subset of participants who had been scanned before they made method changes, which will allow them to compare the sensitivity of results pre- and post-training. Dr. Costello’s team slowed recruitment briefly to upgrade to a new 3 Tesla (3T) MRI scanner (twice as strong as standard clinical MRI), and they have expanded their MRI team to include two additional, experienced members. The 3T machine went online in March 2011 and it is now being used to perform MR venography scans to compare against the ultrasound tests.

    • Dr. Aaron Field, University of Wisconsin School of Medicine and Public Health, Madison:
    His team is now actively recruiting participants to undergo MR venography and ultrasound techniques originally used by Dr. Zamboni to investigate CCSVI in people with early and later stages of MS, controls with other conditions and healthy volunteers, now that they have received approval of the study from the Institutional Review Board. Their ultrasound expert has received training in the Zamboni techniques. The team has refined its MR venography protocol to account for variations in blood flow that occur with breathing and heartbeats. They have determined that they will use a relatively new contrast agent or dye that will permit high-quality images of the veins in the head and neck and for measuring blood flow in the brain. This will enable the entire MRI/MRV exam to be completed with one time-saving injection instead of two. They have also standardized locations along the length of veins where they take blood flow measurements because they have found large differences in both anatomy and size of head and neck veins. The team has submitted a meeting abstract reporting on their protocol development for consideration at the International Magnetic Resonance Angiography Workshop to be held September 25-28, 2011 in Calgary, Alberta, Canada.

    • Dr. Robert Fox, Cleveland Clinic Foundation, Cleveland:
    After his team received IRB approval for using MR venography, ultrasound, MRI and clinical measures in people with MS or who are at risk for MS (CIS) and comparison groups, they began recruiting and scanning participants. The ultrasound team, which underwent training in the technique originally used by Dr. Zamboni, found several aspects of the published methodology ambiguous, and they have standardized the protocol and analysis to achieve consistent results.

    They shared their solutions to these methodological challenges in a poster presented at the American Academy of Neurology’s annual meeting in April 2011 (Abstract P01.263). The poster outlined physiological and technical factors that can complicate screening for vein blockages using ultrasound, including that heartbeat irregularities, stages of breathing, head position and pressure applied by the operator could alter results; and that the state of hydration of the subject (whether they drank adequate amounts of fluids) could impact results of several of the criteria used to determine CCSVI. They concluded that these complications may help explain the mixed results reported thus far related to CCSVI and MS, and they have added to their aims a study designed to evaluate the impact of hydration on CCSVI assessments.

    Dr. Fox’s team has also gathered autopsy specimens of venous tissue from 9 MS tissue donors and 6 donors who did not have MS. The team first had to develop and standardize techniques for studying these specimens for signs of CCSVI. They are analyzing their data and have submitted abstracts reporting preliminary findings related to this pathology study and their scanning results for consideration at the international ECTRIMS (European Committee for Treatment and Research in MS) meeting in October 2011.

    • Dr. Carlos Torres, The Ottawa Hospital, University of Ottawa, Ontario:
    His team obtained Research Ethics Board approval after negotiating details over elements of the informed consent form used to explain the study’s procedures and potential outcomes to participants. The team has been conducting the first phase of scanning, using MRI and MR venography, in people without MS, which will be used to compare with various scans in people with MS. Three team members have been trained using the ultrasound techniques originally used by Dr. Zamboni, and they are on track recruiting more participants for the study. Dr. Torres expects to finalize phase 1 of the study by the end of the summer and then will move on to phase 2, which involves people with MS and other controls.

    • Dr. Anthony Traboulsee, UBC Hospital MS Clinic, UBC Faculty of Medicine and Dr. Katherine Knox, Saskatoon MS Clinic, University of Saskatchewan:
    After both sites received Research Ethics Board approval they began to recruit, they have scanned a significant number of participants, and the level of interest in the MS community remains high. Their ultrasound technologists were trained by Dr. Zamboni, and they are also using catheter venography and MR venography to investigate the prevalence of CCSVI in people with MS and controls without MS. After the radiologists at both sites met in February 2011 to ensure the consistency of their protocols, they did a second wave of recruitment and hope to finish all testing before the end of 2011.

    • Dr. Jerry Wolinsky, University of Texas Health Science Center at Houston: After receiving IRB approval, the team began recruiting participants, and their neurosonographer received intensive training for intracranial and extracranial ultrasound scanning techniques. The team has already scanned a significant number of participants, which include people with different types of MS, people with other conditions, and people with no known health problems. The team is testing whether other imaging methods can confirm the ultrasound findings, while identifying the most reliable technique to screen for CCSVI. Dr. Wolinsky’s team continues to encounter difficulty in recruiting non-MS control subjects who don’t have a personal interest in the purpose of the trial. The executive committee that oversees this study has agreed with the team’s plan to continue aggressively recruit other controls, while at the same time increasing the number of MS participants. In some cases they have also found that some participants who were contacted to go into the next phase of scanning informed the investigators that they had gotten the venoplasty procedure, which made them ineligible to continue in the study.

    Going Forward: These seven teams were chosen by an international panel of experts that included specialists drawn from all key relevant disciplines including radiology, vascular surgery and neurology. The projects were selected for having the greatest potential to quickly and comprehensively determine the significance of CCSVI in the MS disease process.

    At this one-year milepost the investigators are making significant progress on their overall two-year study goals. The teams are making plans for sharing preliminary results at upcoming medical meetings, and have demonstrated a clear willingness to share technical advice so that the projects can move forward as smoothly and quickly as possible. Their results will help guide the development of a phase I/II clinical trial recently announced by the Canadian Federal Minister of Health to test whether treating vein blockages may be safe and effective in treating people with MS.

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

    Source: National MS Society (15/07/11)

    CCSVI 'increases nine times the likelihood to develop MS'

    CCSVI VenogramCCSVI increases by nine times the likelihood of developing multiple sclerosis. "This figure is only the latest sensation emerged in the scientific debate about the relationship between CCSVI (chronic cerebrospinal venous insufficiency, venous disease discovered by Paolo Zamboni, (responsible for vascular diseases Center University of Ferrara) and MS. "

    The is in a statement Gisella Pandolfo, president of the non-profit organization CCSVI SM, adding: "the manner and timing with which it has emerged demonstrating, once again, as not all the stakeholders of this exciting discovery behave in a clear and unassailable way, this is something profoundly unjust-- in the presence of a highly debilitating disease that strikes in Italy, 60,000 people, mostly young adults. "

    The amazing thing, according to Pandolfo, is that "a result of this magnitude has remained in the shadows for many months, because the author of the study that produced it, Claudio Baracchini (Department of Neuroscience, University of Padova), not only do not find, but drew opposite conclusions, resulting in criticism from influential Dr. Robert Zivadinov (director Neuroimaging Analysis Center, BNAC, University of Buffalo). Now, another scholar, Dr. Avruscio Giampiero (responsible for Angiology at the Hospital St. Anthony of Padua) expresses the actual results are so far 'silent'. It reinforces the theory of Zamboni, that CCSVI may be one of the causes of MS. "

    The President reconstructs the last stages of the main studies on the subject. In the issue of January 2011 issue of Annals of Neurology, Baracchini has published a study on the frequency of CCSVI in a group of patients suffering from possible MS, or CIS (Possible Multiple Sclerosis, given that a high frequency of the early form evolves into full-blown multiple sclerosis) compared with a group healthy subjects. The conclusions Baracchini make tends to deny the association between early MS and CCSVI and then to deny the possibility that the CCSVI has a causal role in neurodegenerative disease. The publication had wide media coverage and is still often cited as a refutation of the theory of Zamboni.

    In the same journal published shortly after Dr. Zivadinov who, revisiting the data of Baracchini, shows a highly significant difference between the frequency of CCSVI in the group of PMS than those in healthy subjects. Zivadinov's reproach of Baracchini have somewhat overshadowed this result, central to the stated purpose of the study, and have exemplified in the title and conclusions expressed in the concepts do not correspond to the data presented (".. the results of our study contrasts the 'hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of multiple sclerosis" ) .

    Now comes another strong criticism not so much to the study of Baracchini as to its conclusions. According to Dr. Avruscio Giampiero, using data published by Baracchini an appropriate statistical test, there is a reasonable assurance that the risk of developing PMS increases by 9 times in those who have CCSVI; this, according to Dr. Giampero, can count CCSVI among the factors that contribute to the development of early forms of multiple sclerosis. And supporting the hypothesis of a role at least simultaneously, contribute to the genesis of the disease, countering instead that it might instead be a consequence of inflammation in the brain.

    "In short - concluded Gisella Pandolfo - ironically, it seems that the study of Baracchini, despite the opinions of the author, is a mine of data confirming the so-called" Big Idea "by Paolo Zamboni."

    Here is Dr. Giampiero's Letter to the Editor, published in the Annals of Neurology:

    ANNALS of Neurology - LETTER TO THE EDITOR
    Chronic Cerebrospinal Venous Insufficiency and
    Susceptibility to Multiple Sclerosis
    Avruscio Giampiero, MD

    I read carefully the article published in the January 2011 issue of Annals of Neurology by Baracchini and colleagues on the prevalence of chronic cerebrospinal venous insufficiency (CCSVI) measured with echo color Doppler sonography in patients with high suspicion of initial multiple sclerosis (MS).1 These authors give us 2 very important data that appear underestimated in their report, but are of extreme importance in the scientific debate in progress. In Table 4, they show positive CCSVI Doppler screening in 2% of controls matched for age and gender versus 16% of patients with possible MS. This means that:
    • The prevalence of CCSVI in healthy people is 2%, confirming Zamboni’s data,2 with rates far removed from the 22% recently reported by Zivadinov et al.3

    • The risk of having possible MS is dramatically increased by the presence of CCSVI by >9-fold (odds ratio, 9.3; 95% confidence interval, 1.1–78; p ¼ 0.0180). In contrast to the conclusions of the authors, careful analysis of their results indicates that CCSVI may be among the factors contributing to the development of MS symptoms at onset.

    Potential Conflicts of Interest
    Nothing to report.

    Department of Vascular Medicine, Sant’Antonio Hospital,
    Padua, Italy

    REFERENCES
    1. Baracchini C, Perini P, Calabrese M, et al. No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. Ann Neurol 2011;69:90–99.
    2. Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392–399.
    3. Zivadinov R, Marr K, Cutter G, et al. Prevalence, sensitivity and specificity of chronic cerebrospinal venous insufficiency in multiple sclerosis. Neurology (WNL.0b013e318212a901; published ahead of print April 13, 2011).
    DOI: 10.1002/ana.22451 VC 2011 American Neurological Association

    From the Italian Press---translated by google translate.

    Source: estence.com Copyright © 2011 estense.com (24/06/11)

    Vascular aspects of multiple sclerosis

    MRISummary
    Three types of vascular dysfunction have been described in multiple sclerosis (MS).

    First, findings from epidemiological studies suggest that patients with MS have a higher risk for ischaemic stroke than people who do not have MS. The underlying mechanism is unknown, but might involve endothelial dysfunction secondary to inflammatory disease activity and increased plasma homocysteine concentrations.

    Second, patients with MS have global cerebral hypoperfusion, which might predispose them to the development of ischaemic stroke. The widespread decrease in perfusion in normal-appearing white matter and grey matter in MS seems not to be secondary to axonal degeneration, but might be a result of reduced axonal activity, reduced astrocyte energy metabolism, and perhaps increased blood concentrations of endothelin-1. Data suggest that a subtype of focal MS lesions might have an ischaemic origin, and there seems to be a link between reduced white matter perfusion and cognitive dysfunction in MS.

    Third, the pathology of MS might be the consequence of a chronic state of impaired venous drainage from the CNS, for which the term chronic cerebrospinal venous insufficiency (CCSVI) has been coined.

    A number of recent vascular studies do not support the CCSVI theory, but some elements of CCSVI might be explained by slower cerebral venous blood flow secondary to the reduced cerebral perfusion in patients with MS compared with healthy individuals.

    Dr Miguel D'haeseleer MDa, , , Melissa Cambron MDa, Ludo Vanopdenbosch MDb and Prof Jacques De Keyser MDa, c

    a Department of Neurology, Universitair Ziekenhuis Brussel, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium
    b Department of Neurology, AZ Sint Jan Brugge, Bruges, Belgium
    c Department of Neurology, Universitair Medisch Centrum Groningen, Groningen, Netherlands

    Full Article

    Source: The Lancet Neurology Copyright © 2011 Elsevier B.V. (21/06/11)

    SIR foundation sets research priorities for minimally invasive treatments for MS patients

    CCSVI VenogramEvaluating patients with multiple sclerosis who have narrowed jugular and azygos veins-and the value of widening those veins with angioplasty-warrants careful, well-designed research, noted members of a Society of Interventional Radiology Foundation's Research Consensus Panel.

    And, the multidisciplinary panel indicated that while specific parameters for a large-scale, pivotal multicenter trial are not now available, that type of study is the "mandatory goal" in exploring a condition called chronic cerebrospinal venous insufficiency (or CCSVI).

    "Much work needs to be done to better define, explore and prove the concept of vein obstruction playing a role in causing multiple sclerosis," said Gary P. Siskin, M.D., FSIR, one of the 12 research consensus panel members. The concept that a blockage in the veins that drains blood from the brain and spinal cord and returns it to the heart (CCSVI) might contribute to MS and its symptoms-and that widening those veins with angioplasty to improve blood flow may help lessen the severity of MS-related symptoms-are poorly understood, said Siskin, an interventional radiologist and chair of the radiology department at Albany Medical Center and the co-chair of the SIRF panel. "This is an entirely new approach to the treatment of patients with neurologic conditions, such as MS, and could be transformative for patients," noted Siskin. "Continued investigation is needed in this area. Researchers are clearly very early in their understanding of both the condition and the treatment," he added.

    About 500,000 people in the United States have MS, generally thought of as an incurable, disabling neurologic disease in which a person's body attacks its own cells. Currently, MS is treated with disease-modifying drugs, which modulate or suppress the immune response believed to be central in the progression of the disease, and these drugs carry significant risk. "The idea that there may be a venous component that causes some symptoms in patients with MS is a radical departure from current medical thinking. There is a healthy level of skepticism in both the neurology and interventional radiology communities about the condition, the treatment and the outcomes," said Gordon McLennan, M.D., FSIR, an interventional radiologist with the Cleveland Clinic in Cleveland, Ohio, and chair of the SIR Foundation, which supported the project.

    The special communication in the Journal of Vascular and Interventional Radiology noted that individuals with MS are seeking treatment for CCSVI "despite the still-limited available scientific evidence." Siskin explained that patients are learning about this therapy and the role of interventional radiology in venous angioplasty through the Internet. "Individuals are discussing it among themselves-through blogs and social networking sites-and then turning to interventional radiologists for this minimally invasive treatment," said Siskin.

    To address the needs and concerns of MS patients who feel they cannot wait until definitive studies are completed, many doctors are currently offering endovascular therapy (or angioplasty, the nonsurgical procedure of threading a thin tube into a vein or artery to open blocked or narrowed blood vessels) to patients with MS. These treatments are provided with the hope of helping MS patients who suffer from intractable symptoms, but it is hoped that this work will also provide insights that improve the design of peer-reviewed studies that clarify the role in MS of treating venous disease with angioplasty (and possible stent placement), noted "Development of a Research Agenda for Evaluation of Interventional Therapies for Chronic Cerebrospinal Venous Insufficiency: Proceedings From a Multidisciplinary Research Consensus Panel."

    The panel recommended that safety and efficacy trials should be conducted in well-defined and potentially smaller controlled populations under institutional review board approval and supported continued basic science studies to better understand the relationship between closed veins and the subsequent contribution of CCSVI to patients with MS. Siskin himself released details of a study in March that found that angioplasty is safe and hoped that those results would encourage additional studies for its use as a treatment option for individuals with MS. The SIRF report concluded that if such additional studies confirm initial reports in favor of CCSVI diagnosis and treatment, then large-scale, pivotal multicenter trials must be developed.

    Research consensus panelists represented the fields of interventional radiology, imaging physics, surgery and neurology. Authors of "Development of a Research Agenda for Evaluation of Interventional Therapies for Chronic Cerebrospinal Venous Insufficiency" include Siskin, panel co-chair Ziv J Haskal, M.D., FSIR, and Walter Royal III, M.D., both University of Maryland, Baltimore; McLennan, Michael D. Dake, M.D., Stanford University, Stanford, Calif.; E. Mark Haacke, Ph.D., Wayne State University, Detroit, Mich.; Sandy McDonald, M.D., Barrie Vascular Imaging, Barrie, Ontario, Canada; Suresh Vedantham, M.D., FSIR, Washington University School of Medicine, St. Louis, Mo.; David Hubbard, M.D., and Heidi Sauder, Ph.D., both Applied fMRI Institute, San Diego, Calif.; Salvatore J.A. Sclafani, M.D., FSIR, Kings County Hospital Center, Brooklyn, N.Y.; and R. Torrance Andrews, M.D., FSIR, Swedish Medical Center, Seattle, Wash.

    Source: Medical News Today © MediLexicon International Ltd 2004-2011 (17/06/11)

    SIR panel sets CCSVI research agenda

    CCSVI VenogramA multidisciplinary panel has published its discussions of research priorities evaluating chronic cerebrospinal venous insufficiency (CCSVI) interventions and says “not yet” to a large-scale multicentre trial. At the SIR meeting in Chicago, USA, several key questions surrounding the unproven syndrome of CCSVI were also highlighted

    The panel has agreed that there is currently not enough information on the specific parameters required to run a large-scale, pivotal multicentre trial. However, these types of trials are the “mandatory goal” for the study of CCSVI, it states.

    JVIR has recently published the proceedings as a special communication titled “The Development of a Research Agenda for Evaluation of Interventional Therapies for Chronic Cerebrospinal Venous Insufficiency: Proceedings from a Multidisciplinary Research Consensus Panel." The panel comprises Gary P Siskin (New York, USA), Ziv Haskal and Walter Royal III (both from Baltimore, USA), Gordon McLennan (Cleveland, USA), Michael Dake (Palo Alto, USA), Mark Haacke (Detroit, USA), Sandy McDonald (Barrie, Canada) Suresh Vedantham (St Louis, USA), Salvatore Sclafani (Brooklyn, USA), R Torrance Andrews (Seattle, USA), David Hubbard and Heidi Sauder (San Diego, USA).

    The panel further recommends that prospective safety and efficacy trials should be conducted in well-defined and potentially smaller controlled populations under institutional review board approval. It advocates that it is critical to support and continue the basic science work which seeks to clarify the relationship between venous stenoses and hypertension and the subsequent contribution of CCSVI to patients with multiple sclerosis.

    Treatment for the unproven syndrome of CCSVI is controversial, with some interventional radiologists believing that this could be a new and rewarding area to contribute their services in. Others feel strongly that while rigorous scientific data are lacking, any treatment for this putative theory must be limited to the setting of a randomised trial.

    The JVIR special communiqué also states that “there was near-universal agreement that randomised trials would be required to confirm the role of venous interventions in multiple sclerosis.” However, the proceedings say “It was equally clear from the discussion that several factors could be better understood before large-scale randomised trials are initiated. Among these are […] confirmatory prevalence and diagnosis data, but also the need to define the appropriate study population, the need to optimise the interventional techniques for diagnosis and treatment, and to agree on appropriate endpoints for primary and secondary endpoint analysis.” The panel has encouraged the performance of investigator-initiated single-centre and multicentre studies so that safety and outcome data can be reported. They write that “a foundation of knowledge in these areas can be gathered. This knowledge will help provide the information necessary to appropriately power a prospective randomised trial.”

    There are also interventionalists who are already calling for randomised controlled trials. Lindsay Machan, Vancouver, Canada, told delegates at the Charing Cross Symposium in London in April,“To answer the question if the CCSVI syndrome is real, I still have absolutely no idea, but what I do know is that a sham controlled trial is urgently needed.” He also said, “There is no consensus on the criteria for diagnosis of venous stenosis in the upper body, we do not know what we are treating and we do not have a documented durable method to treat jugular venous stenosis.”

    The JVIR communication also notes that there are likely to be practitioners who will offer endovascular therapy to patients with multiple sclerosis before definitive peer-reviewed data backing this practice is available. The panellists write: “It was the general hope of the committee that this work would lead to additional peer-reviewed studies generating data that clarify the role in multiple sclerosis of treating venous disease with angioplasty and possibly stent placement and the potential adverse events associated with these interventions.”

    Some interventionalists might question the panel’s recommendation by asking whether further non-randomised studies would really satisfy the conditions set, and how treating more patients would facilitate issues such as agreeing on primary and secondary endpoints. The explanations of the panel could also be viewed as procrastination.

    A CIRSE commentary published on 7 December 2010 in CVIR, by authors Jim A Reekers (Amsterdam, The Netherlands), Michael J Lee (Dublin, Ireland), Anna Maria Belli (London, UK), and Frederik Barkhof, (The Netherlands) takes the view that while there has been widespread promotion of balloon dilatation to treat CCSVI, and alleviate multiple sclerosis symptoms, “This theory does not fit into the existing bulk of scientific data concerning the pathophysiology of multiple sclerosis.”

    Reekers et al question whether the anecdotes of successful outcomes which are widely being disseminated on the Internet could be the result of a placebo effect. They write: “In itself, there is nothing with the placebo effect as long as we recognise that this is at play. […] Furthermore, multiple sclerosis can affect emotional and labile responses and is characterised by spontaneous relapses and remissions. This makes the gathering of scientific evidence to support CCSVI theory difficult in anything other than a randomised controlled trial.”

    At the Society of Interventional Radiology’s meeting Dake said, “Personally, I want to know if a patient with multiple sclerosis has CCSVI, and if the narrowing is successfully treated, is it possible to objectively demonstrate physiological improvement in relevant parameters and an associated relief of symptoms.”

    Dake set out some of the unknowns and uncertainty surrounding CCSVI diagnosis. He asked: Is CCSVI something we are born with, develop, or both? What percentage of multiple sclerosis patients and healthy controls has CCSVI? Is CCSVI a consequence of multiple sclerosis or part of the disease pathogenesis? How do we reliably diagnose CCSVI and know if it is physiologically relevant? How does CCSVI fit into the current immune concept of multiple sclerosis pathogenesis or does it not? How can we engage neurologists in meaningful collaboration to study a concept they truly regard as total lunacy?

    With regard to the treatment and endpoint assessment, Dake outlined yet another series of questions: Are any lesions outside the valves important? Is angioplasty the best possible treatment? What about oversized balloons, cutting balloon and when are stents warranted, if at all? What per cent of lesions respond to angioplasty, how do you judge? How do we know intraprocedurally if CCSVI is adequately treated? Is it necessary to treat all lesions? What are the risks and complications of the procedure? Do individuals ever get worse after treatment? Is post-treatment with angioplasty or a stent? What is the ideal regimen for adjunctive medications to prevent thrombus formation?

    Questions also remain with regard to the potential benefits of endovascular treatment and follow-up. “How do we know if there is any real benefit from treating CCSVI, i.e. that it is not a placebo? What percentage of patients notice improvement; in what percentage of patients do these symptoms return? Do cerebral perfusion, tissue oxygenation and venous flow measurements improve post-treatment? What evaluations should be monitored on follow-up? If symptoms return, what is the typical timeframe for this? What should interventionalists do when they return and why do they return? Is there any evidence that the trajectory of disease progression is slowed post-therapy?,” Dake asked. He referred to the scepticism the CCSVI theory has met with from several neurologists, and illustrated it with an editorial published in the American Journal of Neuroradiology (AJNR2011;32: 424–427) which said: “CCSVI is a sonographic construct that is poorly reproducible and questionable in terms of known pathophysiologic factors established in multiple sclerosis. The neuroimaging findings reviewed here do not support the CCSVI theory in multiple sclerosis [...]. As a consequence, endovascular treatment of presumed vascular abnormalities in multiple sclerosis should be discouraged violently.”

    Dake told delegates, “The current state of CCSVI discussions in the medical literature is centred in two silos: its frequency/diagnosis/association with multiple sclerosis and the results of endovascular treatment. The former is highly contentious, confusing and still quite hypothetical, with positions often being argued by those with a pre-existing agenda/bias. In either case, new metrics are needed to specifically address the effects of treatments on new targets—studies that allow an acceleration of the current cycle time to determine if the desired effect of therapy is achieved,” he said.

    Siskin, who presented some results from the latest literature on CCSVI, said that it was important to differentiate between “what we know and what we do not know in order to help effective communication with potential patients, to make sure that discussions with neurology are balanced and to be certain that research is directed towards answering the unanswered questions.”

    At the SIR session, Haskal cautioned against close mindedness on both ends of the spectrum both from the “opposers” of the theory and the “converted.” He noted that reproducibility of results was vital.

    Haskal stated that there was a broad need and opportunity for methodical disassembly of the problem into research elements. “Ultrasound protocols need to be validated and others created that can be accomplished and validated locally. Magnetic resonance screening protocols need to be defined at the highest level and set for local reproducibility; reporting standards must be defined for uniformity; and we need to define appropriate endpoints for studies,” he said.

    With regard to therapeutic gray areas, Haskal questioned: “Are the endpoints being used currently in studies suitable/correct? Are the diagnostic tools not restrictive or too fine? Is the technology adequate? Is investigator bias introduced early regarding mechanism? Can early trials truly mimic existing standards, at this point? We need to identify objective measures: MRI lesions, exams, cytokines, immune mediators,” he said.

    Source: Interventional News © BIBA Medical Ltd 2011 (07/06/11)

    Extracranial venous vessel pathology in MS

    CCSVI VenogramAbstract

    Objectives: Venous vesssel pathology in patients with multiple sclerosis (MS) has increased a great interest in the scientific community. The new vascular entity named chronic cerebrospinal venous insufficiency (CCSVI) is characterised by multiple stenoses of the extracranial veins – jugular and azygous veins. A four patterns of venous stenosis was decribed. Pathohistological studies desribed perivenous distribution of demyelinating lesions, and by high resolution MR venography a cenral vein in the long axis of MS lesions was highlighted. The role of an iron accumulation in the brain tissue is discussed.The aim of our study was to elucidate the occurence of the venous vessel pathology in patients with an advanced progressive course of MS.

    Methods: The MS patients who fulfilled 2 or more of the 5 proposed criteria obtained by Doppler sonography required for the CCSVI, underwent selective venography. Disability status was assessed by the Expanded Disability Status Scale (EDSS). Fatigue was evaluated using Fatigue Severity Scale (FSS). Selective venography by placing a coronary catheter in the right femoral vein was peroformed. Informed consent by participating subjects and agreement of the National ethical committee was obtained.

    Results: In this study we enrolled 30 consecutive MS patients (aged 27-73 years) with progressive course of disease – 17 patients with secondary progressive and 13 with primary progressive MS with mean EDSS 5.53 (range 2.0-7.5). The mean narrowing of the jugular and azygous veins was 75% (range 50-95%). After 95 transluminal dilatations the improvement of the venous outflow was achived. Endovascular treatment did not produce any serious side effects. The significant improvement of EDSS score (less than 1.0 point) was not noticed, but significant amelioration of the fatigue assessed by FSS (p < 0.001).

    Conclusion: In all MS patients with the progressive course of disease venous vessel pathology was dicovered. Selective venography is a very important and sensitive method in detecting stenosis of the extracranial venous pathway. By advanced pyramidal involvement an improvement of disability score is not expected. The amelioration of fatigue plays an important role in defeating daily obstacles in MS patients. Even in advanced disability, quality of life could be well preserved. It seems that the endovascular treatment in more disabled MS patients is promising.

    M. Denislic, Z. Milosevic, M. Zorc, O. Mendiz, M. Leskosek, D. Ravnik (Ljubljana, SI; Buenos Aires, AR; Vrhnika, SI)

    Source: 1st Meeting of the European Neurological Society Lisbon, Portugal 28.05.2011 - 31.05.2011 (01/06/11)

    Normal CSF ferritin levels in MS suggest against etiologic role of CCSVI

    CSF Fluid RetrievalSummary: A new and controversial hypothesis suggests disease progression in MS may be related to CCSVI and the resulting toxic effects of parenchymal iron deposition in the central nervous system (CNS; Singh AV, Zamboni P, J Cereb Blood Flow Metab 2009;29:1867-78). When iron is present in the CNS, it simulates intrathecal expression of ferritin (Keirg et al, Clin Chim Acta 1993;216:153-66). An indirect test for deposition of iron in the CNS is quantification of ferritin.

    The authors postulated that if CSSVI leads to parenchymal iron deposition in MS, there ought to be increased CSF ferritin levels. They quantified CSF ferritin levels from a previously published cohort with clinically definite MS (Petzold A, et al, Brain 2002;15:1462-473; Polman CH, et al, Ann Neurol 2005;58:840-6).

    The current study consisted of a cross-sectional and a longitudinal component. In the cross-sectional part of the study, CSF ferritin levels in patients with MS were compared with levels in patients with subarachnoid hemorrhage and occult bleeding (siderosis). An inflammatory neurologic control group was also included because CSF ferritin is known to increase inflammation.

    The hypothesis was that if CCSVI-related parenchymal iron deposition is a major pathologic feature of MS, CSF ferritin levels in MS patients should be in the range seen with those with subarachnoid hemorrhage or inflammation. In the longitudinal component of this study, each patient with MS was his or her own control. The hypothesis was that ongoing parenchymal iron deposition due to CCSVI should lead to an increase CSF ferritin over time.

    A final analysis was to determine whether CSF ferritin was related to MS progression, as detected on brain magnetic resonance imaging or clinically.

    The cross-sectional component of the study included 1408 patients and the longitudinal component included 29 patients. The definition of pathologic CSF ferritin levels was >12 ng/mL. This level was observed in 4% of the control patients (median, 4 ng/mL), in 91% of those with superficial siderosis (75 ng/mL), in 73% with a subarachnoid hemorrhage (59 ng/mL), in 10% with relapsing-remitting MS (5 ng/mL), in 11% with primary progressive MS (6 ng/mL), in 23% with secondary progressive MS (5 ng/mL), and in 23% with meningoencephalitis (5 ng/mL). In the MS patients monitored longitudinally, there was no change in CSF ferritin levels during the 3-year follow-up period and there was no correlation of follow-up CSF ferritin levels with changes in clinical or brain MRI parameters of MS.

    Conclusion: Cerebral spinal fluid (CSF) ferritin levels do not support an etiologic role for chronic cerebral spinal venous insufficiency (CCSVI)–related parenchymal iron deposition in multiple sclerosis (MS).

    Comment: These data do not support the CCSVI hypothesis for MS. The authors, however, point out a number of short-comings of their study, including that ferritin is only an indirect marker for CSF iron deposition and that they have no longitudinal data on CSF ferritin levels in the control patients. This precludes conclusions about variations over time of individual CSF ferritin levels in an assumed normal population. Also, with respect to MRI, they do not have T2 imaging data potentially permitting correlation of CSF ferritin levels with parenchymal iron deposition or markers of CCSVI.

    Source: Journal Of Vascular Surgery © 2011 Society for Vascular Surgery. Published by Elsevier Inc (26/05/11)

    Hypoperfusion of brain parenchyma and severity of CCSVI in patients with MS

    CCSVI VenogramAbstract
    Background: Several studies have reported hypoperfusion of the brain parenchyma in multiple sclerosis (MS) patients. We hypothesized a possible relationship between abnormal perfusion in MS and hampered venous outflow at the extracranial level, a condition possibly associated with MS and known as chronic cerebrospinal venous insufficiency (CCSVI).

    Methods: We investigated the relationship between CCSVI and cerebral perfusion in 16 CCSVI MS patients and 8 age- and sex-matched healthy controls. Subjects were scanned in a 3-T scanner using dynamic susceptibility, contrast-enhanced, perfusion-weighted imaging. Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the gray matter (GM), white matter (WM) and the subcortical GM (SGM). The severity of CCSVI was assessed according to the venous hemodynamic insufficiency severity score (VHISS) on the basis of the number of venous segments exhibiting flow abnormalities.

    Results: There was a significant association between increased VHISS and decreased CBF in the majority of examined regions of the brain parenchyma in MS patients. The most robust correlations were observed for GM and WM (r = -0.70 to -0.71, P < 0.002 and P corrected = 0.022), and for the putamen, thalamus, pulvinar nucleus of thalamus, globus pallidus and hippocampus (r = -0.59 to -0.71, P < 0.01 and P corrected < 0.05). No results for correlation between VHISS and CBV or MTT survived multiple comparison correction.

    Conclusions: This pilot study is the first to report a significant relationship between the severity of CCSVI and hypoperfusion in the brain parenchyma. These preliminary findings should be confirmed in a larger cohort of MS patients to ensure that they generalize to the MS population as a whole. Reduced perfusion could contribute to the known mechanisms of virtual hypoxia in degenerated axons.

    Full Article

    Paolo Zamboni, Erica Menegatti, Bianca Weinstock-Guttman, Michael G Dwyer, Claudiu V Schirda, Anna M Malagoni, David Hojnacki, Cheryl Kennedy, Ellen Carl, Niels Bergsland, Christopher Magnano, Ilaria Bartolomei, Fabrizio Salvi, Robert Zivadinov

    Source: BMC Medicine 2011, 9:22 (12/05/11)

    Vascular origin for MS still unconfirmed

    CCSVI VenogramTwo more research groups said they couldn't confirm the idea that obstructed veins in the head and neck are responsible for multiple sclerosis.

    The pair of studies, conducted in Europe with a total of more than 100 MS patients and 40 healthy controls, were presented here at the American Academy of Neurology's annual meeting. Both found no difference in the direction of venous blood flow or the presence of stenosis between patients and controls.

    These were the latest attempts to replicate -- or refute -- an astonishing report in 2009 by Paolo Zamboni, MD, of the University of Ferrara in Italy, and colleagues, in which nearly every MS patient they studied showed stenosis and venous reflux with ultrasound exams. Healthy controls, on the other hand, almost never showed these abnormalities.

    Zamboni also performed venous angioplasties on 65 MS patients, some with stenting, with dramatic clinical improvements claimed in many.

    The researchers dubbed the phenomenon chronic cerebrospinal venous insufficiency, or CCSVI. Not surprisingly, it quickly attracted an enthusiastic following in the MS patient community.

    The Italian researchers theorized that the backflow of blood into the brain leads to iron deposition there. These deposits then trigger inflammation in the central nervous system, setting the stage for the immune-mediated demyelination that is conventionally recognized as the cause of MS.

    But several other groups that attempted similar case-control studies came up with very different results. They found that neither patients nor controls had such abnormalities, or else that both groups had the abnormalities at similar rates.

    At the AAN meeting here, Florian Connolly, MD, of Humboldt University in Berlin, Germany, reported on a study of 96 patients and 20 controls. The findings extended an earlier, preliminary report published last year in Annals of Neurology, at which point only 55 of the MS patients had been evaluated.

    Results in the final 41 patients merely confirmed the earlier findings, Connolly reported. In total, only one of the patients showed venous blood reflux. The other 95 and all of the controls had normal flow direction, he told attendees here.

    These findings were the same irrespective of whether patients were scanned in the supine versus sitting position, he added. Patient positioning during ultrasound has been a bone of contention between CCSVI advocates and skeptics.

    Christoph Mayer, MD, of Goethe University in Frankfurt, Germany, followed Connolly onto the podium to present the second study, involving 20 patients (17 with relapsing-remitting MS, three with secondary progressive disease) and 20 controls.

    He said their aim was to replicate Zamboni's protocol as closely as possible, although he did not say whether any of his team had gone to the Ferrara clinic for training.

    One exception was that both the ultrasound technician and the data analyst was blinded as to whether a study participant was a patient or healthy control, Mayer said. The Ferrara studies were conducted with investigators knowing whether a patient or control was being examined.

    Mayer said stenosis of the internal jugular vein was common in both groups, seen in 16 of the controls and 13 of the patients.

    But, as in the Humboldt study, there was no evidence of reflux in any of the patients or controls, irrespective of supine versus sitting position, Mayer said.

    He said his group had concluded that Zamboni's results may have reflected the lack of blinding and/or the choice of cutoffs for interpreting the ultrasound results.

    Both groups didn't mince words in their presentation titles. Connolly's declared, "Patients with Multiple Sclerosis Do Not Suffer from Cerebro-Cervical Venous Congestion."

    Mayer's was even more provocative: "The Perfect Crime? CCSVI Not Leaving a Trace in MS."

    But Robert Fox, MD, an MS specialist at the Cleveland Clinic, told MedPage Today that neither group really proved their cases, nor had Zamboni.

    None of the CCSVI studies appearing so far had described their sonography protocols in enough detail to allow for proper comparisons between them, he said.

    Fox and a colleague, Mei Lu, MD, PhD, presented findings here from their own study in which they showed that nine different aspects of sonography can greatly affect the results. In addition to patient positioning and investigator blinding, they included the patient's hydration status, respiration, heart rate, and external compression, as well as pulse repetition frequency and other "knobology" factors in the ultrasound procedure.

    Changing any one of these parameters can show that a patient is experiencing venous reflux or normal flow, Fox said.

    He said the lack of standardization in the ultrasound protocols, and their reporting, likely accounted for the vastly different results claimed by different research groups.

    Fox recommended that an expert consensus panel be formed to develop a uniform protocol to be followed in all studies intended to test the CCSVI hypothesis.

    Neither study had commercial funding.

    Source: Medpage Today © 2011 Everyday Health, Inc.(16/04/11)

    New study questions theory that CCSVI causes MS

    CCSVI VenogramClogged neck veins that restrict blood flow from the brain are not the cause of multiple sclerosis, but rather a result of the debilitating disease, new U.S. research suggests.

    The University of Buffalo study, the largest to investigate whether vein blockages cause MS, casts doubt on the theory embraced by patients around the world.

    Neurologists say the findings provide crucial insight into their understanding of the proposed link between chronic cerebrospinal venous insufficiency (CCSVI) and MS, but do not provide a definitive answer on the provocative theory.

    Since first proposed by an Italian researcher in 2009, patients desperate for relief have undergone operations to open up their neck veins, many becoming passionate supporters of the so-called liberation treatment. Neurologists, meanwhile, have largely cautioned against the rush to surgery until more research is done

    The findings, published online Wednesday in Neurology, the journal of the American Academy of Neurology, “point against CCSVI having a primary causative roll in the development of MS.”

    Lead author Dr. Robert Zivadinov, associate professor of neurology at the University of Buffalo School of Medicine and Biomedical Sciences, said the study revealed CCSVI was not unique to MS.

    Of the study’s 499 participants, 56 per cent of patients with MS met the criteria for CCSVI, as did 46 per cent of subjects with other neurological diseases and 23 per cent of healthy people acting as controls.

    “That means subjects with other diseases and healthy people may also have CCSVI, which means it is probably not unique just to MS and is not the cause,” said Zivadinov, who is also president of the International Society for Neurovascular Disease.

    Dr. Peter Stys, a professor of clinical neuroscience and an MS researcher at the University of Calgary, said the findings show CCSVI may be a response from the way veins have drained over the years from a brain inflamed by MS and other neuroinflammatory diseases.

    “Importantly, CCSVI is no more the cause of MS than a swollen ankle is the cause of the underlying fractured bone,” Stys said. “Therefore, stenting veins in CCSVI will not cure MS any more than icing the ankle will somehow fix the fractured bone.”

    The study also found the prevalence of CCSVI was different depending on a patient’s stage of the disease. About 38 per cent of patients in the early stage of MS presented with CCSVI, while 80 to 90 per cent of patients in progressive stages had the condition, said Zivadinov.

    Authors of an accompanying editorial said the increased prevalence of CCSVI in patients with progressive stages of the disease “leaves open the possibility that CCSVI may be playing a contributory role in, or be a consequence of, the disease, or may be age-related.”

    Zivadinov said a number of factors, including a patient becoming less mobile and having to use a wheelchair, could be the reason why those with advanced MS are more likely to have CCSVI.

    “We can point to a number of different factors that could point to closure of the veins, but we don’t have an answer,” he said. “Our message on CCSVI is definitely we should proceed to understand why people who have progressive forms have much more prevalence of this phenomenon.”

    In 2009, Dr. Paolo Zamboni postulated that clogged neck veins could trigger multiple sclerosis by causing iron to flow up to the brain.

    That same year, Zamboni published results that suggested the relatively simple procedure to unclog veins, called venous angioplasty procedure — dubbed “the liberation therapy” — held promise to relieve the debilitating symptoms of MS.

    Dr. Anthony Traboulsee, a neurologist at the UBC Hospital MS Clinic, said the University of Buffalo study neither proves nor disproves the CCSVI theory.

    “It illustrates the importance of independent work on any new theory,” he said in an email. “It raises important questions about earlier reports that showed every patient with MS has CCSVI compared to a complete absence in the normal population.”

    Traboulsee cautioned that CCSVI studies conducted with ultrasound, including the original Italian and the recent Buffalo study, are difficult to do well because results can be affected by the timing, angle and position of the patient and probe.

    Results of the well-designed studies sponsored by the Multiple Sclerosis Society of Canada take into account those difficulties and are expected as early as this fall, he said.

    Source: thestar.com © Copyright Toronto Star 1996-2011 (14/04/11)

    Manitoba joins Saskatchewan in MS clinical trials

    CCSVI VenogramStealing a page out of Saskatchewan's MS playbook, Manitoba will spend $5 million to fund clinical trials into a controversial new treatment for multiple sclerosis.

    The province announced Tuesday it has given up waiting for a broad co-ordinated Canadian research effort to emerge. Instead, it will work with its western neighbour in the hope that other provinces join them.

    "It would be excellent if all the governments participated in a multi-site (research) proposal, including the federal government," Premier Greg Selinger told a news conference. "In the absence of that, what's the Plan B that will move the agenda forward? This is a strong Plan B," he said.

    The NDP government has been under pressure from MS sufferers and its opponents in the legislature to do more to assess the worthiness of the so-called liberation therapy for multiple sclerosis -- a treatment many Canadians have paid roughly $18,000 (including travel) to undergo in places like Poland, India and Costa Rica. The procedure involves unblocking veins to achieve normal blood flow from the brain.

    In October, the province anted up $500,000 to fund clinical trials on condition that they first be deemed "safe and ethical" and were part of a national effort. That contrasted with the approach taken by Saskatchewan, where Premier Brad Wall committed $5 million last fall to proceed with provincially managed trials.

    Manitoba Conservative Leader Hugh McFadyen said a looming provincial election, slated for Oct. 4, likely prompted the government to act. Last year, he called for Manitoba to take action similar to what had been announced in Saskatchewan.

    "We're happy for MS patients that they (the NDP) are taking this position but we certainly question the motives," McFadyen said.

    Winnipegger Sharlene Garlinski, who underwent liberation treatment in Costa Rica last summer, said it's done wonders for her. "I feel amazing. Best decision I ever made," she said Tuesday, noting that her energy and balance have improved and she can even wear heels.

    The Canadian medical community has been suspicious of the procedure, arguing more study is needed to prove it is safe and effective. But Garlinski said our health experts should open their eyes to what's happening abroad and get on with performing the procedures.

    "Five million (dollars for research) is a good start, but at the same time they really need to start focusing on the treatment part," she said.

    The Manitoba branch of the MS Society of Canada applauded the province's $5-million commitment -- just as it did last fall's announcement of $500,000 and a promise to help develop a pan-Canadian research effort.
    A local spokesman for the group refused Tuesday to comment on the evolution of the government's policy except to say the society was "pleased that multiple sclerosis has been recognized as a top priority health-care issue" by the province.

    The Manitoba Health Research Council will issue a call for proposals for a Manitoba-centred clinical trial in the coming months. Results from the trial may not be available for three years.

    The province vowed to work collaboratively with Saskatchewan to avoid duplication of research. Health Minister Theresa Oswald said Manitoba will follow research protocols already developed by the Saskatchewan Health Research Foundation, which should speed its own efforts.

    Manitoba always maintained it would participate in MS clinical trials when it was safe and ethical to do so, Oswald said. And in working with Saskatchewan officials, the province has gained "a level of confidence" that it can now proceed.

    Oswald also said the province continues to believe that multi-site clinical trials are the best approach in learning about the safety and efficacy of the liberation treatment.

    "It's worth noting that when this story initially broke, the MS Society of Canada asked the federal government to commit $10 million to clinical trials," she said. "Today what you're seeing are two provinces that are filling that void. And we believe that there will be opportunities for other groups to join in this process."

    Source: Winnepeg Free Press © 2011 Winnipeg Free Press (07/04/11)

    Cerebrospinal venous angioplasty safe in MS - study

    CCSVI VenogramEndovascular treatment of chronic cerebrospinal venous insufficiency (CCSVI) in patients with multiple sclerosis (MS) is safe and can be performed on an outpatient basis.

    Kenneth Mandato, MD, interventional radiologist at Albany Medical Center in New York, presented the results of a retrospective analysis of a single center's safety data here at the Society of Interventional Radiology (SIR) 36th Annual Scientific Meeting.

    Ziv J. Haskal, MD, FSIR, FACR, FAHA, FCIRSE, chief of vascular and interventional radiology at the University of Maryland Medical Center in Baltimore, spoke with Medscape Medical News and described this approach to treating MS as "the most controversial thing I've seen in almost 30 years."

    Dr. Mandato specifically evaluated the results of outpatient endovascular treatment of the internal jugular and azygos veins, identifying and describing adverse events and complications that occurred within 30 days of the procedure. The study consisted of 247 procedures that were performed on 231 patients (147 women and 84 men), who ranged in age from 25 to 70 years. For 99.2% (245 of 247) of the procedures, patients were discharged within 3 hours.

    The authors note that procedure-induced arrhythmias occurred in 3 patients during the procedure, so cardiac monitoring is essential. Furthermore, additional studies are required to determine the utility of this procedure as a treatment option for MS. Specifically, research is needed to elucidate patient selection, angioplasty technique, and efficacy.

    Dr. Haskal is one of the lead investigators of the SIR Research Consensus Panel on the Interventional Endovascular Management of Chronic Cerebrospinal Venous Insufficiency in Patients with MS, convened on October 18, 2010. Last fall, the consensus panel issued a position statement supporting high-quality clinical research to determine the safety and efficacy of interventional treatments for MS.

    Approximately 500,000 people in the United States have MS — generally considered an incurable and disabling disease. According to Dr. Haskal, many patients with MS travel to Costa Rica, Kuwait, India, and other countries to receive angioplasty. He described the approach as "Facebook-driven medicine," and explained that there is a concern that patients will be preyed on by individuals who do not have their best interests at heart. He goes even further and adds that the majority of neurologists find this treatment approach to MS to be abhorrent. According to Dr. Haskal, "I cannot overstate the uproar over [angioplasty as a treatment for MS]."

    The SIR's position statement notes that the use of any treatment in patients with MS should be determined on a patient-specific basis and should be based on the patient's disease status and tolerance of previous therapies, as well as the scientific plausibility of the treatment. SIR encourages patients with MS to continue to discuss treatment options with their neurologists. At this time, the scientific data do not support the routine use of angioplasty and stents as treatments for MS, but the SIR agrees that the preliminary results are very promising.

    Dr. Mandato's research indicates that angioplasty for CCSVI is a safe procedure. If a patient is suspected of having CCSVI, Dr. Mandato suggested to Medscape Medical News that they first receive an ultrasound to determine venous insufficiency. When discussing the technique with Medscape Medical News, Dr. Mandato indicated that this initial research should help physicians understand the safety of the procedure.

    Dr. Mandato also discussed the scientific basis of this approach. He explained that the initial idea came from Paolo Zamboni, MD, a vascular surgeon in Italy whose wife was diagnosed with MS. Dr. Zamboni made the connection between venous outflow and pathology in the brain. He published a series of cases of patients with MS who were improving after angioplasty of the jugular vein. This 2009 publication by Dr. Zamboni suggested that CCSVI might contribute to MS and its symptoms (J Neurol Neurosurg Psychiatry. 2009;80:392-399).

    Dr. Mandato explained that from a medical standpoint, this publication received a great deal of interest — both positive and negative. Dr. Mandato also noted that more work needs to be done to understand the science behind any efficacy. He asked: "Is the venous outflow adding insult to injury, or are we dealing with abnormal veins that were there from the beginning?" He explained that there are still many theories that have yet to be supported by evidence.

    He is currently performing a retrospective analysis of efficacy data from the cohort studied in the safety analysis and is currently gathering data from a prospective trial.

    Source: Medscape Today Copyright © 1994-2011 by WebMD LLC (06/04/11)

    Interventional radiologists advance MS research: vein-opening treatment safe

    CCSVI VenogramEarly Study of 231 Patients Details Safety of Using Angioplasty to Widen Internal Jugular and Azygos Veins; Doctors Hope Results Encourage More Research to Explore Minimally Invasive Treatment Options for Those With Multiple Sclerosis.

    Understanding that angioplasty—a medical treatment used by interventional radiologists to widen the veins in the neck and chest to improve blood flow—is safe may encourage additional studies for its use as a treatment option for individuals with multiple sclerosis, say researchers at the Society of Interventional Radiology's 36th Annual Scientific Meeting in Chicago, Ill.

    "Angioplasty—the nonsurgical procedure of threading a thin tube into a vein or artery to open blocked or narrowed blood vessels—is a safe treatment. Our study will provide researchers the confidence to study it as an MS treatment option for the future," said Kenneth Mandato, M.D., an interventional radiologist at Albany Medical Center in Albany, N.Y. In a retrospective study, 231 MS patients (age range, 25 to 70 years old; 147 women, 84 men) underwent this endovascular treatment of the internal jugular and azygos veins with or without placement of a stent (a tiny mesh tube). "Our results show that such treatment is safe when performed in the hospital or on an outpatient basis—with 97 percent treated without incident," Mandato noted. He added, "Our study, while not specifically evaluating the outcomes of this endovascular treatment, has shown that it can be safely performed, with only a minimal risk of significant complication. It is our hope that future prospective studies are performed to further assess the safety of this procedure." Complications included abnormal heart rhythm in three patients and the immediate re-narrowing of treated veins in four patients. All but two of the patients were discharged within three hours of receiving this minimally invasive treatment.

    About 500,000 people in the United States have MS, generally thought of as an incurable, disabling autoimmune disease in which a person's body attacks its own cells. "There are few treatment options that truly improve the quality of life of those with the disease, and some of the current drug treatment options for MS carry significant risk," said Mandato. In 2009, Paolo Zamboni, a doctor from Italy, published a study that suggested that a blockage in the veins that drain blood from the brain and spinal cord and return it to the heart (a condition called chronic cerebrospinal venous insufficiency or CCSVI) might contribute to MS and its symptoms. The idea is that if these veins were widened, blood flow may be improved, which may help lessen the severity of MS-related symptoms.

    The Society of Interventional Radiology issued a position statement last fall supporting high-quality clinical research to determine the safety and effectiveness of interventional MS treatments, recognizing that the role of CCSVI in MS and its endovascular treatment by an interventional radiologist via angioplasty and/or stents to open up veins could be transformative for patients. "This is an entirely new approach to the treatment of patients with neurologic conditions, such as multiple sclerosis. The idea that there may be a venous component that causes some symptoms in patients with MS is a radical departure from current medical thinking," said Gary P. Siskin, M.D., FSIR, an interventional radiologist and chair of the radiology department at Albany Medical Center and the co-chair of the SIR research consensus panel on MS that was held in October.

    "It is important to understand that this is a new approach to MS. As a result, there is a healthy level of skepticism in both the neurology and interventional radiology communities about the condition, the treatment and the outcomes," said Siskin. "Interventional radiologists have been performing venous angioplasty for decades and have established themselves as pioneers in this area of vascular intervention. Patients are learning about this therapy and the role of interventional radiology in venous angioplasty through the Internet. They are discussing it among themselves—through blogs and social networking sites—and then turning to interventional radiologists for this treatment," he noted. "This is a new entity and one where researchers are clearly very early in their understanding of both the condition and the treatment," added Siskin.

    SIR's position statement agrees with MS advocates, doctors and other caregivers that the use of any treatment (anti-inflammatory, immunomodulatory, interventional or other) in MS patients should be based on an individualized assessment of the patient's disease status, his or her tolerance of previous therapies, the particular treatment's scientific plausibility, and the strength and methodological quality of its supporting clinical evidence. "When conclusive evidence is lacking, SIR believes that these often difficult decisions are best made by individual patients, their families and their physicians," notes the society's position paper, "Interventional Endovascular Management of Chronic Cerebrospinal Venous Insufficiency in Patients With Multiple Sclerosis: A Position Statement by the Society of Interventional Radiology, Endorsed by the Canadian Interventional Radiology Association." SIR stresses the importance for MS patients to continue an ongoing dialogue with their neurologists to discuss their treatment care.

    While the use of angioplasty and stents cannot be endorsed yet as a routine clinical treatment for MS, SIR agrees that the preliminary research is very promising and supports studies aimed at understanding the role of CCSVI in MS, at identifying methods to screen for the condition and at designing protocols for exploratory therapeutic trials. "If interventional therapy proves to be effective, MS patients should be treated by doctors who have specialized expertise and training in delivering image-guided venous treatments," said Siskin. Interventional radiologists pioneered angioplasty and stent placements and use those treatments on a daily basis in thousands of patients with diverse venous conditions.

    Mandato noted that research still needs to be done concerning patient selection, technique and the outcomes after this procedure, including improvement in symptoms and quality of life and the durability of the response.

    More information about the Society of Interventional Radiology, interventional radiologists and minimally invasive treatments can be found online at www.SIRweb.org.

    Abstract 3: "Safety of Outpatient Endovascular Treatment of the Internal Jugular and Azygos Veins for Chronic Cerebrospinal Venous Insufficiency (CCSVI) in Multiple Sclerosis: a Retrospective Analysis," K. Mandato, P. Hegener, G. Siskin, M. Englander, S. Garla, A. Herr; Radiology, Albany Medical Center, Albany, N.Y., SIR's 36th Annual Scientific Meeting March 26–31, 2011, Chicago, Ill.

    This abstract can be found online at www.SIRmeeting.org.

    About the Society of Interventional Radiology
    Interventional radiologists are physicians who specialize in minimally invasive, targeted treatments. They offer the most in-depth knowledge of the least invasive treatments available coupled with diagnostic and clinical experience across all specialties. They use X-ray, MRI and other imaging to advance a catheter in the body, such as in an artery, to treat at the source of the disease internally. As the inventors of angioplasty and the catheter-delivered stent, which were first used in the legs to treat peripheral arterial disease, interventional radiologists pioneered minimally invasive modern medicine. Today, interventional oncology is a growing specialty area of interventional radiology. Interventional radiologists can deliver treatments for cancer directly to the tumor without significant side effects or damage to nearby normal tissue.

    Many conditions that once required surgery can be treated less invasively by interventional radiologists. Interventional radiology treatments offer less risk, less pain and less recovery time compared to open surgery.

    The Society of Interventional Radiology is holding its 36th Annual Scientific Meeting March 26–31 at McCormick Place (West Building) in Chicago, Ill. The theme of the meeting is "IR Rising: Leading Image-guided Medicine," chosen to reflect interventional radiology's continued revolutionizing of modern medicine.

    SOURCE Society of Interventional Radiology (28/03/11)

    Screening of CCSVI by cervical strain-gauge plethysmography

    CCSVI VenogramBackground: Chronic cerebrospinal venous insufficiency (CCSVI) is a syndrome  characterized by venous flow blockages at the level of the jugular and/or azygous veins, compensated by activation of collateral circulation. Blocked outflow is due to truncular stenosing malformation, mainly intraluminal defect like malformed valve, septum, web, etc, or  more rarely, vein hypoplasia and agenesis. It has been described a strong association between CCSVI and multiple sclerosis (MS).

    The CCSVI condition can be diagnosed by vascular Doppler sonography and/or catheter venography. The former is operator dependent and the  latter is of course invasive. MR venography does not represent a valid alternative, since diagnostic accuracy is still low. We experimented strain-gauge plethysmography as a screening device for CCSVI. Aim of the test is to
    assess the gravitational mechanism of venous outflow from the brain.

    Methods: 40 healthy controls (HC) matched  for age and gender with 29 CCSVI-MS patients were screened for CCSVI by means of vascular Doppler sonography by an  expert operator. The entire cohort blindly underwent a protocol using an original straingauge collar connected with a volume transducer and dedicated software. After calibration, the subject is tilted from the upright to the supine posture (Fig.1). The redistribution of blood volume permits to obtain a volume-time curve from which extrapolates the venous volume (VV%), corresponding to the highest point of the filling
    plateau, the 90% VV and the venous filling index (VFI). The subject is tilted to up again, obtaining a reduction in venous volume defined as tilt ejection fraction (TEF and TEF 90%), with a slope curve proportional to the time of emptying. Finally, the residual volume fraction (RVF) corresponds to the  cervical volume after tilting up.

    Results: VV% measured respectively in HC 5.3±2.5 and in CCSVI-MS 6.7±2.5 (p<0.0002); VFI 0.9±0.5 and 1.3±0.8 (p<0.0001); TEF 90% 1.8±0.7 and 2.8±1.1 (p< 0.0001); TEF slope 2.6±1.7 and 1.8±1.1 (p<0.0001); RVF 0.6±1.5 and 1.7±1.7 (p<0.0001). No significant variations were found for VV 90% and TEF between the two populations. 

    Conclusions: Cervical strain-gauge plethysmography showed several parameters significantly different in CCSVI respect to HC. It is a novel tool for non-invasive, nonoperator dependent screening of CCSVI. Imaging techniques remains indispensable for defining location and morphology of venous outflow obstructions.

    Paolo Zamboni, Erica Menegatti, Marianna Morelli, Giorgio Bergamo, Michele Zuolo; Sergio Gianesini, Fabrizio Salvi.
    Univerity of Ferrara, Ferrara, Italy. Bellaria Neurosciences, Bologna, Italy

    Source: ccsvism.xoom.it (18/03/11)

    Safety of outpatient endovascular treatment of the internal jugular and azygos veins in MS patients with CCSVI

    CCSVI VenogramPurpose
    To evaluate the safety of outpatient endovascular treatment of the internal jugular and azygos veins in MS patients with CCSVI.

    Material and Methods
    A retrospective analysis of MS patients with CCSVI undergoing endovascular treatment of the internal jugular and/or azygos veins was performed to identify and describe the adverse events occurring within 30 days.

    Results
    Over 7 months, 247 procedures were performed in 231 patients. The mean patient age was 48.2 years (range: 25.7–70.2 years); 63.7% were female and 36.3% were male. 49.0% (121/247) of the procedures were performed in a hospital and 51.0% (126/247) were performed in the office setting. 92.7% (229/247) were primary procedures while 7.3% (18/247) were secondary due to restenosis. For patients treated primarily, 86.5% (198/229) underwent angioplasty and 11.4% (26/229) underwent stent placement of at least one vessel; the remaining 5 patients were not treated. For patients treated due to restenosis, 50% (9/18) underwent angioplasty and 50% (9/18) underwent stent placement. After 99.2% (245/247) of the procedures, patients were discharged within 3 hours. A post-procedure, transient headache was reported in 8.5% (21/247); this persisted beyond 30 days in 1 patient. Neck pain was reported in 15.8% of patients (39/247); 53.8% (21/39) of these patients underwent stent placement. 1.7% (4/231) of patients were retreated within 30 days due to symptomatic restenosis. Sustained cardiac arrhythmias were observed in 3 patients during the procedure with 2/3 patients requiring hospital admission. One of these patients, who underwent a complex procedure for in-stent thrombosis, required a prolonged hospitalization due to a stress-induced cardiomyopathy.

    Conclusion
    Endovascular treatment of CCSVI in MS patients is a safe procedure when performed on an outpatient basis. Cardiac monitoring is essential to permit detection and rapid treatment of patients with procedure-induced arrhythmias. Post-procedure ultrasound is recommended to detect venous thrombosis. In addition, consideration should be given to performing complex re-interventions in a hospital given the complication risk in this sub-population of patients.

    Source: Journal of Vascular and Interventional Radiology Volume 22, Issue 3, Supplement , Page S4, March 2011 © 2011 SIR. Published by Elsevier Inc.  (14/11/03)

    Hypoperfusion of brain parenchyma is associated with the severity of CCSVI in patients with MS

    CCSVI VenogramAbstract

    Background:Several studies have reported hypoperfusion of the brain parenchyma in multiple sclerosis (MS) patients. We hypothesized a possible relationship between abnormal perfusion in MS and hampered venous outflow at the extracranial level, a condition possibly associated with MS and known as chronic cerebrospinal venous insufficiency (CCSVI).

    Methods:We investigated the relationship between CCSVI and cerebral perfusion in 16 CCSVI MS patients and 8 age- and sex-matched healthy controls. Subjects were scanned in a 3-T scanner using dynamic susceptibility, contrast-enhanced, perfusion-weighted imaging. Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the gray matter (GM), white matter (WM) and the subcortical GM (SGM). The severity of CCSVI was assessed according to the venous hemodynamic insufficiency severity score (VHISS) on the basis of the number of venous segments exhibiting flow abnormalities.

    Results:There was a significant association between increased VHISS and decreased CBF in the majority of examined regions of the brain parenchyma in MS patients. The most robust correlations were observed for GM and WM (r = -0.70 to -0.71, P < 0.002 and P corrected = 0.022), and for the putamen, thalamus, pulvinar nucleus of thalamus, globus pallidus and hippocampus (r = -0.59 to -0.71, P < 0.01 and P corrected < 0.05). No results for correlation between VHISS and CBV or MTT survived multiple comparison correction.

    Conclusions:This pilot study is the first to report a significant relationship between the severity of CCSVI and hypoperfusion in the brain parenchyma. These preliminary findings should be confirmed in a larger cohort of MS patients to ensure that they generalize to the MS population as a whole. Reduced perfusion could contribute to the known mechanisms of virtual hypoxia in degenerated axons.

    Paolo Zamboni , Erica Menegatti , Bianca Weinstock-Guttman , Michael G Dwyer , Claudiu V Schirda , Anna M Malagoni , David Hojnacki , Cheryl Kennedy , Ellen Carl , Niels Bergsland , Christopher Magnano , Ilaria Bartolomei , Fabrizio Salvi  and Robert Zivadinov

    Full Article: http://www.biomedcentral.com/content/pdf/1741-7015-9-22.pdf

    Source: BMC Medical © 1999-2011 BioMed Central Ltd (09/03/11)

    Conflicting CCSVI/MS data lead to call for new research

    CCSVI VenogramMultiple sclerosis patients and endovascular interventionalists were elated when Italian researchers reported in 2009 that they had found evidence of chronic cerebrospinal venous insufficiency in nearly every MS patient they had studied and that in many cases, balloon angioplasty and sometimes stent placement of central thoracic veins reduced or eliminated signs of the disease.

    Neurologists, on the other hand, suggested that hope might be eclipsing reason in the rush to advocate the vascular procedure, given the single-center study’s small sample size and nonrandomized, uncontrolled design.

    The opposing perspectives incited an apparent turf war within the MS community fueled by a firestorm of accusations, with both sides going for the jugular, according to Dr. Jack Burks, chief medical officer of the Multiple Sclerosis Association of America. At issue, he said, is the validity not only of the study results but also of the underlying hypothesis that toxic iron overload in the brain due to chronic cerebrospinal venous insufficiency (CCSVI) might have a primary role in the pathogenesis of MS – a hypothesis that contradicts the compelling body of evidence suggesting that MS is primarily an autoimmune condition.

    On one side of the debate are the MS patients and endovascular interventionalists, dubbed the "liberators" by Dr. Burks because of their unflappable advocacy for what has become known as the liberation procedure – the endovascular surgery designed to open the lesions causing the venous insufficiency, he said. On the other side are the neurologists and MS societies, whom he lightheartedly calls the CCSVI nihilists because of their outspoken criticism of the surgery in the absence of more robust, conclusive scientific evidence.

    "Neurologists believe the interventionalists are overstating the possible value of CCSVI and that commercial interests are overriding scientific inquiry," according to Dr. Burks, a neurologist and clinical professor of medicine at the University of Nevada, Reno. Patients, armed with anecdotal evidence downloaded from the Internet, are certain that CCSVI surgery is the miracle they’ve been waiting for and perceive the hesitancy of U.S. and Canadian neurologists to embrace the treatment as evidence of a possible conspiracy with pharmaceutical companies who stand to lose billions of dollars if the surgery becomes a first-line treatment, he said. Further, he noted, advocates of CCSVI claim that neurologists who refuse patients’ demands for diagnostic testing and surgical referral for CCSVI are jeopardizing the safety of those patients, who are traveling to foreign countries such as Poland, Bulgaria, Mexico, Costa Rica, and India to get the care that they cannot receive in North America.

    Both camps point to the much publicized case of a Canadian MS patient who traveled to Costa Rica for jugular vein angioplasty and died from a ruptured vessel as evidence that supports their respective positions, said Dr. Burks.

    To date, the majority of the evidence regarding CCSVI diagnosis and treatment in MS is inconsistent, and can be confusing, Dr. Burks noted. In the initial study, Dr. Paolo Zamboni of the University of Ferrara in Italy, and colleagues, used Doppler ultrasound to examine venous drainage of the brain and spinal cord in 65 patients with different types of MS and 235 controls without MS and observed abnormal venous flow in all of the MS patients and none of the controls. The patterns of venous obstruction differed depending on MS stage and course, although there was no apparent relationship between disease severity and extent of venous obstruction, and MS treatment status did not influence the signs of CCSVI in any of the patients, the authors wrote (J. Neurol. Neurosurg. Psychiatry 2009;80:392-9).

    The researchers went on to conduct an open pilot study to determine whether percutaneous transluminal angioplasty could safely and effectively treat the narrowing of the extracranial cerebrospinal veins in the 65 MS patients in which the condition was observed – 35 with relapsing-remitting MS, 20 with secondary progressive MS, and 10 with primary progressive MS. They reported significant improvements in MS clinical outcome measures, significant reductions in new brain lesions on MRI, and significant reductions in the number of relapses experienced by some of the patients.

    The findings were limited, however, not only by the study design, but also by the fact that patients remained on their disease-modifying antirheumatic drug therapy during the study period and the timing and type of MRI scans varied among the patients, according to the authors. They also noted that restenosis of the internal jugular veins occurred in nearly half of the patients (J. Vasc. Surg. 2009;50:1348-58).

    Since the initial paper, a number of CCSVI studies of various designs have been undertaken, with contradictory results. Following are some of the investigations reported within the past year:

    • Researchers at the University of Buffalo found that up to 62% of the 280 patients with MS enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation study – the first randomized clinical trial to evaluate MS patients for CCSVI – had the characteristic narrowing of the extracranial veins compared with approximately 22% of 220 healthy controls. While the results, which were reported at the annual meeting of the American Academy of Neurology, did not establish causation, they showed "that narrowing of the extracranial veins, at the very least, is an important association in multiple sclerosis," principal investigator Dr. Robert Zivadinov said in a statement. He acknowledged that the finding of vascular narrowing in nearly a quarter of the healthy controls warranted additional investigation.

    • In an open-label study of extracranial Doppler criteria of CCSVI in 70 MS patients in Poland – 49 with relapsing-remitting MS, 5 with primary progressive MS, and 16 with secondary progressive MS – investigators detected at least two of four extracranial criteria in 90% of the patients. They concluded that, while the extracranial abnormalities could exist in various combinations, "the most common pathology in our patients was the presence of an inverted valve or another pathologic structure [like membranaceous or netlike septum] in the area of junction of the [internal jugular vein] with the brachiocephalic vein" (Int. Angiol. 2010;29:109-14).

    • A comparison of the internal jugular vein hemodynamics and morphology in 25 patients with MS and 25 controls identified abnormal findings in 92% of the MS patients and 24% of the controls, and evidence of CCSVI in 84% of the MS patients and none of the controls, leading the investigators to conclude that both hemodynamic abnormalities and morphologic changes in the internal jugular vein "are strongly associated with MS" (Int. Angiol. 2010;29:115-20).

    • An extended extra- and transcranial color-coded sonography study in 56 MS patients and 20 controls detected no internal jugular vein stenosis and normal blood flow direction in all but 1 patient. There were no between-group differences in intracranial veins and during Valsalva maneuver, and none of the patients fulfilled more than one CCSVI criterion, according to the authors. They concluded that their findings "challenge the hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of MS" (Ann. Neurol. 2010;68:173-83).

    • Swedish investigators used phase-contrast MRI to study 21 relapsing-remitting MS patients and 20 healthy controls and found no differences in internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux between the two groups. Although contrast-enhanced MR angiography showed internal jugular vein stenosis in 3 of the 21 MS patients, the authors stated they found no evidence "confirming the suggested vascular multiple sclerosis hypothesis" (Ann. Neurol. 2010;68:255-9).

    • The authors of an MR venography and flow quantification study in The Netherlands compared the intracranial and extracranial venous anatomy and the intracerebral venous flow profiles of 20 MS patients and 20 age- and gender-matched controls, with image analysis performed by blinded interventional neuroradiologists. They identified venous system anomalies in 50% of the MS patients and 40% of the healthy controls and no venous backflow in either group. "Given the normal intracranial venous flow quantification results, it is likely that these findings reflect anatomical variants of venous drainage rather than clinically relevant venous outflow obstructions," the authors wrote (J. Neurol. Neurosurg. Psychiatry 2010 Oct. 27 [doi: 10.1136/jnnp.2010.223479]).

    • Italian researchers investigating the occurrence of CCSVI in 50 consecutive patients with clinically isolated syndromes suggestive of MS reviewed the patients’ extracranial and transcranial venous echo-color Doppler sonographs and compared the findings to those of 50 age- and gender matched healthy controls as well as those of 60 patients with transient global amnesia (TGA) and 60 healthy controls matched to the TGA patients. They found extracranial Doppler sonographic abnormalities in 52% of patients with possible MS, 68.3% of patients with TGA, and 31.8% of the healthy controls. While eight of the patients with possible MS fulfilled the CCSVI criteria, selective phlebography showed no venous anomalies in seven of them. The authors concluded that there was no evidence of CCSVI at MS onset but recommended further studies to "clarify whether CCSVI is associated with later disease stages and characterizes the progressive forms of MS" (Ann. Neurol. 2011;69:90-99).

    Not only do the findings of this study challenge the hypothesis that CCSVI plays a role in the pathogenesis of MS, they suggest that some patients may be getting unnecessary surgery, according to lead author Dr. Claudio Baracchini of the University of Padua, Italy. "The few patients [in this study] with venous anomalies suggesting a CCSVI pattern had normal cerebral venous hemodynamics and all of the patients who underwent selective venography had predominantly normal findings," he said in an interview. For such patients, the surgery is "unjustified and associated with unnecessary risk," he stressed.

    Despite the media focus on the professional divide sparked by the CCSVI controversy, most in the scientific community agree that more research is needed before interventional surgery for CCSVI can be routinely recommended.

    In a position statement, the Society of Interventional Radiology stated that at present, the published literature is "inconclusive on whether CCSVI is a clinically important factor in the development and/or progression of MS, and on whether balloon angioplasty and/or stent placement are clinically effective in patients with MS" (J. Vasc. Interv. Radiol. 2010;21:1335-7).

    Additionally, in a commentary on the treatment of CCSVI, representatives of the Cardiovascular and Interventional Radiological Society of Europe acknowledged that although several centers worldwide are promoting and performing balloon dilatation, with or without stenting for CCSVI, "no trial data are available, and there is currently no randomized controlled trial [RCT] in progress." Further, anecdotal evidence and patient testimonies on the Internet are not a sound basis to offer a new treatment "which could have possible procedure-related complications to an often desperate patient population," they wrote. "We believe that until real scientific data are available for CCSVI and balloon dilatation, this treatment should not be offered to MS patients outside of a well designed clinical trial" (Cardiovasc. Intervent. Radiol. 2011;34:1-2).

    Toward that end, the National Multiple Sclerosis Society of the United States and the MS Society of Canada have pledged $2.4 million in support of seven CCSVI research studies, including projects designed to evaluate venous abnormalities in children and teens with MS, patients with early and late stage MS, and those at risk for MS. An international review panel comprising radiologists, vascular surgeons, and neurologists evaluated research applications via an expedited review process and chose those that "combined the strongest science with the research goals necessary to most quickly determine the scope and meaning or reported abnormalities in blood drainage from the brain and spinal cord in MS," according to the societies. "It is hoped these findings will provide clarity regarding the need for next-step therapeutic trials to correct such blockages as MS societies around the world pursue this CCSVI lead."

    In a presentation at the annual International Symposium of Endovascular Therapy in January, Dr. Burks outlined the critical issues related to crafting a united CCSVI message with multidisciplinary support, which include the best CCSVI diagnostic tests and outcomes; treatment standards and successful outcomes; diagnostic criteria; standards for qualified CCSVI specialists and treatment centers; uniform institutional review board requirements; standards, by discipline, for follow-up care; and criteria for retreatment and procedural standards.

    Additionally, "we need to establish a CCSVI patient registry that documents outcomes and adverse events, as well as other relevant data, and disseminate that document widely to all groups," Dr. Burks said. Doing so will go far toward mending the fractious community and directing energy toward optimal patient care, he stated.

    Dr. Burks disclosed financial relationships with Acorda, Allergan, Avanir, Bayer, Biogen Idec, Novartis, and Serono. Dr. Baracchini disclosed having no relevant financial relationships.

    Source; Internal Medicine News  Copyright © 2011 International Medical News Group, LLC. (17/02/11)

    Study suggests CCSVI not associated with HLA DRB1*1501 status in MS patients

    CCSVI VenogramAbstract

    Background
    Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients.

    Methodology/Principal Findings
    This study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR = 4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group. The 51.9% frequency of HLA DRB1*1501 positivity (HLA+) in MS was higher compared (OR = 2.33, p<0.001) to 31.6% to controls. The HLA+ frequency in the non-progressive (51.6%) and progressive MS groups (52.3%) was similar. The frequency of HLA+ CCSVI+ was 40.7% in progressive MS, 27.5% in non-progressive MS and 8.4% in controls. The presence of CCSVI was independent of HLA DRB1*1501 status in MS patients.

    Conclusions/Significance
    The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS.

    Full Paper - http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016802

    Bianca Weinstock-Guttman1, Robert Zivadinov1,2, Gary Cutter3, Miriam Tamaño-Blanco4, Karen Marr2, Darlene Badgett4, Ellen Carl 2, Makki Elfadil2, Cheryl Kennedy 2, Ralph H. B. Benedict1, Murali Ramanathan1,4*
    1
    Department of Neurology, State University of New York, Buffalo, New York, United States of America, 2Department of Neurology, Buffalo Neuroimaging Analysis Center, State University of New York, Buffalo, New York, United States of America, 3Department of Biostatistics, University of Alabama, Birmingham, Alabama, United States of America, 4Department of Pharmaceutical Sciences, State University of New York, Buffalo, New York, United States of America

    Source: PLoS One (15/02/11)

    Iron and neurodegeneration in Multiple Sclerosis

    Iron Deposits In BrainAbstract

    Increased iron deposition might be implicated in multiple sclerosis (MS). Recent development of MRI enabled to determine brain iron levels in a quantitative manner, which has put more interest on studying the role of iron in MS.

     Evidence for abnormal iron homeostasis in MS comes also from analyses of iron and iron-related proteins in CSF and blood and postmortem MS brain sections. However, it is not yet clear if iron accumulation is implicated in MS pathology or merely reflects an epiphenomenon.

    Further interest has been generated by the idea of chronic cerebrospinal venous insufficiency that might be associated with brain iron accumulation due to a reduction in venous outflow, but its existence and etiologic role in MS are currently controversially debated.

    In future studies, combined approaches applying quantitative MRI together with CSF and serum analyses of iron and iron-related proteins in a clinical followup setting might help to elucidate the implication of iron accumulation in MS.

    Full Article - http://www.hindawi.com/journals/msi/2011/606807.html

    Michael Khalil,1,2 Charlotte Teunissen,2 and Christian Langkammer1

    1Department of Neurology, Medical University of Graz, A-8036 Graz, Austria
    2NUBIN, Department of Clinical Chemistry, VU University Medical Center, 1007MB Amsterdam, The Netherlands

    Source: Multiple Sclerosis International Copyright © 2011 Hindawi Publishing Corporation (15/02/11)

    Small study suggests CCSVI may not be involved in MS

    CCSVI VenogramAbstract
    Background Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system, believed to be triggered by an autoimmune reaction to myelin. Recently, a fundamentally different pathomechanism termed ‘chronic cerebrospinal venous insufficiency’ (CCSVI) was proposed, provoking significant attention in the media and scientific community.

    Methods
    Twenty MS patients (mean age 42.2±13.3 years; median Extended Disability Status Scale 3.0, range 0–6.5) were compared with 20 healthy controls. Extra- and intracranial venous flow direction was assessed by colour-coded duplex sonography, and extracranial venous cross-sectional area (VCSA) of the internal jugular and vertebral veins (IJV/VV) was measured in B-mode to assess the five previously proposed CCSVI criteria. IJV-VCSA≤0.3 cm2 indicated ‘stenosis,’ and IJV-VCSA decrease from supine to upright position ‘reverted postural control.’ The sonographer, data analyser and statistician were blinded to the patient/control status of the participants.

    Results
    No participant showed retrograde flow of cervical or intracranial veins. IJV-VCSA≤0.3 cm2 was found in 13 MS patients versus 16 controls (p=0.48). A decrease in IJV-VCSA from supine to upright position was observed in all participants, but this denotes a physiological finding. No MS patient and one control had undetectable IJV flow despite deep inspiration (p=0.49). Only one healthy control and no MS patients fulfilled at least two criteria for CCSVI.

    Conclusions
    This triple-blinded extra- and transcranial duplex sonographic assessment of cervical and cerebral veins does not provide supportive evidence for the presence of CCSVI in MS patients. The findings cast serious doubt on the concept of CCSVI in MS.

    Christoph A Mayer1, Waltraud Pfeilschifter1, Matthias W Lorenz1, Max Nedelmann2, Ingo Bechmann3, Helmuth Steinmetz1, Ulf Ziemann1

    1Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany
    2Department of Neurology, Justus-Liebig-University Giessen, Giessen, Germany
    3Institute of Anatomy, University of Leipzig, Leipzig, Germany

    Source: J Neurol Neurosurg Psychiatry doi:10.1136/jnnp.2010.231613 Copyright © 2011 by the BMJ Publishing Group Ltd.(07/02/11)

    No evidence of chronic cerebrospinal venous insufficiency at MS onset

    CCSVI VenogramAbstract
    Objective
    An impaired cerebrospinal venous drainage, defined as chronic cerebrospinal venous insufficiency (CCSVI), has been recently hypothesized to be the possible cause of multiple sclerosis (MS). We investigated this hypothesis by studying the occurrence of CCSVI in clinically isolated syndromes (CISs) suggestive of MS.

    Methods
    Fifty consecutive patients presenting with a CIS and evidence of dissemination in space of the inflammatory lesions (ie, possible MS [pMS]) underwent a detailed diagnostic workup, including extracranial and transcranial venous echo-color Doppler sonography (ECDS-TCDS). Those with CCSVI underwent selective venography. Fifty healthy subjects (HCs) age-matched and gender-matched with pMS patients (HC1); 60 patients with transient global amnesia (TGA); and 60 healthy subjects age-matched and gender-matched with TGA patients (HC2) constituted the control groups and underwent ECDS-TCDS.

    Results
    Mean age of pMS patients was 33.0 ± 8.5 years (range, 14–50); 35 (70%) were female (female:male ratio, 2.3). TCDS was normal in all pMS patients. One or more abnormal ECDS findings were observed in 26 of 50 (52.0%) pMS patients, in 35 of 110 (31·8%) HCs (HC1+HC2), and in 41 of 60 (68.3%) TGA patients. Eight (16%) pMS patients fulfilled the diagnosis of CCSVI. Selective phlebography performed in 7 of these patients (1 denied consent) did not show venous anomalies.

    Interpretation
    Our findings do not support a cause-effect relationship between CCSVI and pMS. Further studies are warranted to clarify whether CCSVI is associated with later disease stages and characterizes the progressive forms of MS.

    Source: Ann Neurol 2011;69:90–99.(01/02/11)

    First 6 month report on CCSVI & MS research released

    CCSVI VenogramSummary
    Six-month progress reports from seven multi-disciplinary teams investigating CCSVI (chronic cerebrospinal venous insufficiency) in MS indicate that they have established rigorous protocols, are successfully recruiting participants, and are on-track to evaluate and deliver important data when the two-year projects are completed.

    All seven studies are two years in length but will be closely monitored while in progress in order to expedite clinical trials should the data show it is warranted. 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).

    Details
    Most of the teams have received approval to begin their studies from the required Institutional Review Boards in the U.S. or the Research Ethics Board in Canada, a required first step established by regulatory authorities to protect human subjects involved in research projects.

    Already more than 200 people have undergone scanning with various imaging technologies being used by the studies, including the Doppler ultrasound technology originally used by Dr. Paolo Zamboni and his collaborators, as well as magnetic resonance studies of the veins (MR venography), catheter venography, MRI scans of the brain, and clinical measures.

    Owing to the significant interest in the MS community about CCSVI, we are providing 6-month updates rather than the more standard 12-month reporting cycle. Because the studies employ rigorous blinding and controls designed to attain objective and comprehensive data, the full results of the ongoing research will be available only after significantly more scans have been completed and evaluated. They will collectively involve more than 1300 people representing a spectrum of MS types, severities and durations, as well as individuals with other disease types and healthy controls.

    “We are pleased with the progress reported by the research teams we have funded,” advised Dr. Tim Coetzee, chief research officer at the National MS Society, “and look forward to providing as quickly as possible the understanding and answers these projects reveal on the relationship between CCSVI and the MS disease process.”

    Jon Temme, senior vice-president of research and programs for the MS Society of Canada concurs, “The grants were selected for having the greatest potential to quickly and comprehensively determine the significance of CCSVI in the MS disease process. It is very encouraging to see how effectively the work has advanced among all groups.”

    The funded investigators, which include an integration of both MS and vascular experts, report progress in establishing their teams, putting their protocols in place, recruiting participants and beginning their studies, as summarized below. 

    Dr. Brenda Banwell, The Hospital for Sick Children, Toronto, Ontario: Her team received Research Ethics Board approval in the fall and has begun enrolling participants and studying vein abnormalities in children and teenagers who have MS, and healthy controls of the same age, using non-invasive MRI measures of vein anatomy and novel measures of venous flow, as well as ultrasound. The team’s ultrasound experts have received training in Dr. Zamboni’s original techniques. Read details of Dr. Banwell’s plans.
    Dr. Fiona Costello, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta: Her team received Research Ethics Board approval in the fall to begin recruiting a cross-section of people with MS compared to other neurological diseases and healthy volunteers. They also recruited two ultrasonography experts who have begun ultrasound scanning as originally used by Dr. Zamboni. Dr. Costello’s team slowed recruitment briefly to upgrade to a new 3T MRI machine (twice as strong as standard clinical MRI) that will be used to perform MR venography scans to compare against the ultrasound tests.

    Dr. Aaron Field, University of Wisconsin School of Medicine and Public Health, Madison: His team will be using MR venography and ultrasound techniques originally used by Dr. Zamboni to investigate CCSVI in people with early and later MS, controls with other conditions and healthy volunteers. A study coordinator is developing a recruitment list and an ultrasound expert has been hired and is slated to receive training in the Zamboni techniques. Dr. Field has been negotiating with the Institutional Review Board on issues related to study details and informed consent, and hopes to have these issues resolved to obtain IRB approval in the coming weeks so that scanning can begin.

    Dr. Robert Fox, Cleveland Clinic, Cleveland: His team has received Institutional Review Board approval for using MR venography, ultrasound, MRI and clinical measures in people with MS or who are at risk for MS (CIS) and comparison groups, and recruitment is ongoing. Two ultrasound researchers underwent training in the technique originally used by Dr. Zamboni, and the team has obtained a new ultrasound machine previously used in other CCSVI studies. The ultrasound team found several aspects of the published methodology ambiguous, and they have standardized the protocol and analysis to achieve consistent results. To share ideas and solutions to these methodological challenges, Dr. Fox’s team has submitted an abstract for consideration for presentation at the American Academy of Neurology’s annual meeting in April.

    Dr. Carlos Torres, The Ottawa Hospital, University of Ottawa, Ontario: His team obtained Research Ethics Board approval in the winter and at once began the first phase of scanning using MR venography in people without MS, which will be used to compare with various scans in people with MS. Dr. Torres’s team has overcome several obstacles including negotiating with the Research Ethics Board over elements of the informed consent form used to explain the study’s procedures and potential outcomes to participants. Team members are slated to be trained using the ultrasound techniques originally used by Dr. Zamboni, and they are on track recruiting more participants for the study.

    Dr. Anthony Traboulsee, UBC Hospital MS Clinic, UBC Faculty of Medicine and Dr. Katherine Knox, Saskatoon MS Clinic, University of Saskatchewan: The teams at both sites have received Research Ethics Board approval and have begun to recruit and scan participants. Their ultrasound technologists were trained by Dr. Zamboni, and they are also using catheter venography and MR venography to investigate the prevalence of CCSVI in people with MS and controls without MS. The radiologists on the teams of Drs. Traboulsee and Knox are meeting in February 2011 to ensure the consistency of their protocols across sites. The teams are on target for accrual of recruits and completion of the study.

    Dr. Jerry Wolinsky, University of Texas Health Science Center at Houston: His team applied in advance and obtained Institutional Review Board approval in the spring, and the team’s neurosonographer has received intensive training for intracranial and extracranial ultrasound scanning techniques. The team has already scanned a significant number of participants, which includes people with different types of MS, people with other conditions, and people with no known health problems. One obstacle Dr. Wolinsky’s team is addressing is the difficulty of recruiting non-MS control subjects who don’t have a personal interest in the purpose of the trial. The team is testing whether other imaging methods can confirm the ultrasound findings, while identifying the most reliable technique to screen for CCSVI.

    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 grants were selected for having the greatest potential to quickly and comprehensively determine the significance of CCSVI in the MS disease process. The teams are now established and scanning procedures are underway at all but one of the study sites. Researchers have demonstrated a clear willingness to share technical advice and information so that projects can move forward as smoothly as possible. At this six-month milepost they are making significant progress on plans for these two-year studies.

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

    Source: MS Society Of Canada (01/02/11)

    Controversial MS treatment lessens fatigue, research shows

    CCSVI VenogramMultiple sclerosis (MS) patients may get some relief from severe fatigue from an experimental procedure to open blocked blood vessels in the chest and neck, suggests preliminary Stanford University research being presented at the 23rd annual International Symposium on Endovascular Therapy (ISET).

    A year after doctors used either angioplasty or stents to open blocked veins of 30 MS patients, they suffered about half the fatigue, on average, than they had before the treatment, according to data being presented by Michael Dake, M.D., Thelma and Henry Doelger Professor in the Department of Cardiovascular Surgery at Stanford University School of Medicine in Stanford, Calif. Patients with the most common type of MS – relapsing-remitting – benefitted most.

    Treatment for chronic cerebrospinal venous insufficiency (CCSVI) is controversial, with some doctors doubting the existence of the condition. Stanford and the Baptist Cardiac & Vascular Institute in Miami, plan to begin a trial in 2011 to assess the condition and treatment with angioplasty. “If a person has MS and has a blood vessel obstruction, and if it’s removed, we will look at whether we can we demonstrate objectively that there is improvement in blood flow,” Dr. Dake said.

    The ISET meeting will feature several presentations on CCSVI. Among the featured speakers are Paolo Zamboni, M.D. of the University of Ferrara, Italy, a vascular surgeon who first proposed and is now testing the theory. Also speaking: patient advocates, skeptics, U.S. and Canadian doctors who provide the therapy, and James F. Benenati, M.D., president of the Society of Interventional Radiology.

    About 400,000 Americans are affected by MS, which can be extremely debilitating, causing problems ranging from numbness and blurred vision to extreme fatigue and paralysis. The symptoms can come and go or become progressively worse.

    Dr. Zamboni theorizes that abnormal blood flow can damage the nervous system and lead to MS. He reported initial results in 2009, suggesting the existence of CCSVI and that endovascular treatment relieved some MS symptoms and improved quality of life in certain MS patients. No U.S. studies have been published.

    Source: Business Wire ©2011 Business Wire (17/01/11)

    Research groups can submit MS 'liberation' treatment clinical trial plans

    CCSVI VenogramResearch groups that want to conduct clinical trials of the "liberation" procedure for multiple sclerosis can now submit their plans for consideration, as Saskatchewan takes another step toward testing the unproven treatment.

    The Saskatchewan Health Research Foundation (SHRF) on Friday issued a formal call for proposals, which looks to answer the question of whether the liberation procedure "is a safe and effective treatment for MS patients to relieve symptoms and improve quality of life."

    The Saskatchewan government has pledged $5 million to finance clinical trials of the procedure, which involves angioplasty to open veins in the neck.

    Researchers need to meet a number of requirements to be eligible for potential funding, including that at least a portion of the research team be from Saskatchewan, the SHRF said.

    "For us, it's really an exciting stage. We've worked really hard with our advisory panel on this call for proposals and we hope that it inspires some really great researchers to put together proposals that will go forward and lead us to the clinical trials," said SHRF chief executive June Bold.

    The SHRF notes that while the focus of the proposal is to achieve MS liberation treatment trials, there may need to be a "multi-stage approach."

    "The reason we phrased it that way is because the science is changing pretty quickly. As the researchers who were funded to do diagnostic and imaging work move forward and some of their results start to be known, that can be factored in as the researchers who we'll be supporting with this funding develop their proposals," Bold said.

    The funding provided by Saskatchewan needs to focus on Saskatchewan patients, but the SHRF said research teams "are welcome to include partners with funding in order to potentially expand the study to include patients from other jurisdictions."

    With pressure mounting from MS patients who want the procedure, the Alberta government earlier this week promised to spend $1million for an observation study and to fund clinical trials if it believes the treatment is safe.

    The procedure is based on the hypothesis of Italian Dr. Paolo Zamboni that some MS cases are linked to blockages in veins carrying blood away from the brain.

    While it's not performed in Canada, that hasn't stopped an untold number of MS patients from travelling out of the country to receive the liberation procedure.

    The SHRF said letters of intent outlining intended proposals must be submitted by Jan. 31. Full proposals are due March 28.

    A scientific peer review is to be completed by mid-April, with funding decision announcements to follow in late April.

    "The successful research team will begin its study as soon as all ethical and operational approvals are in place — ideally mid-to-late spring 2011," the SHRF said in a news release.

    Bold said a precise date for when clinical trials will be underway can't be pinned down at this point.

    "That will be up to the research team that's chosen," Bold said. "They'll put in place their plans and they'll have a process that they will set out and that's the time when we'll actually be able to say the starting point of the clinical trials. We're pretty clear in all our materials that it's a very high priority and we want that to be moving forward but we also want the researchers to be ensuring it's good scientific processes."

    The SHRF also stated in its news release that MS patients in Saskatchewan "will play an important role in this clinical trial" but cautionned that there is no list where patients can register their interest.

    "Patients are encouraged to watch for updates and announcements once the successful research team has been announced in 2011," the foundation said.

    Source: Leader Post © 2008 - 2010 Postmedia Network Inc (20/12/10)

    Alberta commits to study MS treatment

    CCSVI VenogramThe Alberta government will fund an observational study on the safety and effects of venous procedures, including the ‘Zamboni Treatment’, for people with multiple sclerosis (MS). The government is also committing to fund clinical trials if and when it is safe and ethical to proceed.

    “In my discussions with MS patients and advocates, researchers, neurologists and other medical experts, we agreed that an observational study would be very helpful,” said Health and Wellness Minister Gene Zwozdesky. “Our government is committed to help build the body of evidence that will provide a clear indication, one way or the other, about the safety and effectiveness of this new treatment. This study is an important step in that process.”

    The Alberta government will provide up to $1 million for the observational study, to be conducted by researchers from the University of Calgary, the University of Alberta, and other experts. The government has also committed to fund future clinical trials pending the results of the observational study, other research that is already underway, confirmation that the procedure has been deemed safe, and receipt of ethics approval.

    “This study is a response to the remarkable interest amongst MS patients in the new MS treatment proposed by Dr. Zamboni,” said Dr. Tom Feasby, Dean of the University of Calgary’s Faculty of Medicine. “It will help us understand the experiences of MS patients having this intervention, including any complications.”

    The goal of the observational study is to determine the safety and patient-reported impact of chronic cerebrospinal venous insufficiency (CCSVI) treatment procedures. The information will be used to determine whether to move forward with future clinical trials and to determine the followup care needs of Albertans who have received treatment for CCSVI. The venous procedures are not approved for use in Canada. 

    The three-year observational study will begin in spring 2011. Albertans who have received treatment for CCSVI in another country, those who are scheduled to receive it and other Albertans with MS will be eligible to participate.     

    In conjunction with the study, a secure MS research website and database will be developed where Albertans can volunteer and consent to participate in the study, as well as report on treatment they have received. 

    Becoming the Best: Alberta’s 5-Year Health Action Plan, was announced on Nov. 30, and provides Albertans with clear direction on what they can expect from their health care system over the next 5 years.

    Source:  Government of Alberta Copyright(C) 2010 Government of Alberta (17/12/10)

    Science only one factor in MS/CCSVI trials

    CCSVI VenogramA federal research body that dismissed a controversial multiple-sclerosis treatment as totally unproven likely undermined its credibility by failing to seek advice from the public and supporters of the therapy, two prominent medical scientists suggest.

    The researchers at Toronto's St. Michael's Hospital say the Canadian Institutes of Health Research should reach out to ordinary lay people -- not just scientists -- when pondering such emotional medical issues in future.

    A critique from Drs. Andreas Laupacis and Arthur Slutsky in the journal Open Medicine also hints that it might have been worthwhile for the institute to fund a trial of the MS treatment developed by Dr. Paulo Zamboni -- even if the science did not justify doing so.

    The expert panel the agency set up advised against a study until research first shows that Dr. Zamboni's theory about the cause of MS is correct, saying there was an "overwhelming lack of evidence" so far.

    "A number of Canadians are now using their own resources to travel to other countries to undergo endovascular treatment, performed by surgical teams whose quality standards are not always clear," said the authors. "Would these patients be better off, and policy makers and the public better informed, if a randomized trial were conducted now?"

    Dr. Laupacis stressed in an interview that he does not doubt that the expert panel reached the correct scientific conclusion about the Zamboni ideas, but said it was a rare medical-science case where other perspectives were needed, perhaps from a half-dozen "thoughtful" members of the public.

    Dr. Zamboni has theorized that narrowing of veins in the neck cause a backup of blood in the brain, leading to the damage to the organ's myelin coating that triggers MS. The Italian vascular surgeon's treatment involves using angioplasty -- the inflation of a tiny balloon -- to open up those narrowed veins.

    The head of the CIHR said Tuesday he was asked by the federal Health Minister to provide scientific advice on the issue, and gathered a panel of top-flight experts, from neurologists who treat MS patients to vascular surgeons normally do not.

    "The idea here was not to set up a tribunal, the pros and the cons," said Dr. Alain Beaudet. "The idea was to have the best experts in Canada and the U.S. who would give me an appraisal, as unbiased an appraisal as possible."

    The panel did include a member of the public -- an MS patient who asked not to be identified because of the tremendous pressure on sufferers to embrace the Zamboni hypothesis, he said.

    "Patients have been bullied, have been harassed. Patients who were in any way seen as not embracing fully the Zamboni procedure have really had trouble."

    As for including a supporter of the idea, Dr. Beaudet said the few doctors who do endorse it are not recognized "clinician-scientists" who get funding from major research agencies like the CIHR.

    Source: Calgary Herald Copyright (c) National Post (09/12/10)

    Endovascular treatment for CCSVI: is the procedure safe?

    CCSVI VenoplastyObjectives: The aim of this report is to assess the safety of endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI). Although balloon angioplasty and stenting seem to be safe procedures, there are currently no data on the treatment of a large group of patients with this vascular pathology.

    Methods: A total of 564 endovascular procedures (balloon angioplasty or, if this procedure failed, stenting) were performed during 344 interventions in 331 CCSVI patients with associated multiple sclerosis.

    Results: Balloon angioplasty alone was performed in 192 cases (55.8%), whereas the stenting of at least one vein was required in the remaining 152 cases (44.2%). There were no major complications (severe bleeding, venous thrombosis, stent migration or injury to the nerves) related to the procedure, except for thrombotic occlusion of the stent in two cases (1.2% of stenting procedures) and surgical opening of femoral vein to remove angioplastic balloon in one case (0.3% of procedures).

    Minor complications included occasional technical problems (2.4% of procedures): difficulty removing the angioplastic balloon or problems with proper placement of stent, and other medical events (2.1% of procedures): local bleeding from the groin, minor gastrointestinal bleeding or cardiac arrhythmia.

    Conclusions: The procedures appeared to be safe and well tolerated by the patients, regardless of the actual impact of the endovascular treatments for venous pathology on the clinical course of multiple sclerosis, which warrants long-term follow-up.

    T Ludyga *, M Kazibudzki *, M Simka * , M Hartel , M wierad *, J Piegza *, P Latacz *, L Sedlak * and M Tochowicz *
    * EUROMEDIC Specialist Clinics, Department of Vascular & Endovascular Surgery, Katowice;  Magnetic Resonance Imaging Department VOXEL, Medical University Hospital No 1, Zabrze, Poland

    Source: Phlebology Copyright © 2010, The Royal Society of Medicine Press (25/11/10)

    MS treatment trials getting under way in Newfoundland

    CCSVI VenogramA Newfoundland university has started recruiting participants for a study of a controversial multiple sclerosis treatment.

    Jerome Kennedy, Newfoundland’s Minister of Health and Community Services, announced his final approval on Wednesday for research to be conducted by Memorial University, which will receive $320,000 in provincial funding.

    The study will not allow patients to receive the so-called liberation procedure in Canada. Eight participants with MS will travel overseas at their own expense to undergo an angioplasty to open up blocked veins. Italian Paolo Zamboni suggested a year ago that MS might be caused by this blockage, or chronic cerebro-spinal venous insufficiency.

    A team of Newfoundland neurologists who specialize in MS will examine the participants before and after their treatments, along with patients who have not received angioplasties, to see if there has been any improvement.

    “Multiple sclerosis patients, their friends and families are hopeful that Dr. Zamboni’s procedure will be beneficial,” Mr. Kennedy said. “It is our hope that this study will play a role in determining the facts about this procedure, and ultimately, if proven effective, it will provide direction as to the next steps.”

    Earlier this week, Dr. Zamboni called on the federal government to allow Canadians to receive the procedure at home, following the death in October of Ontario MS patient Mahir Mostic.

    Source: The Globe & Mail © Copyright 2010 CTVglobemedia Publishing Inc (25/11/10)

    Benefits vs. risks of surgical intervention for MS patients

    CCSVI VenogramPaolo Zamboni, MD, professor of surgery at the University of Ferrara (Ferrara, Italy), was among the 430 presenters at the 37th annual VEITHsymposium™ held at the Hilton New York (New York, NY).

    In his November 18th discussion of multiple sclerosis patients who are experiencing decreased blood flow as a result of narrowing of specific veins of the head and thorax, Dr. Zamboni evaluated the risks of surgical intervention as opposed to the possible rewards. His summary was based on two recent pilot studies.

    Dr. Zamboni reported, "Narrowing of the veins in the head and neck has been found to be strongly associated with multiple sclerosis, a disabling neurodegenerative disease considered to be autoimmune in nature." As many as 56 to 100 % of MS patients experience narrowing of the veins of the head, neck or both. Multiple sclerosis is a neurodegenerative disease, meaning that it is a condition in which cells of the brain and spinal cord are lost," concluded Zamboni. Dr. Zamboni delivered a comprehensive overview of the actual status of the art of the diagnosis and treatment of this condition. The condition is confirmed using high-resolution ultrasound.

    In the first pilot study, patients were treated with angioplasty or stenting. Patients with narrowing in the vein in the thorax and those with narrowing of the vein in the head both showed significantly lower pressure in their veins after surgery. However, when retested after 18 months, only 53% among those with head vein narrowing had veins that remained cumulatively unobstructed was, while 96% among those whose neck veins had been narrowed were without obstruction.

    A second pilot study confirmed similar results. Follow-up of the first study revealed a significant reduction of chronic fatigue, one of the more debilitating symptoms of MS.

    Source: Medical News Today © 2010 MediLexicon International Ltd (19/11/10)

    CCSVI in focus at ECTRIMS: New data but still little clarity

    CCSVI VenogramNew data on the possible link between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS) have done little to clarify the relationship between these conditions, providing evidence both for and against the controversial hypothesis.

    What does seem clear now, though, is that the relationship, if there is one, is not as simple as it may have first appeared. New findings suggest, for example, that venous lesions may be more common in later stages of disease and so may be a consequence or comorbidity rather than a cause of MS.

    One of the issues appears to be differences in methods and imaging techniques in the cerebral venous system that mean researchers seem to be able to look at precisely the same images or data and settle on interpretations that are diametrically opposed.

    Even Paolo Zamboni, MD, director of the Vascular Diseases Center at the University of Ferrara, Italy, who first proposed the link, is now considering the hypothesis that the vast majority, but perhaps not all, cases of MS may relate to CCSVI.

    The state of knowledge on CCSVI, including new data from some of the leading researchers in this area, was the focus of a number of posters and presentations, as well as a symposium here at the recent 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

    A Matter of Assessment?

    The appealing idea that simple angioplasty of extracranial veins might cure or improve symptoms of this devastating disease caught the attention of highly educated and motivated MS patients late last year and has since engaged many in the unifying demand for access to what has been dubbed by some the "liberation procedure."

    Dr. Zamboni — who denies having called it the liberation procedure — and colleagues presented new data here and addressed some of his critics. At the packed Charcot Symposium dedicated to discussion of the topic at the outset of the meeting, he first emphasized what these venous lesions are and what they are not.

    "CCSVI is composed of several blockages in the main outflow routes, the jugular vein, azygous vein, but this is very important to understand," he said, displaying angiographic and high-resolution B-mode images along with a specimen, these blockages "are merely intraluminal defects; not problems in the wall, but intraluminal defects: webs, membranes, malformed valves."

    One important issue in this debate on CCSVI, he said, is how venous outflow from the brain is assessed and how these lesions are imaged. Veins can be apparent or not on imaging based on a number of factors, including supine vs upright postures, respiration, or the imaging modality, and it does appear that this has some bearing in the interpretation of the contribution CCSVI may or may not be making to MS.

    In his original article, Dr. Zamboni found 100% of MS patients had these abnormalities vs none of the controls (J Neurol Neurosurg Psychiatry. 2009;80:392-399). Since then, others have published prevalence studies, some suggesting a relationship and some not, but no other groups have found this complete separation between patients and controls on the basis of CCSVI.

    In 2 particularly widely reported papers published in the Annals of Neurology last August, investigators found no relationship between CCSVI and MS. Lead author of one of those reports, Florian Doepp, MD, from University Hospital Charité, Humbolt University in Berlin, Germany, discussed his findings at the symposium here and extended their work to include more patients (Ann Neurol. 2010;68:173-183).

    Using extra- and transcranial Doppler ultrasonography, he and colleagues analyzed extracranial blood volume flow, cross-sectional areas, flow in the internal jugular vein during the Valsalva maneuver, and CCSVI criteria in 56 patients with MS and 20 controls.

    Except for 1 patient, blood flow direction in the internal jugular veins and the vertebral veins was normal in all of the subjects, and no stenosis was seen in the internal jugular vein of any of them.

    Blood volume flow in both internal jugular and vertebral veins was equal between groups while subjects were in the supine position, they noted, but when subjects moved to the upright position, the decrease in total jugular blood volume flow was less pronounced in MS patients vs controls, leading to a significantly higher flow in that position.

    No difference was seen in veins between groups during the Valsalva maneuver, and none of the patients to date have met more than 1 of Dr. Zamboni's 5 criteria for CCSVI, Dr. Doepp and colleagues reported.

    However, others, including Dr. Zamboni, have interpreted these same findings by Dr. Doepp and colleagues as actually supporting the link between CCSVI and MS. An exchange of correspondence appeared recently in the Annals of Neurology, published online October 25, and some of these authors also took part in the Charcot Symposium here.

    In his letter, Clive Beggs, PhD, from the Center for Infection Control and Biophysics at the University of Bradford, United Kingdom, says that although the findings by Doepp and colleagues challenge the previous findings by Dr. Zamboni and colleagues with regard to the detection of venous reflux in patients, he writes that he "cannot agree with the main conclusion of the article; namely that the cerebral venous characteristics of MS patients are essentially no different than healthy controls."

    When the MS patients in the study were upright, he notes, the blood flow rate through the internal jugular veins was 2.5 times greater than controls, despite a similar cross-sectional area. Since blood flow through the vertebral veins was also "broadly similar, why then should a much greater proportion of the blood draining from the brain in the MS patients choose to flow through the [internal jugular veins] rather than through other extrajugular pathways?" Dr. Beggs writes.

    "The only plausible answer to this question is that, for some unknown reason, the resistance of the other extrajugular venous pathways must have greatly increased in the MS patients," he added. In short, there is, "something abnormal in the MS patients," Dr. Beggs said during the Charcot Symposium.

    In their response, Dr, Doepp and colleagues agreed that that particular finding requires further investigation. "Contrary to Dr. Begg's conclusions, however, we do not consider this finding to be suggestive of venous congestion," they write.

    "What he didn't explain is why the volume flow in the vertebral veins is exactly the same between patients and controls," Dr. Doepp told Medscape Medical News. "We know very well when we compress the deep neck veins we have an increase in blood flow in the vertebral veins. Therefore, it's not really logical."

    In addition, it is not clear why the blood volume flow was only different in the upright and not the supine position, "and you can't explain this by any flow disturbance in the neck veins," he said. "For this point we don’t have a clear explanation but at least our preliminary data from further patients say that this difference is not as high as it was presumed to be in our first study. So it's probably a side effect;... it's not really important."

    In a letter of his own replying to Dr. Doepp's article, Dr. Zamboni published a high-resolution B-mode image of an intraluminal septum and noted that this is the most frequent stenosing lesion seen in CCSVI in their work. These lesions can only be imaged, he says, with high-resolution probes that are capable of exploring the jugular in the supraclavicular fossa.

    Dr, Doepp's group, though, did not find frequent intraluminal jugular septation in their patients, Dr. Zamboni points out. "This underscores the urgency of establishing an internationally accepted protocol," he concludes. "In the attempt to achieve this cultural osmosis, my group is available to travel to Berlin and rescan with German colleagues the entire series by the means of the proposed methodology."

    Divergent Interpretation

    At the ECTRIMS meeting, another example of divergent interpretation of the same findings. Claudio Baracchini, MD, from the Department of Neurological Sciences at the University of Padua School of Medicine, Italy, presented a study looking at the prevalence of CCSVI in 50 patients with clinically isolated syndrome suggestive of MS and evidence of dissemination in space of lesions, called possible MS (pMS). Findings were compared with healthy controls and patients with transient global amnesia (TGA).

    Abnormal findings on extracranial venous sonography were seen in 26 of the 50 pMS patients (52%) but also in 32% of healthy controls and 68% of TGA patients. Eight of the pMS patients met criteria for CCSVI, and 7 of these underwent venography that was found to be normal in 6; the last patient was found to have hypoplasia of the internal jugular vein.

    "The results of our study do not support a cause-effect relationship between CCSVI and pMS," Dr. Baracchini told delegates here. "Importantly, any invasive endovascular therapeutic procedure, including angioplasty and stenting, is not only dangerous but presently unjustified in these patients."

    During the discussion, Dr. Baracchini noted that he went to Ferrara to view Dr, Zamboni's methods. "To me it was a must to go see how he worked," he said. Ultrasonography is not only operator dependent but is machine dependent, and Dr. Baracchini said he believes most of the discrepancies between Dr. Zamboni's findings and others' are due to the suboptimal machinery that Dr. Zamboni is using.

    However, he was challenged himself during the discussion period by an audience member who retorted that the image Dr. Baracchini had shown during his presentation as an example absent of disease actually showed obvious obstruction. "Did you know what to look for, is my question?" he said.

    Comorbid Factor

    Working initially with Dr. Zamboni on some of these papers, as well as a number of larger independent studies of CCSVI, is Robert Zivadinov MD, PhD, associate professor of neurology from the University of Buffalo, New York. The Buffalo group is currently pursuing a variety of different research directions, Dr. Zivadinov told Medscape Medical News, including prevalence studies, assessing which may be the best diagnostic tools, as well as associations with disease pathogenesis and clinical outcomes.

    Among their findings presented here are the following:

    •The researchers compared Doppler sonography and 2 magnetic resonance venography (MRV) techniques to the gold standard, catheter venography, in 10 subjects with MS and 10 healthy controls. They found "much better specificity and positive predictive value of Doppler to detect venous anomalies with respect to MRV," Dr. Zivadinov noted. "Our conclusion is Doppler is a better noninvasive tool than MRV."
    They suspect that power may be a key factor in explaining divergent findings from different data sets, he noted. In a previous report from the large Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study, presented at the American Academy of Neurology meeting in April and now in press, 56% of MS patients were found to have CCSVI vs 22% of controls, a statistically significant difference.

    In a new paper also in press, where they included only 57 patients and 21 controls studied with MRV, "we're finding only a trend toward a difference, and actually we are writing in that study that it's probably underpowered to detect it," Dr. Zivadinov said.

    Most of the other published studies, including that by Dr. Doepp and colleagues, for example, had 50 patients or fewer, he added. "So if we are really talking about a phenomenon that's not 100% to zero anymore [as Dr. Zamboni originally reported], then...most of the studies that have been published are probably underpowered."

    •Also using the CTEVD data set, the Buffalo researchers presented 3-T magnetic resonance imaging (MRI) results from 351 of the 499 subjects, showing the presence of CCSVI was associated with more advanced disease subtypes, seen in 89.5% of secondary progressive patients vs 49.2% of relapsing-remitting and 38.1% of clinically isolated syndrome (CIS) patients. The presence of CCSVI was also associated with higher lesion burden and brain atrophy in all study subjects but not in the individual study subgroups.
    •In 268 MS patients and 150 healthy controls again from CTEVD, they compared the association of CCSVI with an established genetic risk factor for MS, HLA DR*1501. They found for those with CCSVI, the odds ratio for MS patients vs controls was 4.5 vs 2.3 for the genetic risk factor.
    •Using susceptibility-weighted MRI, they found in 59 MS patients vs 33 healthy controls that patients with increasingly severe CCSVI had fewer veins in the brain parenchyma. "There are a number of different hypotheses, but probably the most important one is that the areas more distant from the occlusion are those getting most affected and we see less veins in the deep white matter and in the deep gray matter structures where most of the lesions are," he noted.
    •Finally, they showed that the more severe the CCSVI, the higher the iron deposition in the brain, thought to be the result in part of poorer venous drainage. In other studies not related to CCSVI, the Buffalo group has shown regions of higher iron accumulation in the brain were associated with loss of brain volume and higher clinical disability, he added, making measurement of iron concentration a potentially interesting biomarker in MS for new clinical trials.
    "So there is definitely an association of CCSVI with MS, at least in our datasets," Dr. Zivadinov said. "Our findings are consistent with an increased prevalence of CCSVI in MS but with modest sensitivity/specificity. Our findings point against CCSVI having a primary causative role in the development of MS," he added. "We are showing that CCSVI is connected to the progression of disease, but whether it is a cause of the progression or a consequence, we don't know at this time."

    A Contentious Issue

    Jeffrey Cohen, MD, from the Cleveland Clinic Foundation summed up the data presented here at ECTRIMS during his review of the meeting highlights at the end of the conference.

    "CCSVI, which continues to be a contentious issue, remained contentious at this congress, mostly because of the very conflicting results that are being presented," he said.

    "My read on the data from the Zamboni and Zivadinov groups is that it appears the incidence of venous abnormalities in fact increases over time; thus, patients with progressive MS have a higher incidence than those with relapsing-remitting MS, who have a higher incidence than those with CIS — so that already suggests that this is not a causative condition," Dr. Cohen said. "If there is in fact an association, it's a modifying factor; maybe a comorbidity or perhaps just reflects a normal aging phenomenon."

    Dr. Zamboni speculates that there may exist different types of MS that have slightly different origins leading to the similar disease outcome, of which only a proportion, although a large proportion in his view, may stem from these intraluminal abnormalities.

    Runaway Train

    During the last year, the CCSVI hypothesis has been the focus of worldwide attention and controversy. On one side are MS patients, many of whom have high and perhaps unrealistic expectations of what is a highly experimental and still singularly unstudied procedure, but who nevertheless have direct access to centers offering endovascular treatment for CCSVI via the Internet.

    On the other are highly sceptical neurologists who have seen quick-fix hypotheses for MS come and go and are concerned for their patients, an unknown number of whom are shelling out thousands of dollars of their own money for procedures at hospitals in India, Mexico, or Bulgaria with no formal neurologic follow-up.

    Some patients in their turn have suggested that neurologists are resisting this simple treatment because they are protecting their turf as prescribers of expensive drugs.

    The problem is that between them, these factions may obscure the potential of a hypothesis that, given the proper study, might at least provide some insight into MS mechanisms.

    "When I began this story I was aware that something like this might happen," Dr. Zamboni told Medscape Medical News. "I'm really determined to root this in science, or at least do my best."

    Simply, he said, he wants "to scientifically proceed with a rigorous randomized controlled trial in order to rapidly understand the value of the angioplasty in MS treatment, rather [than] perform treatments on patients out of any scientific and ethical control."

    Among the "disasters," he says, has been the rush for private practitioners to offer angioplasty procedures for gain and the lack of cooperation between specialties so that neurologists are involved in follow-up of these patients. Dr. Zamboni is clear — as he has in fairness been from the beginning — that the procedure should only be done in the context of randomized clinical trials with neurologic follow-up.

    Endovascular Treatment Results

    At this meeting, Dr. Zamboni and Dr. Zivadinov and colleagues presented results of a small pilot safety trial of endovascular treatment of venous lesions in patients with MS. A first small pilot study was published in December 2009 and reported by Medscape Medical News at that time (J Vasc Surg. 2009;50:1348-1358).

    In the current trial, called the EVTMS study, 15 patients with relapsing-remitting MS and evidence of CCSVI were enrolled and randomized to receive either immediate endovascular treatment (8 patients) or treatment delayed for 6 months (7 patients), and these were compared with 8 healthy controls.

    Treatment of significant stenosis was with angioplasty alone, and patients were prospectively followed up at 3, 6, 9, and 12 months with sonography, MRI (at 6 and 12 months), and clinical examination.

    No serious adverse events were seen, with the exception of 1 transitory vasovagal syndrome 1 hour after the intervention, they report.

    "No significant clinical or MRI differences have been seen, although there were less relapses in the immediate treatment group, 1 vs 4, and a decrease in T2 lesion volume in the immediate group, about 10%," Dr. Zivadinov noted. Restenosis did not occur in any of the azygous veins treated but was seen in 29% in the internal jugular veins.

    "I think based on this study that we can't say more than there is no deterioration of the patients who are getting this type of treatment, and we need to do more specific placebo-controlled trials to understand whether this treatment is useful or not, but I would add that no remarkable differences have been seen in this first study," he said.

    A second group, led by Marian Simka, PhD, from the Department of Vascular and Endovascular Surgery at EUROMEDIC Specialist Clinics in Katowice, Poland, also presented interventional data on a total of 587 endovascular procedures — 414 balloon angioplasties and 173 stent placements — in 347 MS patients, looking specifically at safety.

    They found no life-threatening complications, including no deaths, no major hemorrhage or cerebral stroke, and no instance of stent migration, as well as no injury to nerves. There were 2 stent thromboses, although they point out that because these occurred in a jugular vein that was not patent before the procedures, there was no likely clinical consequence.

    Other complications included 2 cases of postoperative false aneurysm successfully treated with thrombin injection, 1 surgery to open the femoral vein to remove a balloon, transient cardiac arrhythmia in 2 patients, 2 cases of minor bleeding from the groin, 1 minor gastrointestinal bleed, 1 postprocedure lymphatic cyst, and problems with removal or delivery of the catheter.

    "Regardless of the actual impact of the endovascular treatments for venous pathology on the clinical course of multiple sclerosis, which warrants more clinical studies and long term follow-up, these procedures appeared to be safe and well tolerated by the patients," Dr. Simka and colleagues concluded.

    In his highlights talk, Dr. Cohen mentioned both of these interventional studies, noting he was "gratified" to hear that all of these researchers agreed that endovascular procedures should only be done in the context of studies. "And I would add that those need to be legitimate studies," he stressed.

    However, Giancarlo Comi, MD, from Vita-Salute San Raffaele University in Milan, Italy, who acted as moderator for the Charcot Symposium, told Dr. Zamboni that in his view, it is still too early even for clinical trials until more is known about the link between these conditions.

    Dr. Zamboni told Medscape Medical News he disagrees that it is too soon for any such trials, arguing that there is no reason that investigation into the link between CCSVI and MS and clinical trials should not proceed as a "parallel process."

    Dr. Zivadinov compared it to any other novel treatment strategy. "If you have a molecule that's interesting, you test it in a clinical trial, right?" he says. "You don't know if it's going to work or not, so what we need to do is exactly what we are doing, which is to test the efficacy and safety in very small pilot studies and then, if there is something positive there, we should extend it to the bigger clinical trials. If it is not, we need to close the argument that endovascular treatment should be studied in MS."

    A solid answer on this question is needed by both the patient and physician community, Dr, Zivadinov added. "The currently ongoing placebo-controlled study in Buffalo, in collaboration with Department of Neurosurgery at the University of Buffalo, is aiming to answer this question and data should be available by the second part of 2011," he said. "We are against performing open-label endovascular treatment in patients with MS."

    Dr. Zamboni is also critical of those who would offer this procedure without evidence and in an effort to make money. "It is unethical to charge for an experimental procedure," he says bluntly.

    Large Market

    Still, the reality is that the potential pool of interventions to correct CCSVI in MS patients would be a large market, and the patients themselves are pushing hard for it.

    In the recent Annals of Neurology correspondence, Dr. Simka and colleague Marek Kazibudzki, PhD, responded to a previously published commentary by Omar Khan, MD, from Wayne State University School of Medicine in Detroit, Michigan, in which Dr. Khan and colleagues warned that stenting veins can result in serious injury and called for such "invasive and potentially dangerous interventions to be discouraged until further evidence of the connection between CCSVI and MS could be established" (Ann Neurol. 2010;67:286-290).

    In their reply, Dr. Simka and Dr. Kazibudzki point out that the Consensus Document of the International Union of Phlebology on Diagnosis and Treatment of Venous Malformations recommends that, for veins draining the brain and spinal cord, patients receive diagnostic testing, including duplex scanning and MRV, and treatment with angioplasty and stenting for proven obstructive lesions (Int Angiol. 2009;28:434-451).

    They also point to several lines of evidence supporting a link between venous abnormalities and MS.

    Dr. Khan and colleagues in turn respond that they find the letter by Dr. Simka and Kazibudzki to be "an attempt to legitimize the treatment of [CCSVI] with potentially dangerous endovascular procedures."

    They point out that the Polish group has "publicized CCSVI stenting for several thousand Euros per procedure," and they "question the ethics of such commercialization for a condition yet to be established, that is, CCSVI in MS, and exposing patients to a potentially dangerous procedure without any randomized, controlled studies."

    They add that "more recognized societies representing interventional radiology and neuroradiology," including the Society for Interventional Radiology (SIR), the American Society of Neuroradiology, and others, have not yet issued consensus statements on this topic.

    In the meantime, though, the SIR recently published a statement in the September issue of the Journal of Vascular Interventional Radiology, endorsed by the Canadian Interventional Radiology Association (J Vasc Interv Radiol. 2010;21:1335-1337). In it, the SIR recognizes what they call the "challenge and potential opportunity presented by promising early studies of an interventional approach to the treatment of MS."

    The society is moving rapidly to "catalyze" the studies needed, but currently considers the published literature "inconclusive on whether CCSVI is a clinically important factor in the development and/or the progression of MS and on whether balloon angioplasty and/or stent placement are clinically effective in patients with MS."

    These venous procedures, although they've been performed for years by interventional radiologists, are not without risk, the statement notes, and the durability of the procedure, or any impact of the placebo effect — that might be expected to be quite "robust" in MS patients — are presently unknown.

    Nevertheless, the position statement notes that, "when conclusive evidence is lacking, SIR believes these often difficult decisions are best made by individual patients, their families and physicians," a position that apparently leaves the door open for elective procedures.

    In a press release that accompanied the position statement, the SIR refers readers to their Website for more information about the society and "to find those interventional radiologists who provide endovascular treatment for CCSVI."

    Dr. Zamboni told Medscape Medical News he has been invited to participate in SIR's upcoming annual meeting and hopes to convince this group to collaborate with neurologists on multicenter trials. He feels the best role for SIR would be to refine the procedure. "I'd like them to improve this procedure because our results are not very good," he added, referring to the restenosis rates. "Their contribution could be more technical."

    Controversy in Canada

    In Canada, where the incidence of MS is among the highest in the world, the call for access to the procedure, or at least to trials of the procedure, has been at a fever pitch for months. Even small-town newspapers have run stories about local MS patients taking matters into their own hands, paying to get the procedure done, sometimes fundraising for themselves, and reporting various levels of symptomatic relief, such as reduced fatigue or less tingling in hands and feet.

    In online blogs and commentary, some patients seem to view this as a proven therapy that they are being denied, but others simply feel they should be allowed to have the procedure on a compassionate access basis given that so little is otherwise available to those with advanced disease.

    Recently, reports have begun to surface of patients developing complications after receiving intervention abroad. CBC News reported November 16 the case of an Alberta man who developed thrombosis near the stent after a procedure performed in Poland and reports he is having difficulty getting physicians to treat it because of the experimental nature of the procedure. The case is sparking discussion of who should pay to fix the complications from these elective procedures done abroad.

    After the Canadian federal government declined to fund trials in August, some provincial governments have now decided to do so. Saskatchewan, for example, announced October 19 some $5 million in funding for clinical trials. The Canadian MS Society also announced in September it has earmarked a further $1 million for therapeutic trials of angioplasty for these venous abnormalities once the evidence is sufficiently strong to support them.

    In July, 7 studies funded by $2.4 million from the National Multiple Sclerosis Society (NMSS) and the Canadian MS Society with the aim of establishing the prevalence of CCSVI in MS got under way at institutions across Canada and the United States. The 2-year grants went to the following:

    1.Brenda Banwell, MD, at the Hospital for Sick Children, Toronto, Ontario, Canada, who is looking at the occurrence of CCSVI in children and teenagers with MS vs health controls.
    2.Fiona Costello, MD, at the University of Calgary's Hotchkiss Brain Institute, Alberta, Canada, is using ultrasonography and MRV to look at the prevalence of CCSVI in MS patients and controls.
    3.Aaron Field, MD, at the University of Wisconsin School of Medicine and Public Health in Madison will use MRV in patients with early and advanced disease, as well as ultrasonography, to determine the prevalence of CCSVI.
    4.Robert Fox, MD, from the Cleveland Clinic in Ohio, will also use MRV and ultrasonography, as well as MRI, to compare those with MS or CIS to healthy controls and patients with brain atrophy from Alzheimer's disease. They are also obtaining neck and brain tissue at autopsy to evaluate CCSVI.
    5.Carlos Torres, MD, from Ottawa Hospital at the University of Ottawa, Ontario, Canada, is using 3-T MRI and Doppler ultrasonography to assess venous anatomy and iron deposits in 50 patients and 50 healthy controls.
    6.Anthony Traboulsee MD from the University of British Columbia (UBC) Hospital MS Clinic, UBC Faculty of Medicine, and Katherine Knox, MD, from the Saskatoon MS Clinic at the University of Saskatchewan, Canada, are studying the prevalence of CCSVI in those with MS and controls, comparing results using catheter venography, ultrasonography, and MRV. Included in the control group will be family members, including identical unaffected twins of those with MS. And finally,
    7.Jerry Wolinksy, MD, from the University of Texas Health Science Center in Houston, will also attempt to replicate Dr. Zamboni's ultrasonography methods, looking at the association of CCSVI in the major clinical types of MS as well as non-MS controls.

    "These studies are going to look in a variety of different ways both at the anatomy and function of the venous system," said NMSS Chief Medical Officer Aaron Miller, MD, professor of neurology and medical director of the MS Center at Mount Sinai Medical Center in New York City. "So they will not only use the same kind of technology that Dr. Zamboni used, but if they should find that that observation holds up, they will have additional information to tell us whether it's really physiologically meaningful; whether (CCSVI) actually alters venous flow."

    The Charcot Symposium was sponsored by the European Charcot Foundation, a nonprofit, independent organization in Europe sponsored by private organizations, MS societies, and industry.

    26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS): Abstracts P-318, P-265, P-508, 81, 82, P-914, P-773, P-653, P-641, P-663, P-774, and P-579. Presented October 13 – 16, 2010.

    Source: Medscape Today Copyright © 1994-2010 by WebMD LLC (18/11/10)

    Dr. Zamboni responds to the Doepp CCSVI study results

    CCSVI VenogramRegarding ‘‘No Cerebrocervical Venous Congestion in Patients with Multiple Sclerosis. Intraluminal Jugular Septation’’ Paolo Zamboni, MD
     
    I read with interest the article titled ‘‘No Cerebrocervical Venous Congestion in Patients with Multiple Sclerosis’’ by Doepp and coworkers.1 Contrary to their conclusions, I believe that the authors’ results are a further validation of venous flow irregularities in multiple sclerosis (MS) patients.

    One of the major regulators of cerebral venous outflow is posture, due to the gravitational gradient between the cerebral parenchymal veins and the base of the neck (␣30mmHg).The authors demonstrate a much larger change in blood flow volume in normal subjects compared to MS patients when the subjects go from a supine to an upright position. They find a change of 128ml/min and 56ml/min for the right and left sides, respectively, for MS patients. But they find a much larger change of 266ml/min and 105ml/min for their normal subjects. This result actually suggests the presence of chronic cerebrospinal venous insufficiency (CCSVI). Possible causes include intra-luminal septum, membrane, and immobile valve affecting the hydrostatic pressure gradient in the upright position. The presence of such blockages in the extracranial and extravertebral cerebral veins has been proven also by using catheter venography, the unquestionable gold standard in medicine.3,4

    There was a trend toward significance (0.06) when comparing the mean global cerebral blood flow (CBF) in MS patients with that in controls. However, the level of significance is under- estimated by the low control sample, 20 versus 56 patients. The reduction in CBF in MS, meaning in practical terms stasis, might become significant by simply increasing the control sample.

    Both the above-reported results correspond with the reduction in CBF and in cerebral blood volume with increased mean transit time, assessed by means of magnetic resonance imaging (MRI) perfusion study.5

    The authors failed to demonstrate CCSVI through the assessment of the criteria originally proposed by our group. However, it seems the latter were not precisely assessed. For instance, the authors exchange the parameter for defining stenosis we used in angiographic studies (>50% lumen reduction) with those used in Doppler ultrasonography. In addition, the frequent detection of intraluminal jugular septation is not described by the authors.

    The latter is the most common cause of flow blockage, and can only be diagnosed with high resolution ultrasonographic probes capable to explore the jugular in the supraclavicular fossa (Fig. 1) 3-4. Clearly, a complete understanding of the system is required before drawing conclusions about the lack of venous abnormalities, and this requires ultra- sound, MRI, and catheter venography. This underscores the urgency of establishing an internationally accepted protocol. In the attempt to achieve this cultural osmosis, my group is available to travel to Berlin and rescan with German colleagues the entire series by the means of the proposed methodology.

    High Resolution B-Mode image of internal jugular vein 


    FIGURE 1: High resolution B-Mode image of the internal jugular vein (IJV), in longitudinal access. An intraluminal septum/malformed valve (arrow) causing a significant stenosis, with flow block and increased resistance at the junction with the brachiocephalic venous trunk (BCT), is showed. Intraluminal septation is the most frequent stenosing lesion in course of CCSVI and does not involve the reduction of the vessel cross-sectional area. It can be detected by the means of a probe capable to explore the supraclavicular fossa.

    Potential Conflicts of Interest

    Nothing to report.

    Zamboni P.

    Vascular Diseases Center, University of Ferrara, Ferrara, Italy

    References

    1. Doepp F, Friedemann P, Valdueza JM, et al. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol 2010; DOI: 10.1002/ana.22085.

    2. Gisolf, J, van Lieshout JJ, van Heusden K, et al. Human cerebral venous outflow pathway depends on posture and central venous pressure. J Physiol 2004;560:317–327.

    3. Zamboni P, Galeotti R, Menegatti E, et al. A prospective open- label study of endovascular treatment of chronic cerebrospinal ve- nous insufficiency. J Vasc Surg 2009;50:1348–1358.

    4. Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392–399.

    5. Law M, Saindane AM, Ge Y, et al. Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter. Radiology 2004;231:645–652.

    DOI: 10.1002/ana.22152

    LETTER VC 2010 American Neurological Association 

    Source:  Annals of Neurology 2010 Nov 8 © 2010 American Neurological Association & Pubmed PMID: 21061390 (11/11/10)

    No association of abnormal cranial venous drainage with MS

    CCSVI VenogramAbstract
    Background Recent studies using colour-coded Doppler sonography showed that chronic impaired venous drainage from the central nervous system is almost exclusively found in multiple sclerosis (MS) patients. This study aimed to investigate the intracranial and extracranial venous anatomy and the intracerebral venous flow profile in patients with MS and healthy controls using magnetic resonance venography (MRV).

    Methods Twenty patients with definite MS and 20 age- and gender-matched healthy controls were examined. MR imaging was performed on a whole-body 3T MR system including both 3D phase-contrast and dynamic 3D contrast-enhanced MRV as well as flow quantification of the internal cerebral veins and the straight sinus. Image analysis was performed by two experienced interventional neuroradiologists blinded to clinical data and structural brain imaging. The intracranial and extracranial neck veins were analysed for stenosis/occlusion and alternative venous drainage pattern.

    Results A completely normal venous anatomy was observed in 10 MS patients and 12 controls. Anomalies of the venous system (venous stenosis/occlusions) were found in 10 MS patients and eight healthy controls. An anomalous venous system in combination with associated alternative venous drainage was observed in six MS patients and five healthy controls. Flow quantification showed no venous backflow in any MS patient or control.

    Conclusions Findings suggestive of anomalies of the cranial venous outflow anatomy were frequently observed in both MS patients and healthy controls. Given the normal intracranial venous flow quantification results, it is likely that these findings reflect anatomical variants of venous drainage rather than clinically relevant venous outflow obstructions.

    Mike P Wattjes1, Bob W van Oosten2, Wolter L de Graaf1, Alexandra Seewann2, Joseph C J Bot1, René van den Berg1,3, Bernard M J Uitdehaag2,4, Chris H Polman2, Frederik Barkhof1

    1Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands
    2Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands
    3Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands
    4Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands

    Source: Journal of Neurology, Neurosurgery & Psychiatry with Practical Neurology Copyright © 2010 by the BMJ Publishing Group Ltd.(01/11/10)

    Chronic cerebrospinal venous insufficiency and the doubtful promise of an endovascular treatment for MS

    CCSVI VenogramIntroduction
    Recently, a radically different concept regarding the pathogenesis of multiple sclerosis (MS) has been proposed. Termed chronic cerebrospinal venous insufficiency (CCSVI), it suggests that macro occlusive abnormalities of the extracranial venous drainage pathways of the brain and spinal cord can cause or contribute to MS.

    As a consequence of this theory, it has been suggested that angioplasty and possibly stenting of the internal jugular and/or azygos veins can improve the signs and symptoms of MS. These interventions have been performed sporadically across the globe in an open label fashion and never in the context of a well designed, controlled, randomized and blinded clinical trial.

    Despite this, the procedure has been labeled by some as ‘liberation procedure’ and caused a firestorm of interest in the medical and MS communities, both for and against its utilization. The arguments on all sides are passionate, ranging from the belief that venous intervention is a miracle cure that must not be withheld from patients, to the feeling that the procedure is ineffective and unwarranted at best and dangerous at worst. The various camps commonly protest that those with differing views are not acting in the best interest of their patients.

    As neurointerventionalists interested in interventional treatment of neurological disorders, it is time to take a thorough and objective look at CCSVI. This commentary will examine the origin of the CCSVI theory and discuss the data supporting and refuting its existence. An attempt will be made to critically analyze the available data and provide constructive recommendations about whether or not endovascular therapy represents a reasonable option at this point in time for patients with MS.

    Brief review of multiple sclerosis
    MS is a fearful and unpredictable disease that brings an enormous physical, emotional and financial burden on patients, family, relatives, friends and society in general. It is the most common cause of physical disability, with estimated 250 000–350 000 individual diagnosed with MS in the USA. The peak age at onset is 20–40 years. It affects women more so than men and is more common among Caucasians.

    MS can present with just about any neurological symptom in any part of the nervous system, sensory, motor, cranial nerves, visual, autonomic, coordination and myelopathic on different occasions with cumulative disability.1 Diagnosis is based on clinical and imaging criteria (McDonald criteria) to establish the dissemination in place (different CNS sites) and time (at least 30 days between clinical relapses and 90 days for new MRI lesion without clinical relapse). The clinical course of MS is most commonly relapsing remitting, with return to baseline after each relapse, followed by secondary progressive starting as relapsing remitting, then primary progressive MS.1

    The most prevalent hypothesis regarding the pathophysiological basis for MS is that it is an autoimmune inflammatory disease triggered by environmental factors (toxic and infectious triggers) with genetic predisposition leading to myelin and axonal destruction in the brain and spinal cord by the immune system.1 To date, MS management has been limited to the indefinite administration of ‘disease modifying’ medications and immune modulating agents which may reduce the number and severity of relapses.1 These agents are not only costly but are associated with a wide spectrum of side effects ranging from mild to severe.

    The CCSVI theory and supportive data
    In 2006, Zamboni, an Italian vascular surgeon, in an article titled ‘The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis’ suggested that there were similarities between chronic venous disease of the extremities and MS.2 He raised the possibility that venous reflux or obstruction in cerebral and spinal veins might have a relationship to MS.2

    Several years later, Zamboni et al reported on blinded transcranial and extracranial color Doppler sonographic findings in patients with MS and matched healthy controls and those with other neurological disorders.3 They focused on five findings: (1) reflux in the internal jugular vein (IJV) or vertebral veins >0.88 s; (2) reflux propagated in at least one out of the three deep cerebral veins >0.55 s; (3) high resolution B mode evidence of proximal IJV stenosis; (4) flow not Doppler detectable in the IJV or vertebral veins despite deep inspirations; and (5) negative difference of the cross sectional area of the IJV comparing the value obtained in the supine versus the sitting position. The authors concluded that detection of two or more of these findings constitutes the diagnosis of CCSVI. They found CCSVI in all MS patients and in none of the controls. The sensitivity, specificity, positive predictive value and negative predictive value of the test were all 100%. They concluded that there was CCSVI in MS patients.3

    In a second paper, Zamboni et al published that catheter venography in patients who met CCSVI Doppler criteria showed stenosis in the azygos vein 86% of the time and one or both IJV were affected in 91%. In this study, the venographer was not blinded to the patients' diagnosis.4 The study proposed four venographic patterns: (A) large IJV with one IJV or proximal azygous vein stenosis; (B) both IJV and proximal azygos vein stenosis; (C) both IJV and normal azygous system; and (D) multilevel azygous stenosis with or without IJV involvement.

    Finally, in 2009, Zamboni et al reported their results on the endovascular treatment of 65 MS patients with CCSVI.5 No isolated venous lesion was found, and the distribution of venographic patterns was 30%, 38%, 14% and 18% of types A to D, respectively.5 They performed percutaneous transluminal angioplasty (PTA) on all but one azygos lesion that did not respond to PTA alone and required stent placement. Pretreatment pressures beyond the stenosis were not significantly different than normal venous pressure and there was no significant change in pressure after angioplasty. Mean follow-up using extracranial Doppler was 18 months, with an overall restenosis rate of 47%; more common in the jugular than azygos veins. Clinical outcome at 18 months was reported as showing relapse free of 50% versus 27% preoperatively. It is important to note that the interpretation of the clinical results of this uncontrolled study is confounded since patients were continued on ‘immunomodulating’ therapy after endovascular therapy. These medical therapies have been shown to significantly reduce relapse rates as well as the accumulation of MRI detectable enhancing lesions1 Finally, there was no improvement in patients with primary progressive or secondary progressive MS.5

    Data against CCSVI role in MS
    Although the Zamboni papers have been quite supportive of CCSVI, there are a growing number of papers that raise serious questions about its validity. In early 2010, Khan et al described a number of independently accepted characteristics of venous disease and MS that contradict the CCSVI theory.6

    1.Similar to other autoimmune diseases, MS is more common in young women while chronic venous insufficiency syndromes are not.

    2.There are well known strong epidemiological associations between MS and geography, ethnicity, sun exposure, low vitamin D levels, gender, genetics and immigration studies that are not mirrored by chronic venous insufficiency.

    3.Central veno-occlusive disease can lead to syndromes of idiopathic intracranial hypertension, ischemic and hemorrhagic infarcts and edema, none of which is typically seen in MS patients.

    4.Vascular abnormalities related to chronically diminished venous flow would be expected to increase over time, yet after the age of 50 years the incidence of MS is quite low.

    5.There is no other model of decreased venous drainage and an organ specific immune response.

    6.Transient global ischemia is known to occur with jugular insufficiency but this entity is not seen in MS.

    7.Radical neck dissections remove all jugular veins but they have never been seen to cause MS.6

    The above cited challenges to the Zamboni thesis are based on largely theoretical considerations. In an attempt to replicate the Doppler findings of Zamboni, Doepp et al studied 56 MS patients and 20 controls using similar CCSVI criteria.7 The authors found no patients in either the MS or control groups who had the two or more criteria required for a diagnosis of CCSVI. They concluded based on these results as well as their extensive longitudinal experience with cranial venous Doppler ultrasound, that there is typically tremendous reserve capacity of the extrajugular pathways for cerebral venous drainage and that it is highly unlikely that IVJ stenosis would cause central venous congestion. Furthermore, they went on to discourage interventional procedures for CCSVI outside of the context of appropriately designed clinical research studies.8

    Additionally, Sundstrom et al looked at MRI of 21 patients with relapsing remitting MS and 20 healthy controls, and found no differences in internal jugular venous outflow between the two groups.9 Finally, preliminary data from Zivadinov et al, from the MS research group at the State University of New York in Buffalo, presented findings in the first 500 participants studied with venous Doppler looking at the prevalence of CCSVI in MS patients and controls. Using the requirement that ≥2 CCSVI Doppler criteria be met, CCSVI was found in 62.5% of MS patients, 25.9% of healthy controls and 45% of other neurological disorders.10 At least preliminarily, these results are different from the 100% sensitivity and specificity found by Zamboni and colleagues.3

    Commentary
    There is little debate as to the potential ravages of MS and the sincere desire to improve outcomes in patients suffering from this terrible disease. As such, when seemingly miraculous cures are proffered, we believe that it is our responsibility as neurointerventionalists to rationally review its use.

    There are few data to support the validity of CCSVI. The lack of data seems counterbalanced by the great hope for the miracle of an endovascular treatment for MS. The topic has caused widespread attention and debate in the media, medical literature and the internet.11–17 As of late August 2010, a Google search on ‘liberation procedure’ yielded about 2 650 000 results and approximately 181 000 for ‘CCSVI’. Sponsored links appear for treatment in Mexico, Poland, Costa Rica, India and other locations. At least one toll free telephone number akin to ‘1-800-I Treat MS’ has been created.18

    The prospect of opening an open label, non-study related MS endovascular CCSVI practice can be very seductive. For physicians, the barriers to entry are small since most interventionalists are technically able to perform these procedures and the required devices are readily available. At the same time, there are many patients who are desperate for a procedure which might improve their condition despite the lack of evidence to support its benefits and almost regardless of its potential risks. Indeed, some might argue that because the procedure is safe, if there is any possibility of ameliorating some of the symptoms of MS patients the procedure should be offered to them. However, no invasive procedure is completely safe. In fact, there are increasing reports of complications related to PTA or stenting for CCSVI, including intracranial hemorrhage, stent migration into the heart and jugular vein thrombosis19

    The moniker, ‘liberation procedure’, is a marketer's dream and by itself suggests unrealistic but compelling expectations. Many patients are willing to pay cash, sometimes tens of thousands of dollars, for a single procedure. Many patients rave about their procedures, yet outside of a well controlled trial, it is hard to disprove the placebo effect and prove the true clinical benefits.

    In view of the forgoing, and in an attempt to help resolve the CCSVI conundrum, it would seem that the fundamental questions are:

    1.Is there a cause and effect relationship between CCSVI and MS, and in which direction does this work?

    2.If CCSVI does cause or worsen MS, should this be treated with endovascular therapies?

    3.If endovascular treatment is contemplated, which therapy should be offered and under what technical and clinical circumstances should they be applied?

    There is paramount need for credible scientific evidence that will allow us to address these questions. Firstly, we should encourage trials using non-invasive studies to test if CCSVI–MS actually exists. At the current time, the corroboratory evidence supporting Zamboni's initial findings of an association between CCSVI and MS are limited. In fact, the majority of additional evidence—including the work of Doepp et al and Sundstrom et al, cited in this review—actually failed to replicate the findings of Zamboni and colleagues.7–9

    Moreover, the early results of Zivadinov et al are also not very compelling.10 In addition, the initial claim by Zamboni et al that they had developed a perfect test for CCSVI–MS raises serious questions about the credibility of their evidence. As pointed out by Novella, few if any tests in medicine have 100% sensitivity and 100% specificity.20

    Fortunately, the US and Canadian MS societies have undertaken seven studies to investigate the CCSVI–MS association.14,15 The necessity of requiring an invasive diagnostic study such as catheter venography to evaluate the CCSVI–MS association is more difficult to reconcile at this point, particularly since the seminal findings of Zamboni et al which initiated this entire controversy were based on non-invasive Doppler ultrasound.

    If the association between CCSVI and MS cannot be confirmed, then further studies evaluating CCSVI treatment are unnecessary. While it could be argued that even if the prevalence of venous ‘abnormalities’ is similar in patients with MS and controls, venous intervention in MS should still be studied since MS patients might be more susceptible to the detrimental effects of CCSVI than normal patients, this position seems tenuous at best.

    If an association between CCSVI and MS can be established, then the next logical step would be to design multicenter randomized clinical trials to assess the benefits of endovascular interventions.

    Conclusion
    More evidence is needed to establish the association between CCSVI and MS. If more solid clinical evidence can confirm that the CCSVI–MS relationship is real, randomized clinical trials will be required to assess the benefits of endovascular interventions. If these trials establish a benefit for endovascular therapy, then at that point treatment can be made widely available. However, until these steps are taken, in our opinion, there is no role for the endovascular treatment of CCSVI in the MS patient outside of approved clinical trials.

    Footnotes
    Competing interests None.

    Provenance and peer review Not commissioned; not externally peer reviewed.

    References
    1.↵Compston A, Coles A. M1 “Multiple sclerosis”. Lancet 2008;372:1502–17.[CrossRef][Medline]2.↵Zamboni P. The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med 2006;99:589–93.[FREE Full text]3.↵Zamboni P, Menegatti E, Galeotti R, et al. The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis. J Neurol Sci 2009;282:21–7.[CrossRef][Medline][Web of Science]4.↵Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392–9.[Abstract/FREE Full text]5.↵Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg 2009;50:1348–58.e1–3.[CrossRef][Medline][Web of Science]6.↵Khan O, Filippi M, Freedman MS, et al. Chronic cerebrospinal venous insufficiency and multiple sclerosis. Ann Neurol 2010;67:286–90.[CrossRef][Medline][Web of Science]7.↵Doepp F, Paul F, Valdueza J, et al. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol 2010;68:173–83.[Medline]8.↵Doepp F, Schreiber SJ, von Munster T, et al. How does the blood leave the brain? A systematic ultrasound analysis of cerebral venous drainage patterns. Neuroradiology 2004;46:565–70.[Medline][Web of Science]9.↵Sundström P, Wåhlin A, Ambarki K, et al. Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study. Ann Neurol 2010;68:255–9.[Medline]10.↵Zivadinov R, Marr K, Ramanathan M, et al. Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD Study). Description of the design and interim results of an epidemiological study of the prevalence of chronic cerebrospinal venous insufficiency in MS and related diseases. Neurology 2010;74(P06.144):A545.11.↵Burton TM. “MS program halted amid controversy”. Wall Str J 2010. http://online.wsj.com/article/SB10001424052748704211704575140313904335240.html?mod=wsj_hpp_MIDDLTopStories (accessed 14 August 2010).12.↵Grady D. “From MS patients, outcry for unproved treatment”. New York Times, 2010. http://www.nytimes.com/2010/06/29/health/29vein.html (accessed 14 August 2010).13.↵Burton TM. “Studies cast doubt on new MS theory”. Wall Street J 2010. http://online.wsj.com/article/SB10001424052748703787904575403160155710380.html (accessed 14 Aug 2010).14.↵Multiple Sclerosis Society of Canada. CCSVI and MS: overview and FAQ. Multiple sclerosis society of Canada, 2010. http://mssociety.ca/en/research/medmmo_20091021_faq.html. (accessed 14 Aug 2010).15.↵National Multiple Sclerosis Society. Update: CCSVI: pursuing promising avenues in MS research. National Multiple Sclerosis Society, 2010. http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=2206 (accessed 14 Aug 2010).16.↵Stanbrook MB, Hébert PC. Access to treatment for multiple sclerosis must be based on science, not hope. CMAJ 2010;182:1151.[FREE Full text]17.↵News-Medical.Net. Research shows no link among CCSVI and development of multiple sclerosis. News-Medical.Net. 2010. http://www.news-medical.net/news/20100802/Research-shows-no-link-between-CCSVI-and-development-of-multiple-sclerosis.aspx (accessed 14 Aug 2010).18.↵http://www.pacificinterventional.com/about_ccsvi.html. (accessed 14 Aug 2010). 19.↵Sclafani SJA. Chronic cerebrospinal insufficiency syndrome: new paradigm and therapy for multiple sclerosis. I Endovascular Today 2010;41–6.20.↵Novella, Steven. 2010. CCSVI—The importance of replication. NeuroLogica Blog. http://www.theness.com/neurologicablog/?p=2172 (accessed Aug 14).

    Howard Dorne1, Osama O Zaidat2, David Fiorella3, Joshua Hirsch4, Charles Prestigiacomo5, Felipe Albuquerque6, Robert W Tarr7

    1St Joseph Hospital Health System, Orange, California, USA
    2Department of Neurology, Neurosurgery and Radiology, Froedtert Hospital/Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    3Stony Brook University Medical Center, Stony Brook, New York, USA
    4Massachusetts General Hospital, Boston, Massachusetts, USA
    5New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
    6Barrow Neurological Institute, Phoenix, Arizona, USA
    7University Hospitals Case Medical Center, Cleveland, Ohio, USA

    Source: J NeuroIntervent Surg doi:10.1136/jnis.2010.003947 Copyright © 2010 by the BMJ Publishing Group Ltd (28/10/10)

    Saskatchewan slates $5 million for CCSVI trials
    CCSVI VenogramThe Government of Saskatchewan today announced it is following through on its commitment and investing $5 million to fund clinical trials for the Multiple Sclerosis (MS) CCSVI liberation procedure.

    The Saskatchewan Health Research Foundation (SHRF) will develop the call for clinical trials, and provide the scientific, ethical and financial expertise to manage this initiative on behalf of the government.

    Saskatchewan is the first province to move forward on initiating clinical trials of the liberation procedure.

    "I am proud that our province is taking leadership on this important health issue which affects so many people in Saskatchewan and in Canada," Premier Brad Wall said. "We want to put our patients first by helping to find the answers they need and deserve."

    "We are pleased to provide financial support to fund clinical trials and important research in this area," Health Minister Don McMorris said. "With the leadership and assistance of the Saskatchewan Health Research Foundation, we are ensuring any clinical trials undertaken will proceed based on the best expertise science can offer."

    The liberation procedure is a potentially ground-breaking discovery for the treatment of MS. However, it is in the trial stages and is not yet proven as a scientifically valid therapy. The funding announced today will help determine its validity as a treatment for MS.

    "MS research is extremely important to the people of Saskatchewan," Chief Executive Officer of SHRF June Bold said. "We welcome this opportunity to establish a competitive call for clinical trials and manage the process that moves the province toward clinical trials for the MS liberation procedure. Since our formation in 2003, we've developed considerable expertise in managing publicly funded health research from program design, through scientific review, to financial management."

    With this announcement, SHRF will initiate the development of a competitive process that will invite research proposals based on a well-defined set of criteria. The first step will be two-fold: to establish an expert advisory panel drawn from Saskatchewan and other jurisdictions; and to begin developing the call for proposal documents.

    "The advisory panel will play an important role in developing criteria for a call for research proposals and in overseeing the selection process," Bold said. "An expert peer-review panel will assess all of the proposals received and provide recommendations."

    The advisory panel will be convened in early November, with an expedited call for proposals occurring in early December. It is expected that the successful recipient will be chosen in early 2011 and a process leading to clinical trials will be announced by April of 2011.

    MS patients in Saskatchewan will play an important role in this clinical trial. Until a research team has been announced, however, there is no list or requirement for patients to register their interest in participating. Neither the Ministry of Health nor SHRF will be collecting information related to a patient's future interest; that role lies solely with the successful research team. Patients are encouraged to watch for updates and announcements once the successful research team has been announced in 2011.

    Information will be posted on the SHRF website at http://www.shrf.ca about this call for clinical trials

    Source: Government Of Saskatchewan (20/10/10)

    Manitoba to help fund CCSVI research in future

    CCSVI VenogramThe Manitoba government is setting aside $500,000 for future clinical trials of a controversial treatment for multiple sclerosis, one of several MS funding measures announced Friday by Health Minister Theresa Oswald.

    The money would be used to test the "liberation" treatment developed by Dr. Paolo Zamboni. The Italian vascular specialist has hypothesized that MS is related to blocked neck veins, a condition he has dubbed chronic cerebrospinal venous insufficiency, or CCSVI.

    “We have always said our government is willing to fund CCSVI clinical trials and today we are taking a step forward by establishing a fund for this research, if and when it is deemed safe and ethical to proceed,” said Oswald.

    The Manitoba government wants to see a pan-Canadian, multi-site approach to clinical trials of the experimental therapy instead of small, unco-ordinated studies using different methods that could produce conflicting findings.

    The funding being put in reserve will allow the province to move quickly if evidence from diagnostic studies now underway in Canada and elsewhere support the move to clinical trials of the treatment, Oswald said in a release. A national scientific working group has been established by the federal government to monitor current research and advise if and when clinical trials should proceed.

    The health minister also announced that the provincial MS Clinic at Winnipeg's Health Sciences Centre will receive more than $500,000 to meet a growing demand for services, allowing it to hire more staff to reduce wait times.

    “Over the last three years, our clinic has had a steady increase in referrals for diagnosis and management of MS,” said Dr. Ruth Ann Marrie, director of the clinic. “This funding will enable us to improve our service to patients, particularly by seeing newly referred patients sooner.”

    Oswald said the province has also decided to cover the cost of Tysabri (natalizumab), a drug used to treat the relapsing-remitting form of multiple sclerosis.

    Source: Metro Calgary Copyright 2001-2010, Free Daily News Group Inc. (17/10/10)

    No evidence for cerebro-cervical venous congestion in patients with MS
    CCSVI VenogramBackground: Multiple sclerosis (MS) is characterized by demyelination centered around cerebral veins. Recent studies suggested this topographic pattern may be caused by cerebral venous congestion, a condition termed 'chronic cerebro-spinal venous insufficiency' ('CCSVI').

    In a recently published study we were unable to reproduce the reported findings of reflux in the deep cerebral veins and/or the internal jugular and vertebral veins (IJVs and VVs), stenosis of the IJVs, missing flow in IJVs and VVs, and inverse postural response of the cerebral venous drainage (Ann Neurol, in press).

    Methods: We performed extra- and transcranial Doppler ultrasound studies including analysis of extracranial venous blood volume flow (BVF), cross-sectional areas, IJV flow analysis during valsalva manoever (VM) and ' CCSVI' criteria in 59 patients with MS (target: 80 patients) and 20 reference subjects.

    Results: Except for one patient, blood flow direction in the IJVs and VVs was normal in all subjects. In none of the subjects was IJV stenosis detected. IJV and VV BVF in both groups were equal in the supine body position. The decrease of total jugular BVF upon turning into the upright position was less pronounced in patients (173 ± 235 vs 362 ± 150 ml/min; p<0.001), leading to higher BVF in the latter position (318 ml/min ± 242 vs 123 ± 109 ml/min; p<0.001). No difference between patients and controls was detected in intracranial veins and during VM. None of the subjects investigated in this study fulfilled more than one criterion for 'CCSVI'.

    Conclusion: This data confirms in a larger cohort our recently published study challenging the hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of MS. Future studies should elucidate the difference between patients and healthy subjects in BVF regulation.

    F. Doepp, F. Paul, J.M. Valdueza, K. Schmierer, S.J. Schreiber (Berlin, Bad Segeberg, DE; London, UK)

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    MS patients with CCSVI present with increased iron concentration on susceptibility-weighted imaging in deep-grey matter
    MRIBackground: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular phenomenon recently described in multiple sclerosis (MS) that is characterized by stenoses affecting the main extracranial venous outflow pathways that may lead to increased iron concentration (IC) in the brain parenchyma.

    Objective: To investigate the relationship between presence of CCSVI and IC, measured on susceptibility-weighted imaging (SWI), in deep-gray matter (DGM) regions of MS patients and age- and sex-matched healthy controls (HC).

    Methods: Ninety three (93) consecutive MS patients [66 relapsing-remitting (RR) and 27 secondary-progressive (SP], and 51 age- and sex-matched HC were imaged on a 3T GE scanner using SWI. Mean age in MS patients was 46.9 yrs, mean disease duration 14.6 yrs and median EDSS 2.5. The presence of CCSVI was determined by using extracranial and transcranial Doppler evaluation (Zamboni et al., JNNP 2009), with >=2 fulfilled criteria indicating diagnosis of CCSVI. High-iron tissue mean IC (HITMIC) was determined for the total DGM, caudate, putamen, globus pallidus, thalamus, pulvinar nucleus of the thalamus (PVNT), hippocampus, amygdala, nucleus accumbens, red nucleus and substantia nigra regions by in-house developed software.

    Results: CCSVI criteria were fulfilled in 62 (66.7%) of MS patients and 14 (27.5%) of HC (p< 0.001). The two venous scales - venous haemodynamic insufficiency severity score (VHISS) and number of venous haemodynamic criteria fulfilled (VH) - were both significantly correlated with CCSVI diagnosis (Spearman r = .89 for VHISS and r = .83 for VH, p < 0.001 for both scales). MS patients who presented with CCSVI showed significantly increased HITMIC in total DGM, thalamus and PVNT compared to patients without presence of CCSVI (p<0.05). No differences were found in HC with and without presence of CCSVI. Higher VH and VHISS were related to increased HITMIC in total DGM, PVNT, thalamus and caudate (p<0.05) in MS patients. The relationship between presence and severity of CCSVI and increased HITMIC in various DGM measures was stronger for SP than for RRMS patients.

    Conclusion: This is the first large cohort study suggesting an important association between presence and severity of CCSVI and increased IC in DGM regions of MS patients.

    R. Zivadinov, M. Heininen-Brown, C. Schirda, C. Magnano, D. Hojnacki, C. Kennedy, E. Carl, N. Bergsland, S. Hussein, M. Cherneva, L. Willis, M. Dwyer, B. Weinstock-Guttman (Buffalo, US)

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    Chronic cerebrospinal venous insufficiency is an unlikely cause of MS
    CCSVI VenogramIntroduction: A state of chronic cerebrospinal venous insufficiency (CCSVI) secondary to extracranial venous stenosis (EVS) was suggested as a possible cause of multiple sclerosis (MS).

    Methods: In this study we performed selective extracranial venous angiography (SV) on 42 patents with early MS (EMS): clinically isolated syndrome (CIS) or relapsing remitting MS (RRMS) of less than 5 years duration, and late MS (LMS): RRMS of more than 10 years duration. We also reviewed available MRI and clinical relapse data in patients with documented EVS.

    Results: EVS was present in 7/29 (24%) patients with EMS and 12/13(92%) patients with LMS, a highly significant statistical difference (p<0.0001). Only 3/42 (7%) patients (all in the LMS group) had 2 vessel stenosis, while the rest had only 1 vessel involved. The incidence of EVS in CIS was 9% compared to 33% in RRMS of less than 5 years duration. The most important factor in determining presence of EVS was disease duration: mean=9.4±6.8 years in 19 patients with EVS compared to 3.2±4.1 years in patients without (p<0.005), which stayed significant after controlling for age at disease onset and gender (p<0.002). Within the EMS group, patients with (n=7) and without (n=22) EVS had similar EDSS (1.43±2.13 and 0.8±0.008, p=0.85) and disease duration (mean =2.1 and 2.4 years, p=0.521), suggesting similar disease severity. The 7 EMS patients with stenosis had a total of 14 relapses since disease onset. No clear correlation could be found between site of EVS and relapse anatomical localization. A total of 97 spine and brain MRIs available since disease onset on all 19 patients with stenosis were reviewed. Again no clear correlation could be seen between the location of gadolinium enhancing (Gd+) lesions and site of EVS.

    Conclusion: CCSVI is an unlikely cause of MS since it is not present in most cases early in the disease, and in only a minority of MS patients affects more than 1 extracranial vein. It is likely to be a late secondary phenomenon, possibly related to chronic central nervous system (CNS) disease and atrophy.

    B. Yamout, A. Herlopian, Z. Issa, R.H. Habib, A. Fawaz, J. Salameh, H. Wadih, H. Awdeh, N. Muallem, R. Raad, A. Al-Kutoubi (Beirut, LB) 

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    Correlation of localisation and severity of extracranial venous lesions with clinical status of MS
    CCSVI VenogramPurpose: The discovery of chronic cerebrospinal venous insufficiency (CCSVI), which comprises stenoses in the extracranial veins that drain the central nervous system, has shed new light on the potential source of multiple sclerosis (MS).

    The aim of this report is to assess the correlations between patterns of CCSVI and clinical characteristics of MS.

    Methods: Localization and degree of venous outflow blockages in the internal jugular veins (IJV) and the azygous vein (AV) in MS patients was assessed using standard venography. Analysis of clinical parameters of MS included: patients' age, duration of the disease, severity of disability using Multiple Sclerosis Impact Scale-29 (MSIS-29), evaluation of chronic fatigue using Fatigue Severity Scale (FSS), assessment of heat intolerance, and evaluation of the thickness of the ganglion cell complex (GCC) in optical coherence tomography (OCT).

    Results: A total of 331 MS patients with previously diagnosed CCSVI, using color Doppler sonography and magnetic resonance venography, were evaluated. OCT was performed in 451 eyes. Severity of venous obstacles neither correlated with patients' age, nor did it with duration of the disease. It was also found that neither chronic fatigue, nor heat intolerance correlated with the localization or intensity of venous outflow blockages. On the contrary, more disabled MS patients, as revealed using MSIS-29 questionnaire, were found to suffer from bilateral and/or severe occlusions of the IJVs.

    Moreover, the patients with stenosed AV presented with the most aggressive clinical course of MS. Pathologic values of GCC were found in 61% of eyes, and this pathology was found more often in the cases with unilateral lesions in the IJV, interestingly: not necessarily at the diseased side. On the contrary, bilateral stenoses in the IJVs correlated with a less frequent pathology of the optic nerves. Stenoses in the AV had no impact on the frequency of pathologic GCC values.

    Conclusion: It has been revealed that at least some elements of clinical characteristics of MS correlated with parameters of CCSVI. These findings indicate that most likely both pathologies are interconnected and CCSVI may play a role in the pathogenesis and progression of MS. Importantly, venous lesions in differently aged patients were comparable, and severity of venous lesions did not correlate with duration of MS. This finding favors the idea of congenital nature of those vascular malformations

    M. Simka, T. Ludyga, M. Kazibudzki, A. Adamczyk-Ludyga, J. Wrobel, P. Latacz, J. Piegza, M. Swierad (Katowice, PL)

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    Clinical correlates of chronic cerebrospinal venous insufficiency in multiple sclerosis

    CCSVI VenogramObjectives: To evaluate the clinical correlates of chronic cerebrospinal venous insufficiency (CCSVI) in a large cohort of patients with multiple sclerosis (MS).

    Background: CCSVI is a complex vascular condition characterized by anomalies of the primary veins outside the skull (Zamboni et al, JNNP, 2009). We previously showed in a pre-planned Combined Transcranial (TCD) and Extracranial Venous Doppler Evaluation (CTEVD) blinded study that the prevalence of CCSVI was significantly higher in the MS cohort vs. healthy controls (HC) (56.1% vs. 22.7%, p< 0.001).

    Results: This study enrolled 499 subjects; 163 HC, 289 MS patients, 21 CIS patients, 26 subjects with other neurological disorders underwent a clinical examination and a combined Doppler and TCD scan of the head and neck. Thirty patients that were defined as borderline (technical limitation for criteria 2 and not meeting definition of CCSVI) were considered negative for this analysis.

    CCSVI prevalence was significantly higher in more advanced MS disease subtypes: 89.5% in relapsing secondary-progressive (SP), 67.2% in non-relapsing SP, 54.5% in primary-progressive (PP), 49.2% in relapsing-remitting (RR) and 38.1% in CIS (p = 0.033). The mean venous haemodynamic insufficiency severity score (VHISS) was higher for subjects diagnosed with CCSVI (mean VHISS ± SD: 4.05 ± 1.4, n = 218) than for subjects without CCSVI (1.20 ± 1.0, n = 281; p < .001). Criteria 2, 4 and 5 showed significant associations with an EDSS >=4.0 (Criteria 2: OR of 2.25, p=0.005; criteria 4: OR: 3.28, p=0.004 and Criteria 5 OR: 2.67, p=0.008). MS subjects with CCSVI had significantly higher Pyramidal (p = 0.020), Cerebellar (p = 0.049), and Brain Stem (p = 0.010) EDSS sub-scale score than subjects without CCSVI. Subjects with CCSVI were significantly older than subjects without CCSVI (p = 0.04). However, the mean Multiple Sclerosis Severity Score (MSSS) trended higher for subjects with CCSVI (4.22 ± 2.6, n = 160) than for subjects without CCSVI (3.63 ± 2.4, n =127), but this difference was not significant (p = .073).

    Conclusions: The presence of CCSVI in MS patients was associated with more advanced MS disease subtypes and more severe motor, cerebellar and brainstem involvement.

    B. Weinstock-Guttman, G. Cutter, K. Marr, D. Hojnacki, M. Ramanathan, R.H.B. Benedict, C. Morgan, E.A. Yeh, E. Carl, C. Kennedy, J. Reuther, C. Brooks, M. Elfadil, M. Andrews, R. Zivadinov (Buffalo, Birmingham, US)

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    Use of MRV for visualisation of the internal jugular veins in patients with MS diagnosed with CCSVI and treated with percutaneous angioplasty
    CCSVI VenogramBackground: Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in patients with multiple sclerosis (MS).

    CCSVI is diagnosed non-invasively by Doppler sonography (DS) and invasively by selective venography (SV). The role of magnetic resonance venography (MRV) in defining presence of CCSVI is not completely elucidated.

    Objective: To assess the role of MRV for visualization of the internal jugular veins in patients with MS diagnosed with CCSVI and in healthy controls (HC) who obtained serial MRV and DS exams over the period of 12 months.

    Methods: Ten MS patients diagnosed with CCSVI (as evidenced by DS and SV), and treated with percutaneous angioplasty as part of the endovascular venous treatment MS study (EVTMS), underwent a 2D-Time-Of-Flight venography (TOF), a 3D-Time Resolved Imaging of Contrast Kinetics angiography (TRICKS), DS and SV at baseline. They were re-evaluated 6 months post-treatment with MRV and DS. Four additional MS patients obtained exams post-treatment at 6 and 12 months respectively, without obtaining baseline MRV. Six HC underwent a baseline and a 6-month follow-up evaluation by DS and MRV. The internal jugular veins (IJVs) were examined and compared between MRV, DS and SV.

    Results: The following observations were found at baseline in MS patients: 1) the overlap between DS and SV findings was 90%, 2) there was no overlap between TOF or TRICKS and DS findings in the IJVs in 85% of the examinations, 3) there was no overlap between TOF and SV in 80% and between TRICKS and SV in 70% of examinations, 4) there was no overlap between both MRV techniques in 22% of the exams. At 6-month follow-up, 20% of the patients showed changes on TOF from normal to abnormal; whereas on TRICKS, 50% of the patients showed changes, 4 of them from normal to abnormal and one from abnormal to normal.

    On TOF, 50% of the patients showed changes in the IJVs between the 6-month and the 12-month follow-up exams, whereas, 25% of the patients showed changes on TRICKS, being all these changes from normal IJVs to abnormal. Most of these changes did not overlap with DS findings at follow-up examinations. In HC, 50% of the TOF and 41% of the TRICKS showed no overlap with DS findings in IJVs at baseline. At 6-month follow-up, 33% of the HC showed changes from normal to abnormal IJVs and vice versa on TOF and 16% on TRICKS.

    Conclusion: MRV has limited value to assess CCSVI for both diagnostic and follow-up purposes.

    A. Lopez-Soriano, R. Zivadinov, R. Galeotti, D. Hojnacki, E. Menegatti, C. Schirda, A.M. Malagoni, K. Marr, C. Kennedy, I. Bartolomei, C. Magnano, F. Salvi, B. Weinstock-Guttman, P. Zamboni (Buffalo, US; Bologna, IT)

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    Safety and complications related to endovascular treatment for CCSVI in MS patients
    CCSVI VenogramPurpose: The aim of this report is to assess the safety of endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI). Although balloon angioplasty and stenting in other vascular territories are already accepted and seem to be safe procedures, there are currently no data on such treatments of a large group of patients with compromised venous outflow in the internal jugular (IJV) and/or the azygous vein (AV).

    Methods: A total of 587 endovascular procedures: 414 balloon angioplasties and 173 stent implantations were performed during 361 interventions in 347 CCSVI patients with associated multiple sclerosis.

    Results: There were only few, rather minor and occasional complications or technical problems related to the procedures. These included: (i) life threatening complications: death - 0, major hemorrhage - 0; cerebral stroke - 0; stent migration - 0; (ii) major complications: early stent thrombosis - 2 (1.2%) (all two occlusions occurred after the stenting for severely hypoplastic internal jugular vein; there were no likely clinical consequences due to these thrombotic events because the veins were not patent before the procedures, and the hemodynamics did not worsen despite the unsuccessful stenting); postoperative false aneurysm in the groin - 2 (0.6%) (successfully treated with thrombin injection); surgical procedure (opening of femoral vein) to remove angioplastic balloon - 1 (0.3%); injury to the nerves - 0; (iii) minor complications: transient cardiac arrhythmia - 2 (0.6%); minor bleeding from the groin - 2 (0.6%); minor gastrointestinal bleeding - 1 (0.3%); postprocedural lymphatic cyst in the groin - 1 (0.3%); problems with the removal of angioplastic balloon or delivery system - 5 (0.9%); unsuccessful catheterization of the stenosed internal jugular vein - 4 (0.7%).

    Conclusion: Regardless of the actual impact of the endovascular treatments for venous pathology on the clinical course of multiple sclerosis, which warrants more clinical studies and long term follow-ups, these procedures appeared to be safe and well tolerated by the patients.

    M. Simka, T. Ludyga, M. Kazibudzki, M. Hartel, M. Swierad, J. Piegza, P. Latacz, L. Sedlak, M. Tochowicz (Katowice, Zabrze, PL)

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    Endovascular treatment for CCSVI in multiple sclerosis. A longitudinal pilot study
    CCSVI VenogramBackground: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular picture characterized by multiple strictures at the level of the main extracranial cerebrospinal venous outflow routes that may interfere with normal venous drainage.

    Objective: To evaluate safety and tolerability of minimally invasive endovascular treatment (EVT) for CCSVI associated to MS using MRI, clinical and haemodynamic outcome measures.

    Methods: We designed an open-label, MRI-blinded, two-center, randomized, EVT intervention parallel-group, 12 month study (EVTMS). Of 16 relapsing-remitting patients who were screened for hemodynamic venous anomalies, 15 (8 from Italy and 7 from the Buffalo) accepted participation in the EVT intervention prospective study (EVTMS). Additional 8 age- and sex-matched healthy controls (HC), 4 from Italy and 4 from Buffalo were followed. All enrolled patients presented with CCSVI and were on disease-modifying therapy.

    Half of the cohort (immediate treatment group [IEVT], 4 from Buffalo and 4 from Italy) were randomly selected to obtain the EVT procedure (in Italy) immediately after the screening, and half (delayed treatment group [DEVT]) at 6 months. The EVT procedure consisted of selective venography complemented by balloon dilatation (PTA) when significant stenoses were detected. All patients were prospectively evaluated at 0, 3, 6, 9 and 12 months with sonography, MRI (0, 6 and 12 months only), and clinical examinations.

    Results: No serious adverse events occurred during the study except one transitory vaso-vagal syndrome approximately an hour after intervention.. One subject in DEVT group was lost from the study at 6 month follow-up. Three HC were lost to follow-up. Restenosis occurred in 29% of the study cohort after intervention (2 in DEVT arm at 3-month, 1 in the DEVT at 6-month and 1 in the IEVT arm at 12-month follow-up). There were no significant differences between the 2 groups at 6 months follow-up after the intervention for MRI and clinical outcomes. There was a significant decrease (p=0.0227) in T2 lesion number from the 6 month baseline time period to the 6 months following the intervention in DEVT arm. No significant worsening in mean change for other MRI and clinical metrics was observed in both groups over the follow-up.

    Conclusions: Treatment with PTA was safe and well tolerated. Rate of restenosis was low, 0% in the AZY and 29% in the IJV. Further and larger studies are needed to determine the effect of EVT for CCSVI in MS.

    P. Zamboni, R. Galeotti, B. Weinstock-Guttman, G. Cutter, E. Menegatti, A.M. Malagoni, D. Hojnacki, M. Dwyer, N. Bergsland, M. Hiennen-Brown, A. Salter, C. Kennedy, I. Bartolomei, F. Salvi, R. Zamboni (Ferrara, IT; Buffalo, Birmingham, US; Bologna, IT)

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    Associations of HLA DR*1501 status and chronic cerebrospinal venous insufficiency in MS
    CCSVI VenogramBackground: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of veins outside the skull (Zamboni et al, JNNP, 2009).

    The Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study was designed to independently confirm whether the presence of CCSVI was associated with multiple sclerosis (MS).

    Objectives: To evaluate the associations of HLA *1501 status and CCSVI correlates within the CTEVD study.

    Results: The CTEVD study enrolled 499 subjects: 163 healthy controls (HC), 289 MS patients, 21 clinically isolated syndrome patients (CIS), 26 controls with other neurological disorders (OND's). Genotyping was obtained for 472 of 499 subjects. All subjects underwent a clinical examination and a combined transcranial and extracranial Doppler scan of the head and neck. The HLA DR*1501 status was obtained by genotyping DNA from peripheral blood for rs3135005, a SNP strongly correlated with DR*1501 status.

    The controls group consisted of HC and OND's. The MS group was dichotomized into the non-progressive (relapsing remitting, CIS and Devic's disease) and progressive forms (secondary progressive and primary progressive). The frequency of CCSVI was higher (OR = 3.57, p < 0.001) in the MS group 54.8% vs. 25.4% in the controls group and also higher in the progressive MS group 69.6% vs. 48.6% in the non-progressive MS group. The frequency of HLA DR*1501 positivity (HLA+) in the MS group 49.5% was higher compared (OR = 2.15, p < 0.001) to 31.3% in the control group. The frequencies of HLA+ in the non-progressive and progressive MS groups were similar, 48.3% and 52.3% respectively.

    In the controls group, 53.1% were negative for both HLA DR*1501 and CCSVI (denoted HLA' CCSVI'), 22.3% were HLA+ CCSVI', 15.6% were HLA' CCSVI+ and 8.9% were HLA+ CCSVI+.

    In the non-progressive MS group, 27.1% were HLA' CCSVI', 23.7% were HLA+ CCSVI', 24.6% were HLA' CCSVI+ and 24.6% were HLA+ CCSVI+. In the progressive MS group, 18.6% were HLA' CCSVI', 11.6% were HLA+ CCSVI', 29.1% were HLA' CCSVI+ and 40.7% were HLA+ CCSVI+.

    Conclusions: These cross sectional data support an association between CCSVI and MS progression separate from HLA*DR1501. This association could imply that CCSVI is a risk factor for the progression of disease or that it is a consequence of the progression. Longitudinal studies need to be conducted to decipher the meaning and implications of this association

    B. Weinstock-Guttman, R. Zivadinov, G. Cutter, M. Tamano-Blanco, D. Badgett , K. Marr, E. Carl, M. Elfadil, C. Kennedy, M. Ramanathan (Buffalo, Birmingham, US)

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    MRI results of blinded CCSVI study in patients with MS, healthy controls & patients with other neurologic diseases
     MRIBackground: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by stenoses of the main extracranial veins with hampered cerebral venous outflow.

    Objective: To determine the relationship of CCSVI and conventional MRI outcomes in a large cohort of patients with multiple sclerosis (MS), clinically isolated syndrome (CIS), other neurological diseases (OND) and healthy controls (HC).

    Methods: A pre-planned examination of the first 499 consecutively enrolled subjects in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) blinded study included 289 MS, 163 HC, 26 OND and 21 CIS subjects. All subjects received extracranial and transcranial Doppler evaluation according to the proposed criteria (Zamboni et al., JNNP 2009). Of these, 20 (95.2%) CIS, 243 (84.1%) MS, 73 (45.6%) HC, and 15 (42.3%) OND received MRI examinations using a standardized protocol. In total, 351 (70.3%) of 499 subjects obtained MRI examination. T2, T1 and gadolinium (Gad) lesion number and volume (LV) were calculated. Normalized measures of global and central brain atrophy were also assessed. Differences in group means were assessed using the Kruskal-Wallis test and all correlations are reported using Kendall's tau.

    Results: The two venous scales' venous haemodynamic insufficiency severity score (VHISS) and number of venous haemodynamic criteria fulfilled (VH) were both significantly correlated with CCSVI diagnosis (Kendall's tau = .694 for VHISS, tau = .804 for VH, p < .001 for both scales). Subjects diagnosed with CCSVI (i.e. those who met at least 2 of the CCSVI criteria) had a significantly higher mean number of T2 lesions (x= 31.10, sd = 21.3, n = 173) than subjects classified as not having CCSVI (x= 24.96, sd = 22.7, n = 178; p < .001). Subjects diagnosed with CCSVI also had a significantly higher mean T2-LV (x= 20.69, sd = 8.9, n = 173) than those without CCSVI (x= 17.46, sd = 8.8, n = 173; p < .001). There was no significant difference between subjects with and without CCSVI for number or LV of either T1 or Gad lesions. Subjects diagnosed with CCSVI had significantly higher lateral ventricle volume (p < .001) than subjects without CCSVI. Subjects with CCSVI showed significantly lower gray matter volume (p = .023), brain parenchymal volume (p = .025) and cortical volume (p = .023) than subjects without CCSVI.

    Conclusions: Presence of CCSVI is significantly related to more severe lesion and brain atrophy MRI measures.

    R. Zivadinov, G. Cutter, K. Marr, M. Ramanathan, R.H.B. Benedict, M. Elfadil, N. Bergsland, C. Morgan, E. Carl, D. Hojnacki, E. Yeh, L. Willis, M. Cherneva, S. Hussein, J. Durfee, C. Kennedy, M. Dwyer, B. Weinstock-Guttman (Buffalo, Birmingham, US)

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
    & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    No evidence of chronic cerebrospinal venous insufficiency in clinically isolated syndrome suggestive of multiple sclerosis
    CCSVI VenogramBackground: A complex scenario of abnormalities of the cerebrospinal venous outflow termed "chronic cerebrospinal venous insufficiency" (CCSVI), has been reported in patients with multiple sclerosis (MS).

    Sonographic criteria of CCSVI include reflux in the deep cerebral veins and/or the internal jugular (IJVs) and vertebral veins (VVs), stenosis of the IJVs, missing flow in IJVs and VVs, and inverse postural response of the cerebral venous drainage. CCSVI has been suggested to be the cause of MS, however no data on the prevalence of CCSVI at MS clinical onset has been published up to this date.

    In order to demonstrate a possible causative relationship between CCSVI and MS, we performed extra- and transcranial color-coded venous sonography (ECCvS, TCCvS) in clinically isolated syndromes (CIS) suggestive of MS.

    Materials and Methods: Fifty consecutive patients with CIS suggestive of MS and evidence of dissemination in space of lesions (i.e., possible MS, pMS) were enrolled into the study. All patients underwent a detailed diagnostic workup, including CSF examination, brain and spinal MRI with gadolinium, ECCvS and TCCvS. Patients with abnormal ultrasound findings underwent selective venography (VGF). Healthy individuals (HC) and patients with transient global amnesia (TGA) constituted our control groups.

    Results: Mean age of pMS was 33.0+/-8.5 years, 35 (70%) were female, EDSS was 1.6+/-0.5. The onset was monosymptomatic in 27 (54%). Forty-two (81%) had IgGOB in the CSF. TCCvS was normal in all pMS patients. ECCvS abnormal findings were found in 26/50 (52.0%) pMS, in 32% of HC and in 68% of TGA patients. Eight out of 50 pMS patients (16.0%) met the CCSVI criteria: 6 were classified as Type C, one as Type B, one as type A, while none as Type D. VGF was completed in all these patients, except for one who developed a paroxysmal supraventricular tachycardia and the exam was stopped. Venography was normal in 6, while 1 patient had a hypoplasia of the right IJV.

    Conclusions: Our findings do not support the hypothesis that cerebral venous congestion plays a causative role in the pathogenesis of MS.

    C. Baracchini, P. Perini, M. Calabrese, F. Causin, F. Farina, F. Rinaldi, P. Gallo (Padua, IT)

    Source: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
    & 15th Annual Conference of Rehabilitation in MS (RIMS) (15/10/10)

    Study finds no link between neurological iron deposits and MS
    Iron Deposits In BrainNormal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency

    Objectives: Chronic cerebrospinal venous insufficiency (CCSVI) has been suggested to be a possible cause of multiple sclerosis (MS). If the presumed mechanism of venous stasis–related parenchymal iron deposition and neurodegeneration were true, then upregulation of intrathecal iron transport proteins may be expected.

    Methods: This was a cross-sectional (n = 1,408) and longitudinal (n = 29) study on CSF ferritin levels in patients with MS and a range of neurologic disorders.

    Results: Pathologic (>12 ng/mL) CSF ferritin levels were observed in 4% of the control patients (median 4 ng/mL), 91% of patients with superficial siderosis (75 ng/mL), 73% of patients with a subarachnoid hemorrhage (59 ng/mL), 10% of patients with relapsing-remitting MS (5 ng/mL), 11% of patients with primary progressive MS (6 ng/mL), 23% of patients with secondary progressive MS (5 ng/mL), and 23% of patients with meningoencephalitis (5 ng/mL). In MS, there was no significant change of CSF ferritin levels over the 3-year follow-up period.

    Conclusion: These data do not support an etiologic role for CCSVI-related parenchymal iron deposition in MS.

    V. Worthington, PhD, J. Killestein, MD, PhD, M.J. Eikelenboom, MD, PhD, C.E. Teunissen, PhD, F. Barkhof, MD, PhD, C.H. Polman, MD, PhD, B.M.J. Uitdehaag, MD, PhD and A. Petzold, MD, PhD
    From the Department of Neuroimmunology (V.W., A.P.), UCL Institute of Neurology, Queen Square, London, UK; and MS Center Amsterdam (J.K., M.J.E., C.E.T., F.B., C.H.P., B.M.J.U., A.P.), Free University Medical Center, Amsterdam, the Netherlands

    Source: Neurology (Neurology 2010, doi:10.1212/WNL.0b013e3181fb449e) (05/10/10)

    MS Society sets aside $1M in case CCSVI patient trial developed and approved
    CCSVI VenogramThe Multiple Sclerosis Society of Canada is setting aside $1 million for a clinical trial of a controversial treatment in the event studies now underway determine the procedure shows promise in alleviating symptoms of the disease.

    “We want to hit the ground running when a therapeutic trial is warranted and approved,” Yves Savoie, president and CEO of the MS Society, said Thursday. "Ensuring funds are available to support a Canadian trial will accelerate our ability to get definitive answers to the questions people touched by MS urgently seek.”

    The unproven "liberation" therapy involves unblocking narrowed neck veins using a procedure called balloon angioplasty. The technique is the same one used to widen coronary arteries plugged by a buildup of plaque to prevent a heart attack or stroke.

    The treatment was developed by Italian vascular specialist Dr. Paolo Zamboni, who has hypothesized that MS may be caused by a narrowing and twisting of veins that drain blood from the brain — a condition he has dubbed CCSVI, or chronic cerebrospinal venous insufficiency.

    Zamboni has said poor drainage could lead to a buildup of blood-borne iron deposits in the brain, which could cause damage to neurons characteristic of MS.

    But multiple sclerosis has long been viewed as an autoimmune disease, and Zamboni's contention that it is caused instead by vascular anomalies has been hotly debated.

    Savoie said the decision as to whether a patient trial of the procedure is warranted will depend on the results of seven diagnostic studies being funded with $2.4 million from the Canadian and American MS societies, as well as other international research.

    Before undertaking a trial of the angioplasty treatment itself, researchers need a reliable imaging method for determining if a person's neck veins are indeed blocked, he said. "At the moment there's divergence about that reliability, the percentage that have blockage."

    "Because the person who doesn't have blocked veins, if you unblock their unblocked vein, it's not going to show any improvement in their MS."

    In other words, scientists wouldn't know definitively if the procedure actually works.

    "Let's be clear," he said. "The evidence for a trial today and to enrol patients today, that evidence is not available."

    Linda Molyneux, a member of the Blocked Veins MS Research Group, called the funding announcement a good start.

    "I'm looking at this as encouraging, but it would be nice if the MS Society would come out with a consistent position," she said. "They seem to keep flip-flopping, which is confusing a lot of people."

    Molyneux of Toronto, whose 23-year-old son was diagnosed with multiple sclerosis over two years ago, said the society made a big deal in the spring about having asked Ottawa to commit $10 million to research, then last month recommended that the government should hold off for now on funding clinical trials.

    "I think they're trying to get some positive PR going for them, because let's face it, they definitely have been roundly criticized by the MS community," she said.

    Savoie denies the society has been flip-flopping.

    "Absolutely not. We've been fairly logical," he said. However, he acknowledged there has been pressure from many MS patients and their loved ones to investigate Zamboni's theory and treatment.

    "There's no question there is unprecedented engagement and mobilization. There's an unprecedented level of hope and optimism."

    That's why, said Savoie, the society wants to be ready with the $1 million — which he hopes will be significantly topped up by Ottawa and the provinces and territories — once the go-ahead for a trial is approved and ethical standards to ensure patient safety are in place.

    But a growing number of MS patients are unwilling to wait for science to prove or disprove anecdotal reports of the treatment's effectiveness, and they want governments to allow Canadian doctors to perform the procedure now.

    At the very least, this often vocal group wants clinical trials to test Zamboni's theory — even though it is not even known if CCSVI causes MS, or whether narrowed neck veins are a product of the disease or completely unrelated.

    In the meantime, an untold number of Canadian MS patients have travelled to clinics in countries such as Poland, Mexico and India, spending thousands of dollars to have the procedure.

    Molyneux's son was among them, recently travelling to Bulgaria for venous angioplasty — a treatment that appears to have improved his symptoms and allowed him to resume some activities he'd had to give up, his mother said.

    The money the family spent was worth it if her son's condition continues to improve or remains stable, she said.

    "I don't think that anybody is saying that this is the whole story," Molyneux said of CCSVI. "It's just time that this was looked at properly and thoroughly."

    At the health ministers meeting in Newfoundland and Labrador earlier this week, provinces and territories said the issue of CCSVI is a top priority. Saskatchewan has said it wants to proceed with a clinical trial, and a few others have signalled at least support for the idea.

    Last month, federal Health Minister Leona Aglukkaq announced that an expert scientific working group would be created to monitor studies already underway, based on advice from the Canadian Institutes of Health Research.

    CIHR, along with the MS Society, advised Ottawa to put off funding clinical trials until it sees results from the seven research projects investigating various aspects of the liberation procedure.

    The funding body said there is no evidence that Zamboni’s CCSVI theory has any merit or that the liberation therapy is effective or even safe.

    Source: Winnipeg Free Press © 2010 Winnipeg Free Press (17/09/10)

    Canadian health minister rejects MS therapy trial
    CCSVI VenogramThe Canadian government will not fund a clinical trial of the so-called liberation therapy for multiple sclerosis at this time, Health Minister Leona Aglukkaq says.

    Aglukkaq spoke to reporters in Ottawa on Wednesday, a day after a panel of North American experts announced they unanimously recommended against supporting a clinical trial of the treatment in Canada as yet.

    Aglukkaq commissioned the expert panel's report from the Canadian Institutes of Health Research, which funds medical research, and the MS Society of Canada.

    "I feel the most prudent course of action at this time is to accept the recommendation of the country's leading researchers," Aglukkaq told a news conference.

    Liberation therapy is based on an unproven theory of chronic cerebrospinal venous insufficiency (CCSVI) — put forward by Italian doctor Paolo Zamboni — that blocked veins in the neck or spine are to blame for MS. Zamboni proposed treating multiple sclerosis by inflating small balloons to open up veins.

    Some Canadians are spending thousands of dollars to seek the experimental treatment overseas.

    CIHR head Dr. Alain Beaudet said experts weren't convinced Zamboni's procedure works and is safe. Beaudet said he advised Aglukkaq that it was too early to back clinical trials.

    Safety questions
    In June, the MS society and its U.S. counterpart awarded a combined $2.4 million in research grants to diagnostic studies aimed at testing whether Zamboni's theory is correct, by checking for abnormal blood flow in the veins in people with MS and healthy controls using ultrasound, MRI or catheters with dye. The research projects are expected to take two years.

    Yves Savoie, the president of the MS Society of Canada, said Wednesday that his organization would monitor the results of the studies.

    If they suggest there is a clear link between occluded veins and MS, then the society will recommend that a clinical trial testing vein opening be started quickly.

    Beaudet said Zamboni's treatment is currently too risky to try in Canada.

    "Any procedure where you inject a catheter in a vein, where you compress the vein, where you risk damage to the internal sheath of the vein, is not without risk."

    But MS patient Tim Cant of Whitehorse, who travelled to India to undergo liberation therapy earlier this year, said he and others have seen their conditions improve.

    "They talk about us being one of the best medical systems in the world," Cant told CBC News on Wednesday. "Why is it so many Canadians are now travelling to other places in the world to get this operation done?"

    Cant, who was diagnosed with MS three years ago, said if politicians could experience first-hand the physical and mental pain that multiple sclerosis inflicts on people, they would fund clinical trials without hesitation.

    Objective measurements
    To show liberation therapy works would require objective measurements, such as changes in muscle strength, a reduction in the frequency of relapses of MS symptoms or differences in MRI brain scans, Beaudet said.

    Aglukkaq agreed that if evidence from the research projects supports the launching of a clinical trial, then the federal government would allow a pan-Canadian study of the ballooning therapy, called angioplasty, on patients.

    Agulukkaq said she doesn't know anyone with MS but has heard anecdotes of Canadians who travelled for the treatment at their own expense.

    For months, the federal Liberal position has been that the government should fund research to figure out whether the treatment is of benefit to Canadian patients or not, Liberal Leader Michael Ignatieff said Wednesday at the party's caucus meeting in Baddeck, N.S.

    Ignatieff said it's not appropriate for politicians to say which treatment is going to work, but for doctors and scientists to do so, assisted by the federal government.

    Saskatchewan Premier Brad Wall has said his province would fund a clinical trial into the procedure if it receives a research proposal for one.

    People with MS say they will return to Parliament Hill on Sept. 22 to urge the federal government to listen to their calls to offer the procedure in Canada.

    Source: CBC News © CBC 2010 (02/09/10)

    Canadian experts & MS Society dismiss experimental MS therapy
    CCSVI VenogramA group of leading Canadian medical experts is advising the federal government against funding clinical trials for a controversial new multiple sclerosis therapy.

    The Canadian Institutes for Health Research and the MS Society of Canada held a joint meeting on research priorities for the progressive and debilitating disease last week and provided recommendations to federal Health Minister Leona Aglukkaq.

    They concluded there is not enough evidence at this time to support beginning mass clinical trials for an experimental treatment – the so-called “liberation procedure” – that opens up veins transporting blood from the brain to the heart in MS patients.

    “There was unanimous agreement from the scientific experts that it is premature to support pan-Canadian clinical trials on the proposed (procedure),” Alain Beaudet, president of the federal granting agency, said in a statement in advance of a news conference Tuesday. “There is an overwhelming lack of scientific evidence on the safety and efficacy of the procedure, or even that there is any link between blocked veins and MS.”

    The treatment was pioneered by Italian vascular surgeon Paolo Zamboni and has been championed as a medical breakthrough by patients desperate for a way to alleviate their symptoms.

    Hundreds of MS patients have been travelling around the world and paying thousands of dollars to obtain the treatment, which is not available in Canada, often against the advice of their own neurologists at home.

    They have also been lobbying the MS Society of Canada and provincial and politicians to fund research into the treatment.

    That is why the conclusions reached at the joint meeting are expected to be harshly criticized by patient groups.

    But the experts also recommended establishing a scientific working group to monitor and analyze results from seven studies of the liberation procedure sponsored by the MS Society of Canada, which will then reach conclusions on the worthiness of the treatment.

    The working group can then recommend further studies if warranted.

    Saskatchewan was the first province to decide to pay for clinical trials, but Ontario has already decided against it, while leaving the door open for future possibilities.

    “It is just early days yet,” Premier Dalton McGuinty told reporters in July. “It is very interesting, I think it holds some promise and our responsibility now is to work together and make sure it is something we should be supporting.”

    The treatment, which is officially known as “chronic cerebrospinal venous insufficiency” (CCSVI), is based on the theory that the disease could be the result of narrowed veins in the chest and neck blocking the drainage of blood from the vein.

    Inflammation and a malfunctioning immune system have traditionally been pinned as the culprits for the disease, which damages the nervous system.

    The treatment method developed by Zamboni is a relatively low-risk procedure that clears blocked veins in the neck.

    It has been compared to coronary angioplasty, which opens blocked arteries of heart patients.

    There are about 75,000 Canadians with MS in Canada.

    Source: healthzone.ca © Toronto Star 1996-2010 (31/08/10)

    Chronic cerebrospinal venous insufficiency (CCSVI) found in 97.1% of patients
    CCSVI VenogramCorrelation of localization and severity of extracranial venous lesions with clinical status of multiple sclerosis

    Background. Chronic cerebrospinal venous insufficiency is suspected to play a role in pathogenesis of multiple sclerosis.

    Objective. Assessment of the correlations between patterns of venous lesions and clinical characteristics of multiple sclerosis.

    Methods. Localization and degree of venous blockages in multiple sclerosis 381 patients were evaluated using catheter venography. Analysis of clinical severity included: Multiple Sclerosis Impact Scale-29 (MSIS-29), chronic fatigue and heat intolerance assessment.

    Results. Venous blockages were found in 97.1% of the patients.

    Abnormalities were more severe in older patients. No correlation existed between duration of the disease and severity of venous pathologies. Patients with younger age at onset of multiple sclerosis presented with milder venous lesions. Significant correlations existed between severity and localization of venous lesions and clinical burden in terms of MSIS-29 and chronic fatigue scores, but not of heat intolerance.

    Conclusion. Prevalence of chronic cerebrospinal venous insufficiency among multiple sclerosis patients is very high. Indirect data analysis indicated that venous abnormalities are probably congenital, slowly progress, but are unlikely to be caused by multiple sclerosis.

    Their severity and localization significantly modify clinical course of this disease. However, they are not likely to directly trigger multiple sclerosis, but there may be another factor initiating the disease.

    Simka M, Ludyga T, Kazibudzki M, Latacz P, Świerad M, Piegza J

    EUROMEDIC Specialist Clinics, Department of Vascular & Endovascular Surgery, Katowice; Poland.

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    Source: Euromedic Specialist Clinics (31/08/10)

    Launch CCSVI MS clinical trials immediately, researcher urges
    CCSVI VenogramClinical trials of the controversial liberation treatment for multiple sclerosis should happen immediately, says a former University of Saskatchewan researcher who proposed an eerily similar theory more than a decade ago.

    Bernhard Juurlink published a hypothesis in 1998 that MS is related to decreased blood flow in the brain and spinal cord.

    "It was very difficult to get anyone interested in this idea — the idea was easily testable by, for example, looking for blood flow in white matter in MS patients," Juurlink said in an interview this week. "I tried to first interest clinical colleagues to image brains of MS and non-MS patients, to look at blood flow, with no success."

    Last year, Italian vascular surgeon Dr. Paolo Zamboni proposed that narrowed or blocked veins in the neck are related to MS and inflating the veins with a balloon angioplasty procedure can alleviate symptoms.

    The procedure isn't available in Canada because it hasn't been scientifically validated, but Saskatchewan Premier Brad Wall has called for clinical trials, which he'd like to see start soon.

    Meanwhile, a growing number of Canadians with MS have travelled to Bulgaria, Poland, India, Mexico and the United States to have their veins widened. They bring back anecdotal reports of immediate results, such as restored warmth to their feet and hands, clearer vision and decreased fatigue.

    Juurlink was at the University of Saskatchewan from 1975 until 2008, when he moved to Saudi Arabia as a founding faculty member of Alfaisal University; he serves a professor of anatomy and cell biology.

    He said his research into strokes intersected with MS research during the 1990s when he started looking at the development of the cells that form myelin, the fatty sheaths around the brain's axons — portions of nerve cells that transmit electrical impulses. Damage to the myelin sheaths caused by immune cell attacks is the commonly accepted cause of MS.

    MS research has almost completely focused on the immune attack, but Juurlink found reports of myelin breakdowns in the absence of immune cells. That led him to wonder what else could cause the damage.

    Because of his research into strokes, he knew the first tissues affected when blood flow in the brain is reduced are the myelin-covered nerve fibres — and that some of the changes caused in the brain resemble the changes in the brains of MS patients.

    While a scientist at the Cameco MS Neuroscience Research Centre in Saskatoon, he hypothesized that reduced blood flow could be the cause of MS lesions in the brain and, consequently, lesions may be prevented by increasing the blood flow.

    "It wasn't covered up, but it went against the grain of what was considered to be common knowledge, that everybody knew, despite the evidence to the contrary. This was completely ignored," said Juurlink. "Once ideas are accepted, it's very difficult to get individuals to look at a problem in a different light.

    "Despite what scientists claim — that they're open-minded — it's actually not the case, usually, because everybody says, 'Of course, it's an immune attack, we know it's an immune attack.' "

    However, the relation of vein obstructions to MS won't be known without carefully controlled, double-blinded clinical trials, Juurlink said. "Personally, I don't understand why we don't have immediate clinical trials."

    Current work related to Zamboni's theory at Saskatoon's research centre focuses on whether the veins are restricted. The lead researcher, Dr. Katherine Knox, said this week her team is focusing on that work before moving on to any potential clinical trials.

    The dean of the U of S's college of medicine, Dr. William Albritton, and provincial Health Minister Don McMorris have both spoken recently of clinical trials being fast-tracked.

    The Montreal Gazette © 2008 - 2010 Postmedia Network Inc (28/08/10)

    Society of Interventional Radiology Supports Research for New M.S. Treatments
    CCSVI VenogramPosition Statement in September Journal of Vascular and Interventional Radiology Outlines Society's Stance as It Actively Promotes and Expedites Needed Research, Recognizes Potential Value of Interventional Treatment Options for Vulnerable Patients

     Recognizing that venous interventions may potentially play an important role in treating some patients who suffer from multiple sclerosis -- an incurable, disabling disease -- the Society of Interventional Radiology has issued a position statement indicating its support for high-quality clinical research to determine the safety and effectiveness of interventional M.S. treatments. SIR's position statement is endorsed by the Canadian Interventional Radiology Association and will be published in the September Journal of Vascular and Interventional Radiology.

    "The Society of Interventional Radiology would like to be actively involved in developing evidence-based therapies for the potential treatment of patients with multiple sclerosis," said SIR President James F. Benenati, M.D., FSIR. "Completing high-quality studies -- for example, on chronic cerebrospinal venous insufficiency (CCSVI, a reported abnormality in blood drainage from the brain and spinal cord) and interventional M.S. treatments -- should be a research priority for investigators, funding agencies and M.S. community advocates," added Benenati, who represents nearly 4,700 doctors, scientists and allied health professionals dedicated to improving health care through minimally invasive treatments.

    About 500,000 people in the United States have M.S., and SIR understands the public's desire to advance treatment for M.S., generally thought of as an autoimmune disease in which a person's body attacks its own cells. Currently, medicines may slow the disease and help control symptoms. The role of CCSVI in M.S. and its endovascular treatment (through a catheter placed in a vein) by an interventional radiologist via balloon angioplasty and/or stents to open up veins "could be transformative for patients and is being actively investigated," said Benenati. "The idea that there may be a venous component to the etiology (or cause) of some symptoms in patients with M.S. is a radical departure from current medical thinking," he noted.

    "SIR recognizes the challenge and the potential opportunity presented by promising early studies of an interventional approach to the treatment of M.S.," said Benenati. SIR is moving rapidly to "catalyze" the development of needed studies by bringing together expert researchers in image-guided venous interventions, neurology, central nervous system imaging, M.S. outcomes assessment and clinical trial methodology, he added. While the use of balloon angioplasty and stents cannot be endorsed yet as a routine clinical treatment for M.S., SIR is committed to assuming a national leadership role in launching needed efforts, said Benenati.

    SIR's position statement agrees with M.S. advocates, physicians and other caregivers that the use of any treatment (anti-inflammatory, immunomodulatory, interventional or other) in M.S. patients should be based on an individualized assessment of the patient's disease status, his or her tolerance of previous therapies, the particular treatment's scientific plausibility, and the strength and methodological quality of its supporting clinical evidence. "When conclusive evidence is lacking, SIR believes that these often difficult decisions are best made by individual patients, their families and their physicians," notes "Interventional Endovascular Management of Chronic Cerebrospinal Venous Insufficiency in Patients With Multiple Sclerosis: A Position Statement by the Society of Interventional Radiology, Endorsed by the Canadian Interventional Radiology Association."

    If interventional therapy proves to be effective, M.S. patients should be treated by doctors who have specialized expertise and training in delivering image-guided venous treatments, said Benenati. Interventional Radiologists pioneered balloon angioplasty and stent placements and use those treatments on a daily basis in thousands of patients with diverse venous conditions. "Interventional radiologists are steeped in a tradition of innovation and invention -- of pioneering modern medicine with the devices, drugs and methods to treat patients minimally invasively," said Benenati.

    For more information about the Society of Interventional Radiology and to find those interventional radiologists who provide endovascular treatment for CCSVI, visit SIR's Web site at www.SIRweb.org and its Doctor Finder at http://doctor-finder.SIRweb.org/.

    About the Society of Interventional Radiology

    Interventional radiologists are physicians who specialize in minimally invasive, targeted treatments. They offer the most in-depth knowledge of the least invasive treatments available coupled with diagnostic and clinical experience across all specialties. They use X-ray, MRI and other imaging to advance a catheter in the body, such as in an artery, to treat at the source of the disease internally. As the inventors of angioplasty and the catheter-delivered stent, which were first used in the legs to treat peripheral arterial disease, interventional radiologists pioneered minimally invasive modern medicine. Today, interventional oncology is a growing specialty area of interventional radiology. Interventional radiologists can deliver treatments for cancer directly to the tumor without significant side effects or damage to nearby normal tissue.

    Many conditions that once required surgery can be treated less invasively by interventional radiologists. Interventional radiology treatments offer less risk, less pain and less recovery time compared to open surgery. Visit www.SIRweb.org.

    SOURCE Society of Interventional Radiology (26/08/10)

    Dr Sclafani's view on the recent German and Swedish studies on CCSVI
    Dr SclafaniIt is regretful that Drs. Doepp and co-authors' attempt to reproduce Professor Zamboni's discovery of a link between multiple sclerosis and disturbance of the outflow veins of the brain and spine has been unsuccessful.

    It is particularly unfortunate that the authors' misunderstanding of Dr. Zamboni's publications about this subject have led to their conclusions that "No cerebrocervical venous congestion in patients with multiple sclerosis" exists. 

    The authors mis-state several of the criteria for a positive ultrasound examination. They state that reflux must be present in both internal jugular veins or both vertebral veins. This is not accurate. Reflux in any one of these veins was considered a positive criteria by Zamboni. 

    It appears to me that Dr Doepp and colleagues have tried to elicit reflux by testing for incompetent valves in the lower jugular vein. Incompetent valves result in reversal of blood flow from the heart back up into the jugular veins. They used the Valsalva maneurer, a technique to increase pressure in the chest that reverses blood flow. However, Zamboni explicitly states that one should assess flow "never in (by) a forced condition such as the Valsalva manoeuvre." 

    That the authors' attempts were unsuccessful is not surprising. The ultrasound examination used by Zamboni is a simple one but the description of the technique has not been fully elaborated in his papers. Thus performance of the ultrasound by some investigators is often at variance and this may lead to differences of results. At my own institution, we were surprised that non-invasive testing by ultrasound did not correlate with the very obvious obstructive phenomena seen on catheter venography, which remains the Gold Standard of assessing veins. We also had difficulty identifying CCSVI on ultrasound, initially using the Valsalva maneuver during out testing. In fact we were able to find an obstruction in only one patient of twenty. It was only after being shown how to correctly perform this simple screening test by the Zamboni team during a visit to Ferrara, that we have become facile in detecting these abnormalities. It is clear that there is a learning curve to the use of this technique. 

    Nor does this paper refute the concept of CCSVI. Doppler ultrasound is only a screening test for CCSVI. When Doppler shows signs of CCSVI, the gold standard test of catheter venography is indicated to detect the sites of potential obstruction. 

    Doppler is not the definitive test of CCSVI because it cannot assess the azygous vein, an important contributor to cerebrspinal venous outflow resistance. Catheter venographies routinely show evidence of outflow obstructions. Sluggish flow, reversal of flow, extensive collateral veins, strictures, duplications, reversed valves, thickened incompletely opening valves and misplaced valves are among the many abnormalities seen in MS patients that we never see in patients without MS.

    The paper by Sundstrom and coauthors similarly rejected the CCSVI hypothesis by performing MR venograms and flow quantification in the neck. MR venography is suboptimal as a screening test because it underestimates and overestimates stenoses quite regularly. 

    One can see from their illustrations two MRV images. It is noteworthy that neither image shows the portion of the jugular vein where lesions causing flow resistance are usually found: behind the clavicle as the vessel enters the chest. Both images show considerable collateral vasculature suggestive of CCSVI. Moreover the image on the right on page 258 purports to show a stenosis with an arrow. It is well known that most of the narrowings referred to by the white arrow are a common transient, non-stenotic narrowing caused by a true narrowing below the clavicle. Catheter venography shows abnormalities that cannot be detected by MRV.

    I was struck by the rapidity of publication of both articles. Surprising! Both papers were accepted within six weeks. I have never had such rapid decision, editing and publication of any of my more than 120 publications.

    This debate is going to be a challenging one. One side wants randomized prospective trials to prove efficacy.

    However while many proceduralists have noted sometimes impressive gains for patients, these proceduralists need to evaluate nuances of techniques before consensus can be built regarding the best approach to therapy. Only then can intelligent, carefully designed randomized prospective trials begin. Some who commonly perform randomized trials will try to reduce the work of those who will try to develop the best practices because they are not randomized. However, in my view this is a necessary initial step toward the final trials.

    Source: ThisisMS © 2002-2010 by thisisMS.com (12/08/10)

    Science may prove angioplasty technique helpful in treating MS
    CCSVI VenogramMultiple sclerosis occupies a particularly terrifying niche among chronic, disabling diseases. While all serious threats to health are to one degree or another fearsome, those we understand least, and that leave us feeling most vulnerable and defenseless, are the most feared.

    Variable in its course and at times indolent for years, MS can, when extreme, progress rapidly and culminate in total disability and premature death. Characterized by most as an auto-immune disease, MS is still poorly understood. We don’t really know exactly why some people get it; we don’t know how to prevent it; and there is treatment, but no cure.

    This is a situation that screams necessity, and thus invites inventiveness, such as that of Dr. Paolo Zamboni, for whom the need became personal. Zamboni, an Italian vascular surgeon whose wife has MS, was frustrated with the ineffectiveness of conventional therapies, which mainly involve suppressing immune system function.

    Seeking, initially, to account for the common occurrence of iron deposits in the brains of MS patients, Zamboni conducted brain scans. He noted apparent blockages in veins that drain blood from the brain in MS patients, consistently absent from the brains of healthy control subjects. He also noted that the blocked veins corresponded well with the location of iron deposits, and the more severe the blockages, in general, the more severe the MS.

    Zamboni next converted his insight into an angioplasty procedure — now known as “liberation therapy” — in which a balloon-tipped catheter is used to open up the partially blocked veins.

    In Zamboni’s published work, responses to liberation therapy have been very encouraging, although even at best the procedure is not a panacea. Zamboni suggests the longer veins are blocked before liberation, the more potentially irreversible damage to the brain becomes. Some veins re-occlude after angioplasty. And some patients simply don’t respond well. But the testimonials of those who do, including Zamboni’s wife, are quite compelling, telling tales of restored function and quality of life.

    But there are, as yet, dark clouds of doubt wrapped around the silver lining, if not silver bullet, liberation therapy might represent. From the start, many mainstream neurologists have found the entire theory implausible. I am troubled by the fact that MS occurs almost exclusively in those born and raised above the 40th parallel, and see no obvious means by which Zamboni’s theory can account for this.

    Now, two studies just published in the Annals of Neurology, one from Sweden, one from Germany, compound that doubt. Both studies used imaging techniques to examine the neck veins of MS patients and matched controls; neither detected any consistent difference at all.

    So, Zamboni, and the patients who claim significant responses to his treatment, believe his observations constitute an epiphany. Much of the medical and research community is far less sanguine, and considers the approach a potential boondoggle.

    The premier of Saskatchewan, Brad Wall, confronted this dilemma with a greater sense of urgency than most. Canada has one of the highest rates of MS in the world; the prairie province has the highest rates in Canada. So as of July, Saskatchewan became the first Canadian province to dedicate research dollars to study liberation procedure, and actively encourage clinical trials.

    I was privileged to speak with Wall and discuss the basis for his decision. I found him knowledgeable, informed, thoughtful and measured.

    Wall knows liberation therapy is not certain to work, and is certainly not devoid of risk. But like most residents of Saskatchewan, he knows the toll of MS within his own circle of friends and family. He knows how fervent is the hope, and need, for new therapies.

    Wall has not endorsed liberation therapy, even in the face of compelling anecdotes from citizens of his own province. Rather, he has endorsed the hope engendered by the therapy, and the need to cultivate that hope by determining — responsibly, but swiftly — whether the promise of the remedy is one it can truly fulfill.

    In theory, the prime directive of medicine is “primum non nocere,” first do no harm. Even the statistical underpinnings of all biomedical research are designed to protect us from a rush to folly: studies conventionally permit up to a 20 percent risk of a false negative result (i.e., concluding something doesn’t work when it does), but only a 5 percent risk of a false positive (i.e., concluding something works when it doesn’t). But without boldly accepting some risk of doing harm, we have no real potential to do good. And harm can be done by inaction; there are sins of omission, just as there are sins of commission.

    I do not yet know if liberation therapy works. I agree with Wall that we need to find out. I commend Wall for exercising bold leadership betwixt the perils of commission and omission. Saskatchewan’s policy, which I hope others will adopt, will help us determine sooner, rather than later, what happens when the hope kindled by liberation therapy is fed the fuel of science.

    Between now and then, I urge patience. Hope is a powerful impulse that readily invites a leap of faith; good science is much more reliable. There is apparent promise in liberation therapy, but we need well-done research to tell us if it is promise the procedure can keep.

    By Dr. David Katz.

    Source: New Haven Register © Copyright 2010 New Haven Register (09/08/10)

    Joint CCSVI MS study to begin within weeks
    CCSVI VenogramSt. Joseph's Healthcare will start testing whether multiple sclerosis is a vascular disease within two weeks despite European studies questioning the controversial theory.

    The highly-anticipated study funded by more than $250,000 in private donations is being tweaked after a test run involving 10 patients and 10 similar healthy people and is expected to be ready to go by the end of next week.

    "There were no major wrinkles," lead researcher, Dr. Ian Rodger, said of the test run. "We are validating everything we're going to do to make sure we've got it right because for the next 200 (subjects) we're changing nothing."

    Rodger says Hamilton's study -- a joint effort by St. Joseph's, McMaster University and Hamilton Health Sciences -- is not impacted by two recent studies contradicting the theory by Italian vascular surgeon Dr. Paolo Zamboni called chronic cerebrospinal venous insufficiency (CCSVI).

    Zamboni's study of 65 MS patients shows veins draining blood from the head are blocked, creating a buildup of iron in the brain. He opens the veins using angioplasty -- a common medical procedure -- in what he has called the liberation treatment.

    A Swedish study of 21 MS patients and 20 similar healthy people and a German study of 56 patients and 20 healthy people published in the Annals of Neurology found no differences in the veins of the two groups.

    "When negative results come out people say, 'I told you so,'" said Rodger.

    But he says the European studies are small and different from what McMaster plans to do. The Swedish study used MRI and only tested patients with one type of MS. The German study primarily used ultrasound.

    The Hamilton study will use both ultrasound and MRI to study the veins of 100 MS patients with four different types of the disease and compare it to 100 similar healthy people.

    "One of the controversies is how you make the measurements," said Rodger. "People do some things one way and get one answer and others do it another way and get another answer."

    Earlier studies have had opposite results to the European research. Research on 500 people in Buffalo and another large Kuwait study both backed up Zamboni's theory.

    Rodger says the contradicting results show that much more research is needed.

    MS patients and their families have funded the research at St. Joseph's, so far.

    An Ancaster chef who has no connection with MS is also raising money. Ronald Reeleder is holding a dinner and auction on Aug. 16 as part of his campaign to raise $20,000 for the MS Society of Canada and $20,000 for the Hamilton study. As part of his fundraising efforts, he plans to climb to the base camp at Mount Everest in October.

    "I'm healthy," he said. "I'm blessed because I've never had any sickness and neither have my family. If you're blessed like that, you should help others. I'm able to do it, so I want to do it."

    Source: theSpec.com © Copyright Metroland 2010 (05/08/10)

    Two studies cast doubt on new MS theory
    CCSVI VenogramResearch has emerged casting doubt on a popular new theory that multiple sclerosis is caused or worsened by blockages in the jugular veins.

    In separate studies from Germany and Sweden, to be published Monday in the Annals of Neurology, researchers report they found no such trend of blockages in patients' jugular veins, which carry blood away from the brain back to the heart.

    The theory, championed by an Italian vascular surgeon and some doctors in the U.S., has inspired thousands of MS patients to get tested and, in some cases, to get treatment such as the insertion of metal stents in jugular veins to keep them open.

    "Our results challenge the hypothesis that cerebral venous congestion plays a significant role in the [disease process] of MS," wrote Florian Doepp, a neurologist at Humboldt University in Berlin, and colleagues. They did ultrasound and other imaging exams on 56 MS patients and 20 normal control-group patients. "Our results suggest the cerebral venous drainage in patients with MS is not restricted," they wrote.

    A smaller study from Umea University in Sweden looked at 21 MS patients and 20 healthy patients and concluded, "We found no differences regarding internal jugular venous outflow."

    MS is generally thought of as an autoimmune disease, meaning that a patient's body attacks its own cells. Symptoms vary widely but often involve progressive weakness and pain and can include speech disorders and spasticity.

    The theory about jugular-vein blockage originated from Paolo Zamboni of the University of Ferrara in Italy. Dr. Zamboni's reports have spread rapidly among patients through the Internet, propelling thousands of MS patients to get examined or treated.

    At Stanford University in California last year, a doctor treated 40 MS patients with balloon angioplasty or stents to open veins. Some patients reported symptom improvement. After one patient died and another underwent emergency surgery for a stent that floated into his heart, the university shut down the program but says it is considering further research.

    Currently, a study at the State University of New York at Buffalo is examining 1,000 patients after about 10,000 sought to participate in the research.

    Dr. Zamboni said he stands by his findings. He said he hasn't read the Swedish report, but he questions some methodology in the German research. He said his own multiyear survey of 500 MS patients has found that 90% have vein blockage, compared with only 2% of 1,000 control-group patients who are healthy or have other neurological diseases.

    The reports from Germany and Sweden won't be the final word. The National Multiple Sclerosis Society, along with its sister group in Canada, have funded more than $2.4 million in studies to evaluate the vein-blockage theory. However, these two reports from Europe have heightened the skepticism of some MS experts about vein-blockage underlying MS.

    Stephen L. Hauser, editor-in-chief of Annals of Neurology and chief of neurology at the University of California, San Francisco, said of the European research that "these two papers tried to replicate" Dr. Zamboni's findings, and that "the original concept hasn't been confirmed." Dr. Hauser had complained to Stanford after his patient had to undergo emergency surgery there after a stent in a vein floated into his heart.

    Source: The Wall Street Journal  ©2010 Dow Jones & Company, Inc (02/08/10)

    Visualizing iron deposition in Multiple Sclerosis cadaver brains
    Iron Deposition in MS BrainAbstract

    Aim: To visualize and validate iron deposition in two cases of multiple sclerosis using rapid scanning X-Ray Fluorescence (RS-XRF) and Susceptibility Weighted Imaging (SWI).

    Material and Methods: Two (2) coronal cadaver brain slices from patients clinically diagnosed with multiple sclerosis underwent magnetic resonance imaging (MRI), specifically SWI to image iron content. To confirm the presence of iron deposits and the absence of zinc-rich myelin in lesions, iron and zinc were mapped using RS-XRF.

    Results: MS lesions were visualized using FLAIR and correlated with the absence of zinc by XRF. XRF and SWI showed that in the first MS case, there were large iron deposits proximal to the draining vein of the caudate nucleus as well as iron deposits associated with blood vessels throughout the globus pallidus. Less iron was seen in association with lesions than in the basal ganglia. The presence of larger amounts of iron correlated reasonably well between RS-XRF and SWI. In the second case, the basal ganglia appeared normal and acute perivascular iron deposition was absent.

    Conclusion: Perivascular iron deposition is seen in some but not all MS cases, giving credence to the use of SWI to assess iron involvement in MS pathology in vivo. ©2010 American Institute of Physics

    Charbel A. Habib,a Weili Zheng,a E. Mark Haacke,a Sam Webb,b and Helen Nicholc

    aDepartment Of Biomedical Engineering, Wayne State University, Detroit, MI 48202, USA

    bStanford Synchrotron Radiation Lightsource, Stanford Linear Accelerator Complex National Accelerator Laboratory, Menlo Park, California, USA

    cDepartment of Anatomy and Cell Biology, University of Saskatchewan, 107 Wiggins Rd. Rm A302, Saskatoon, SK S7N5E5, Canada

    Source: AIP Conf. Proc. -- July 23, 2010 -- Volume 1266, pp. 78-83
    6TH INTERNATIONAL CONFERENCE ON MEDICAL APPLICATIONS OF SYNCHROTRON RADIATION; doi:10.1063/1.3478203 (30/07/10)

    Chronic cerebrospinal venous insufficiency - A new paradigm and therapy for multiple sclerosis
    CCSVI VenogramBy Salvatore J.A. Sclafani, MD,
    Commentary by Michael D. Dake, MD,
    and Barry T. Katzen, MD

    Chronic cerebrospinal venous insufficiency (CCSVI) is a hemodynamic condition in which cerebrospinal venous drainage is altered and inhibited.

    Outflow obstructions of the internal jugular veins (IJVs), vertebral veins, and/or azygos vein (AZV) and their tributaries result in stasis or reflux of these outflow veins and redirection of flow through vicarious circuits.

    Cerebral blood flow and brain perfusion are retarded and may result in cerebral atrophy, venous microhemorrhage, and cerebral hypertension. Moreover, stasis may evolve into occlusions of these veins or the dural sinuses.1

    The previously reported acute outflow obstructions of the dural sinuses and jugular veins have been due to hypercoagulable states, inflammation, iatrogenic trauma during prolonged catheterization, and compression by neck neoplasms and adenopathy.2-5 These occlusions and stenoses cause acute manifestations of cerebral venous outflow obstruction. Mental confusion, severe headaches, weakness and lethargy, acute visual disturbances, and facial and glottic edema are clinically obvious and quite severe.

    Treatment of the obstructions, by angioplasty, angioplasty and stenting, or thrombolysis and stenting, results in prompt and satisfactory amelioration of these symptoms. It has also been shown that acute jugular incompetence can result in transient global amnesia.6

    The fact that venous insufficiency can cause acute neurological disturbances was convincingly demonstrated in a case report about a patient with a patent arm dialysis arteriovenous shunt who developed increasing headaches, gait disturbance, and cognitive dysfunction that significantly improved after ligation of that shunt.7

    The majority of patients with CCSVI appear to have multiple sclerosis (MS), and the majority of patients with MS have CCSVI. MS is an inflammatory demyelinating disorder of the brain and spine with protean neurological manifestations. It is the most common neurological disorder of young adults. It is quite possible that some of the protean manifestations of MS, including fatigue and lethargy, headaches, and cognitive dysfunction, may actually represent symptoms of CCSVI itself.8

    CCSVI is more insidious in its onset than acute venous insufficiency. In fact, the association of CCSVI with MS has been largely ignored despite Charcot’s original description of the relationship of the cerebral veins and inflammatory lesions that are the hallmark of MS.9

    Zamboni proposes that CCSVI has a role in the pathogenesis of MS. He suggests that resistance to cerebrospinal venous outflow causes vicarious redistribution through small collateral veins that cannot handle high flow.10 He also suggests that tight endothelial junctions widen to allow diapedesis of red blood cells, T cells, and other immune cells into the brain, resulting in inflammation and hemosiderosis that is reminiscent of what is seen with venous insufficiency of the lower extremities. This is supported by iron deposition as seen on susceptibility-weighted magnetic resonance imaging (SW-MRI), which reveals that the inflammatory MS plaques always surround a central venous structure. MRI shows that the central vein and surrounding plaque have abnormal quantities of iron. Pathologically, the basement membranes of these deep veins are thickened, and hemosiderin deposits are present in the wall of and adjacent to the deep cortical veins. T cells and macrophages violating the blood-brain barrier provide a working explanation for the autoimmune cascade that result in demyelination and the neurological manifestations associated with MS.

    DIAGNOSIS
    Ultrasound
    One could argue that the diagnosis of MS is sufficient to justify catheter venography to identify venous abnormalities worthy of angioplasty. However, Zamboni used ultrasound imaging to noninvasively screen patients who might have CCSVI, and this algorithm persists as the route of detection. His protocol includes transcranial and extracranial Doppler to detect deranged hemodynamics and B-mode ultrasound to detect stenoses and changes in cross-sectional diameters in the supine and the upright positions. He states that two of five characteristics lead to a diagnosis of CCSVI. The five characteristics are (1) reflux within the IJVs or vertebral veins, (2) reflux within any of the deep cerebral veins, (3) no flow in the IJV on activation of the thoracic pump upon inspiration, (4) failure of the IJV to increase in diameter in the supine position compared to the erect position, and (5) any B-mode abnormality such as septum, stenosis, abnormal valve, etc.

    MR Venography and Computed Tomographic Venography
    Others have used cross-sectional venography to evaluate venous stenosis (Figure 1). The majority of sites use MR venography, but occasionally, computed tomographic venography is also used. To evaluate the dural sinuses and the veins of the neck, two-dimensional and two-dimensional contrast-enhanced imaging is used. These cross-sectional studies show a variety of findings that include venous narrowing and collateral vessels throughout the neck. Occasionally, narrowing or occlusions of the dural sinuses are noted, but for the majority of times, findings are restricted to the neck. However, there is poor correlation between the anatomical findings on MR venography and subsequent catheter venography. Many areas of narrowing on MR venography are not constant and are not reproduced during catheter-based studies.

    Hemodynamics of Cerebral Venous Drainage Explain False-Positive Findings on MR Venography
    To explain this enigma, one must understand the hemodynamics of cerebral venous outflow. The brain has two methods of venous drainage: blood drains anteriorly through the internal jugular system in the supine position and posteriorly through the vertebral system when erect. In the normal, upright patient, the jugular vein collapses (narrows) because there is not enough blood flow through it to maintain distension. In the supine position, the normal IJVs distend because the supine position favours jugular flow. The same issues apply when there is increased resistance to jugular flow. The alternate vertebral venous outflow system shunts blood away from the jugular veins. Because pressure is normally low and only marginally rises with obstruction, distension of the obstructed system does not occur.

    As a result, many of the narrowings seen in CCSVI are caused by compression of a collapsed system by external forces rather than due to stenoses. This may lead to unnecessary angioplasty. The common areas of questionably physiological stenosis seen on MR venography are located at the skull base, adjacent to the carotid bulb, or where strap muscles exert compression.

    VENOGRAPHY AND VENOGRAPHIC OBSERVATIONS
    Venography remains the gold standard for evaluating the anatomy of the veins draining cerebrospinal blood flow. It should be emphasized that a reliable assessment of the azygos system can only be done by using catheter venography.

    Technique
    The venographic evaluation is begun by placing a headhunter catheter in the left femoral vein with the purpose of excluding May-Thurner syndrome. The catheter is subsequently placed in the left ascending lumbar vein to assess the lumbar veins for hypoplasia and other abnormalities. The left renal vein is then catheterized to look for abnormalities of the renal vein tributaries. The purpose of these three studies is to look for causes of increased blood flow into lumbar veins that might be compromised by azygos stenosis.

    The catheter is then placed in succession into the AZV and both IJVs. The catheter is positioned in the AZV at the junction with the hemiazygos vein. Contrast venography is done twice: first at 3 mL/s for a total volume of 10 mL to look for reflux, followed by a second, fuller injection at 8 to 10 mL/s for a total volume of 20 to 30 mL to delineate all the anatomy. The AZV and its tributaries are imaged to include the chest and abdomen. Some physicians measure pressures, but I have not found this to be helpful. Any stenosis is treated, as will be described later.

    The catheter is then withdrawn from the AZV and advanced sequentially into each IJV. Catheterization of the IJV may be challenging because funneled narrowing of stenotic valve leaflets occurs near the origin of the vessel. Occasionally, an incomplete duplication is present posterior to the main ostium. This may make catheterization confusing and difficult. Two contrast injections are performed: one with a slow injection of 3 mL/s for a total volume of 10 mL and one with a fuller injection of 8 to 10 mL/s for a total volume of 20 mL. Film rates of 3 to 6 frames per second are necessary to get sufficient detail of the valves and to detect ostial narrowing that may become obscured as contrast enters the brachiocephalic veins and overlaps the confluens where stenosis is often located. Any stenoses or other outflow obstructions are treated at this time. Diluted contrast abnormalities (50:50 mixture of saline) is helpful in the IJV evaluation because valve abnormalities and some webs may be obscured by very dense contrast media.

    Venographic Findings
    First, there are numerous collateral veins when outflow obstructions are present (Figure 2). These veins may be wildly abnormal and include hypoplasias and early divisions that reconnect to a larger conduit. The vertebral veins may be enlarged and can be confusing in their appearance. The pathology of this disease is a truncal malformation of the veins that is probably genetically determined; it is not an inflammatory or postphlebitic stenosis. Much of the resistance to blood flow is related to abnormal valve development. Fused, reversed, thickened, and other abnormally located and developed valves cause resistance to flow. Atresias, hypoplasias, duplications, webs, septums, and kinks also occur. Most of these abnormalities are located centrally near the confluens. Challenges occur when more peripheral narrowings are present, which may be physiological.

    INTRAVASCULAR ULTRASOUND
    Diagnosis by venography can also be subtle. I have found that intravascular ultrasound (IVUS) is very helpful in identifying some of these abnormalities, as well as in differentiating the narrowed veins caused by inadequate volume from the narrowed veins resulting from stenosis (Figure 3). IVUS enables a real-time assessment of the distensibility of collapsed veins. Simple maneuvers, such as slow sustained inspiration by activating the thoracic pump, allow improved distension of the vein and confirms that the narrowing is not fixed. Further, IVUS allows detection of improper or incomplete valve movement. Finally, incomplete duplications of the jugular vein may not be detected without IVUS.

    TREATMENT OPTIONS
    Treatment of these abnormalities is still in development, and the ideal methodologies for treatment have not yet been established. Essentially, only one team has published an outcomes study.1 Results were encouraging but showed limitations. Angioplasty with high-pressure balloons of diameters 4 mm greater than nominal diameters in 2- to 4-cm lengths is performed with venographic control. Inflations to maximum pressures for 30 to 60 seconds were used several times. Some of these obstructions are very resistant, and Cutting balloons (Boston Scientific Corporation, Natick, MA) are used with increasing frequency. Dr. Sinan Tariq, the leader of the Kuwaiti national trial, has been using valvulotomy devices with some success (personal communication, April 2010). Stenting is performed by some investigators for resistant narrowings. However, no reports have been published about their outcomes. I have not used stents in any cases yet.

    AFTERCARE AND FOLLOW-UP
    The procedure is performed under local anesthesia in an ambulatory setting. Most patients are kept in the hospital for 1 or 2 hours and then discharged. Most physicians treat patients with clopidogrel or short-term anticoagulation with heparins, enoxaparin, or fondaparinux. Clinical and imaging follow-up varies among investigators. Assessment tools are predominantly clinical and include an expanded disability status score (EDSS), which is a neurological assessment of eight areas of the central nervous system, along with certain measures of disability and restriction in daily life. These scores are added up to give a rating on the EDSS, which ranges from 0 (normal) to 10 (death due to MS). From step 4 onward, the ability to walk becomes the key factor in determining the EDSS score.

    OUTCOMES
    It must be emphasized that only one team has published any clinical results, and although promising, they were not overwhelming. Zamboni’s group described an open-label experience of patients with MS who were allowed to stay on disease-modifying drugs for their MS. The results were encouraging, with statistically significant improvements in cognition and motor function and reduced exacerbation rates, and MRI confirmed diminished new brain lesion development. The patients who have shown the most positive results are those in the relapsing-remitting phase of the disease. Patients with primary progressive MS, for whom there is no proven treatment, had the least positive effects.

    However, the dilatations are not always durable, with approximately half of the patients developing restenosis between 8 to 14 months. It is interesting that all patients who suffered from an exacerbation of symptoms had a restenosis and that no patients who had durable angioplasty experienced restenosis.

    Overall, the procedure is well-tolerated, and patients do not require sedation. The complications reported in Zamboni’s trial were minimal. I have had one early thrombosis that did not respond to thrombolytics and one case of atrial fibrillation that I thought might have been a response to treatment that modified autonomic neural transmission, but resolved within 12 hours. Those interventionists who have used stents have not yet reported outcomes in the literature.

    Dr. Zamboni cautions against stents because they are not designed for placement at the confluens of the jugular vein with the subclavian vein where the jugular vein widens. Improved flow is shown to significantly increase the diameter of these veins. He worried about migration in his article, and indeed, one of the early patients treated with stenting by another interventionist is reported in the lay press to have required open heart surgery for stent retrieval.

    CAVEATS
    CCSVI has not been well-accepted by the neurological community. Many leaders strongly oppose this treatment on the grounds that no randomized prospective trials have taken place, and they describe the procedure as dangerous and invasive. Patients who are not enamored by current treatments find this mechanical solution alluring. They have become activists and are seeking physicians with catheter skills to begin these treatments. The fact that clinical improvements occur cannot be disputed. Although the placebo effect cannot be ignored, some of the anecdotal positive results have been impressive. Even before leaving the procedure room, patients describe improved cognition and a return of sensation and reduction in neuralgia within minutes. One patient, who was confined to a wheelchair because of spasticity, ataxia, and weakness, returned the next morning after a quick run up the stairs to show his ability to stand on one leg without difficulties.

    However, these improvements may not persist, and exacerbation may occur within weeks of the procedure. Is this caused by recurrent stenosis or increased reflux? Nonetheless, the improvements warrant further investigation and well thought-out trials. The diagnosis is not always obvious. The current experience is about discovering who, what, and how to treat. Safety studies are needed to develop more information and experience. Additional work and publication of results are also necessary before there is advocacy of the widespread application of venoplasty for CCSVI.

    Salvatore J.A. Sclafani, MD, is Professor and Chairman of Radiology and Professor of Surgery and Emergency Medicine, State University of New York Downstate Medical Center in Brooklyn, New York. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein. Dr. Sclafani may be reached at (718) 245-4447; [email protected].

       1. Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg. 2009;50:1348-1358.
       2. Huang P, Yang YH, Lin WC, et al. Successful treatment of cerebral venous thrombosis associated with bilateral internal jugular vein stenosis using direct thrombolysis and stenting: a case report. Kaohsiung J Med Sci. 2005;21:527-531.
       3. Philips MF, Bagley LJ, Sinson GP, et al. Endovascular thrombolysis for symptomatic cerebral venous thrombosis. J Neurosurg. 1999;90:65-71.
       4. Chaloupka JC, Mangla S, Huddle D. Use of mechanical thrombolysis via microballoon percutaneous transluminal angioplasty for the treatment of acute dural sinus thrombosis: case presentation and technical report. Neurosurgery. 1999;45:650-6; discussion 656-657.
       5. Gurley MB, King TS, Tsai FY. Sigmoid sinus thrombosis associated with internal jugular venous occlusion: direct thrombolytic treatment. J Endovasc Surg. 1999;3:306-314.
       6. Schreiber SJ, Doepp F, Klingebiel R, et al. Internal jugular vein valve incompetence and intracranial anatomy in transient global amnesia. J Neurol Neurosurg Psychiatry. 2005;76:509-513.
       7. Hartmann A, Mast H, Stapf C, et al. Peripheral hemodialysis shunt with intracranial venous congestion. Stroke. 2001;32:2945-2946.
       8. Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009;80:392-399.
       9. Charcot JM. Histology of “sclerose en plaque” (in French). Gazette Hosp (Paris). 1868;41:554-566
      10. Zamboni P, Menegatti E, Bartolomei I, et al. Intracranial venous hemodynamics in multiple sclerosis. Curr Neurovasc Res. 2007;4:252-258.

    Commentary

    The Relationship Between CCSVI and MS
    BY MICHAEL D. DAKE, MD, AND BARRY T. KATZEN, MD
    In this article, Dr. Salvatore Sclafani presents an introduction to chronic cerebrospinal venous insufficiency (CCSVI) and the current understanding of its association with multiple sclerosis (MS). Much of the initial evidence supporting this possible relationship has been reported by Dr. Paolo Zamboni and colleagues. Using duplex ultrasonography and transcranial Doppler studies, they have documented the frequent association of abnormal venous hemodynamics with MS. In one study of 109 MS patients and 177 age- and gender- matched controls, subjects underwent a blinded transcranial and extracranial color Doppler sonographic assessment (TCCS-ECD) of five parameters related to venous outflow hemodynamics. These five criteria are detailed by Dr. Sclafani in his review. In controls, only 2.7% of the measurements were abnormal, whereas in MS patients, 47% of measurements were anomalous.1

    In a study comparing duplex ultrasound with contrast venography, 40% to 70% of MS patients had evidence of flow disturbances and/or venous stenosis by TCCS-ECD. Of these patients, 86% and 91% had obstructive disease of the azygos or internal jugular veins, respectively, as assessed by traditional catheter venography.2

    Some of the symptoms of MS mimic those observed in patients with superior vena cava syndrome. Relief of superior vena cava obstruction with venous angioplasty and stent placement, if required, provides swift and dramatic resolution of the symptoms of impaired cognition and fatigue.3 Thus, it is not surprising that patients with CCSVI associated with MS also report rapid relief of these nonlocalizing symptoms.

    It is well-recognized, however, that many symptoms of MS fluctuate and are largely subjective. It is possible that in the initial nonrandomized patient series reported to date, the improvement in symptoms could reflect a strong placebo effect. Nonetheless, the biological plausibility linking cerebral venous congestion to inflammation that is the hallmark of MS requires serious consideration. Whether the relief of the venous obstruction will have an impact on the course of the neurological disease remains to be seen.

    Although the initial observations relating CCSVI and MS are interesting and potentially paradigm-shifting, they now need rigorous testing. As Dr. Sclafani correctly points out, there are life-threatening adverse effects that may complicate endovascular management of CCSVI. A randomized clinical trial is needed to assess the risks and benefits of endovascular treatment of this condition. There are many physicians and others who have endovascular skills who are promoting and developing centers for treating these patients without regard for the lack of scientific data to support therapy. Patients with this disease have frequently suffered for long periods of time, often without great relief of symptoms and are often desperate for any alternative that may offer hope.

    We remain very concerned about the possibility of misleading these individuals or exposing them to additional risk, outside of scientific efforts to get a better understanding of this potentially exciting therapy. Given the concerns of the neurology community, it would be unfortunate if the attempts to advance this field suffer the consequences of premature promotion of a procedure that could mislead patients, payors, and regulators.

    Accordingly, we propose a global initiative to meticulously document the prevalence of venous anomalies in MS, by comparison to age- and gender-matched healthy individuals, as well as those with neurological disease not due to MS. In part, recent grants from the National MS Society awarded to seven investigative groups to study CCSVI will help initiate this effort in the United States and Canada. These observations may provide a basis for a clinical trial in MS to assess the long-term safety and efficacy of endovascular procedures in restoring normal venous hemodynamics, in relieving the nonlocalizing symptoms secondary to venous obstruction, and in slowing or halting the inflammatory and demyelinating processes. In parallel, the development of animal models will advance our understanding of how CCSVI may influence or even initiate the pathophysiology of MS.

    Michael D. Dake, MD, is Professor, Department of Cardiothoracic Surgery, Stanford University School of Medicine in Stanford, California. He has disclosed that he receives grant/research funding from Cook Medical. Dr. Dake may be reached at [email protected].

    Barry T. Katzen, MD, is Founder and Medical Director of Baptist Cardiac and Vascular Institute and Clinical Professor of Radiology at the University of South Florida College of Medicine in Florida. He has disclosed that he is a member of the scientific advisory board for W. L. Gore & Associates. Dr. Katzen may be reached at [email protected].

       1. Zamboni P, Menegatti E, Galeotti R, et al. The value of cerebral Doppler venous hemodynamics in the assessment of multiple sclerosis. J Neurol Sci. 2009;282:21-27.
       2. Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009;80:392-399.
       3. Kee ST, Kinoshita L, Razavi MK, et al. Superior vena cava syndrome treatment with catheterdirected thrombolysis and endovascular stent placement. Radiology. 1998;206:187-193.

    Source: Endovascular Today © Bryn Mawr Communications LLC (23/07/10)

    County surgeon to pursue Multiple Sclerosis trials
    Sandy McDonaldWith health officials clamouring for more scientific research before green-lighting the new liberation treatment for multiple sclerosis (MS), local supporter and cardiovascular-thoracic surgeon Sandy McDonald is stepping up to provide it.

    “I’m working with colleagues to design a double-blinded study for assessing CCSVI and its treatment,” he said, anticipating a more extensive test group than the preliminary trials first published by pioneering Italian vascular surgeon Paolo Zamboni.

    “We have two neurologists, three vascular surgeons and interventional radiologists interested in being involved.”

    In the process of gaining Institutional Review Board approval, McDonald said the trial is moving forward as quickly as possible, but “we have a lot of hurdles to get past before we get there.”

    Zamboni rocked the global MS community last November by linking blocked veins in the head, neck and shoulders to the symptoms of the disease – a condition he dubbed Chronic Cerebrospinal Venous Insufficiency (CCSVI). He took his hypothesis a step further when his team performed balloon angioplasties to free the blood flow. The reported results, detailing alleviated MS symptoms, were groundbreaking.

    McDonald traveled to Italy to study Zamboni’s unique vein-scanning techniques first hand to avoid the false negatives often obtained through more traditional imaging.

    He has since provided the non-subsidized tests at no cost to patients or the health-care system upon physician referral to his Alliance Boulevard clinic.

    The actual procedure, however, is currently not available in Canada.

    Earlier this year, McDonald requisitioned six MS-related angioplasties for patients showing the tell-tale vein abnormality and associated iron debris, with follow-up visits revealing encouraging results across the board.

    Some reported increased mobility and speech, and another claimed no further symptoms at all.

    One young man’s parents had installed an elevator in their house to help their son’s mobility prior to the procedure. Now he is not only able to climb stairs without hesitation, but McDonald reports his patient has since moved into his own home where he lives independently.

    After the positive results in his first few cases, McDonald and the interventional radiologists who performed the procedure decided to take a brief hiatus to first establish a method of capturing the data and tracking the results in order to share their findings.

    Although the timeframe has stretched on longer than he initially anticipated, the surgeon now hopes to accept qualified patients into a full-scale research trial, complete with a treatment arm, come fall.

    In the meantime, McDonald said the approximately 1,000 successful liberation treatments done to date around the world should be enough to encourage the Canadian health-care system to allow the treatment as an option to patients – even if on a pay-per-service basis.

    Source: Simcoe.com © Copyright Metroland 2010 (23/07/10)

    Study raises new questions about vascular theory for MS
    CCSVI VenogramA new study from Germany has found that multiple sclerosis (MS) patients showed no evidence of chronic cerebrospinal venous insufficiency (CCSVI) -- striking a blow against the theory that obstructed blood flow in veins exiting the brain may be a cause of MS.

    Ultrasound exams of jugular and vertebral veins in 56 MS patients and 20 controls yielded normal findings in nearly all of them, reported Florian Doepp, MD, of Humboldt University in Berlin, and colleagues online in Annals of Neurology.

    The findings directly contradict results reported last year and in 2007 by Paolo Zamboni, MD, of the University of Ferrara in Italy, and colleagues from a 300-participant ultrasound study, in which nearly all the MS patients but few controls had CCSVI.

    MS is thought to be an autoimmune disease caused by the destruction of the fatty myelin coating that surrounds and protects nerve cells, hampering or interrupting nerve impulses traveling to and from the brain and spinal cord, leading to a variety of symptoms and disabilities.

    The disease is thought to affect 2.5 million people worldwide and around 400,000 patients in the U.S., according to the National Multiple Sclerosis Society (NMSS).

    The hypothesis behind CCSVI is that obstructed blood flow due to stenosis of veins exiting the brain causes blood to back up, leading to inflammation.

    In the new German study, blood flow direction in both jugular and vertebral veins was found to be normal in 55 of the patients and all of the controls, and no evidence of internal jugular stenosis was seen in any participant, the researchers reported.

    Zamboni had listed five criteria for a diagnosis of CCSVI. However, "none of the subjects investigated in this study fulfilled more than one" of those criteria, Doepp and colleagues wrote.

    The report by German researchers is the second study in recent months to cast doubt on the prevalence of CCSVI among MS patients.

    Interim findings from a large, ongoing trial led by researchers at the State University of New York at Buffalo, reported in April at the American Academy of Neurology annual meeting, found middling percentages of MS patients, as well as a large minority of controls, met criteria for CCSVI.

    At the AAN meeting, Robert Zivadinov, MD, PhD, presented data from the first 500 participants in the projected 1,700-subject study.

    He reported that 56% of MS patients, 43% of those with other neurologic illnesses, and 22% of healthy volunteers met at least two of the CCSVI criteria, which include venous reflux, stenosis, missing flow, and abnormal blood flow in the jugular or vertebral veins following postural changes.

    In the study by Doepp and colleagues, there were some differences in venous flow responses to postural changes between patients and controls, but they fell short of confirming CCSVI, the researchers indicated.

    They found a decrease of total jugular blood volume flow when patients sat upright that was less pronounced in patients. The decrease was about half the magnitude seen in controls, Doepp and colleagues reported, such that blood flow volume in the sitting position was nearly three times as great in MS patients relative to controls.

    There were no differences between patients and controls in intracranial venous flow, or in jugular flow when the Valsalva maneuver was performed.

    "Against this backdrop we discourage interventional procedures as more work is being done to investigate 'CCSVI' and its possible role in MS," Doepp and colleagues wrote.

    Robert J. Fox, MD, a neurologist at the Cleveland Clinic, said the findings from the German and Buffalo studies suggested "caution before we jump up and embrace [the CCSVI theory] fully."

    Fox spoke this week during a live webcast sponsored by the NMSS, which recently awarded $2.4 million in grants for seven research projects -- including one led by Fox -- evaluating the CCSVI hypothesis in detail.

    He noted that the Buffalo data found a substantially lower prevalence of CCSVI among the MS patients and a greater prevalence in the healthy controls than in the Italian studies.

    Moreover, Fox said, the finding that nearly half the non-MS patients with other neurological conditions met CCSVI criteria might argue against a causative role in MS specifically.

    "This raises the question of, maybe the venous findings are not directly related to MS, but are related to some injury of the brain -- maybe a downstream but maybe an upstream effect of injury," he said.

    Patricia O'Looney, PhD, vice president for biomedical research at the NMSS, echoed the cautions about CCSVI, particularly as it relates to treatment.

    Zamboni and colleagues have reported successful reversal of symptoms in MS patients following venoplasty, with stenting performed in some patients.

    But there was no blinding or control group, raising the question of a placebo effect or, as Fox suggested, a natural regression in MS symptoms often seen in patients.

    Nevertheless, neurologists have reported that patients are now asking about such treatments and even traveling overseas to receive them.

    Indeed, during the NMSS webcast, questions from patients focused on the advisability and availability of ultrasound evaluations and venoplasty treatment.

    "The society shares in the public urgency to advance the understanding of CCSVI as quickly as possible," O'Looney said during the webcast.

    But she noted the "conflicting results in the current reported studies" and said the society's research grants were intended to "quickly and comprehensively determine the significance of CCSVI."

    In the meantime, she said, the U.S. and Canadian MS societies agree that data supporting treatment based on the CCSVI theory "are not yet available," and hence it would be premature to recommend them to patients.

    Fox said he tells patients not to seek venous ultrasonography precisely because any treatments based on the findings remain scientifically untested.

    "As with any therapy, it comes down to the cost-benefit ratio," he said. "What are the risks of treatment, and what are the benefits? Without a controlled trial and further study, I think we really don't know the answer to either part of that tradeoff."

    The study by Doepp and colleagues was funded by the German Research Foundation.

    One author reported speaking fees from Sanofi-aventis, Novartis, and Merck Serono.

    O'Looney reported no potential conflicts. Fox has had relationships with Biogen Idec, Teva, and Genentech.

    Primary source: Annals of Neurology
    Source reference:
    Doepp F, et al "No cerebro-cervical venous congestion in patients with multiple sclerosis" Ann Neurol 2010; DOI: 10.1002/ana.22085.

    Source: Medpage Today © 2004-2010 MedPage Today, LLC. (05/07/10)

    Clinical trial testing new Multiple Sclerosis treatment to launch in Buffalo
    CCSVI VenogramResearchers at the University at Buffalo, led by the Department of Neurosurgery, will embark on a landmark prospective randomized double-blinded study to test the safety and efficacy of interventional endovascular therapy—dubbed “liberation treatment”—on MS symptoms and progression.

    Recently, chronic cerebrospinal venous insufficiency CCSVI) has been strongly associated with multiple sclerosis (MS). In a series of original studies, Dr. Paolo Zamboni of the University of Ferrara, Italy demonstrated blockage of major venous outflow from the brain and spinal cord in patients with MS. Researchers from many institutions, including the University at Buffalo, have confirmed the association.

    It is hypothesized that the narrowing in the large veins in the neck and chest might cause improper drainage of blood from the brain, resulting in eventual injury to brain tissue. It is thought that angioplasty—a treatment commonly used by cardiologists and other endovascular surgeons to treat atherosclerosis—may remedy the blockages. Dr. Zamboni has further conducted preliminary studies suggesting the efficacy of venous angioplasty (“liberation procedure”) in the amelioration of MS symptoms.

    Now, researchers at the University of Buffalo will launch PREMiSe (Prospective Randomized Endovascular therapy in Multiple Sclerosis) to determine if endovascular intervention via balloon angioplasty to correct the blockages improves MS symptoms or progression. PREMiSe is believed to be the first IRB-approved prospective randomized double-blinded study of balloon angioplasty for MS being performed in a rigorous fashion in the US with significant safeguards in place to ensure careful determination of risks and benefits.

    The study is being led by principal investigator Dr. Adnan Siddiqui along with co-principal investigators Dr. Elad Levy and Dr. L.N. Hopkins of the University at Buffalo Department of Neurosurgery. Additional independent researchers from University at Buffalo will participate in the evaluation and follow-up of study patients. An independent Data Safety Monitoring Board (DSMB) will ensure the safety and effectiveness of the study on an ongoing basis.

    In the first phase of the study, ten MS patients from the United States and Canada exhibiting venous insufficiency will undergo minimally invasive venous angioplasties to determine if the procedure can be performed safely. The procedures, scheduled for June 29 and 30, 2010, will be performed by Drs. Siddiqui and Levy at Kaleida Health’s Millard Fillmore Gates Hospital in Buffalo, New York.    

    The second phase of the study will randomize 20 MS patients to undergo either venous angioplasty or a “sham angioplasty” (i.e. a catheter will be inserted but there will be no inflation of the balloon). The treatment will be blinded in such a way that neither the patient undergoing the procedure nor the clinicians evaluating the patient will be aware which procedure was performed.

    If results suggest an appropriate safety profile and preliminary effectiveness, then researchers will approach the University at Buffalo Institutional Review Board (IRB) for an extension of the protocol to study a larger number of patients in order to convincingly prove or disprove a causal relationship between CCSVI and MS.

    Multiple sclerosis is estimated to affect more than 400,000 people in the United States and over 2 million people worldwide. It is typically a disease of young adults characterized by either a relapsing or progressing decline in neurologic function with resultant significant disability. It is an inflammatory neurological disease widely considered to be autoimmune in nature, though its exact origins remain elusive.

    If angioplasty is proven effective at improving MS symptoms, the resultant implications for the future of MS treatment could be monumental. The physicians conducting PREMiSe are cautious but optimistic that initial findings will be promising.

    Source: PR Web © Copyright 1997-2010, Vocus PRW Holdings, LLC. (29/06/10)

    Canadian agency aims to fund research into angioplasty for MS
    CCSVI VenogramThe Canadian Institute for Health Research wants scientists to submit grant proposals to study whether treating vein abnormalities in multiple sclerosis patients helps relieve their symptoms.

    CIHR President Dr. Alain Beaudet told the parliamentary Subcommittee on Neurological Disease in Ottawa Tuesday that his agency, which is the major federal agency responsible for funding health research in Canada, wants scientists to submit proposals for such research.

    "What I'm asking is for Canadian researchers to propose a protocol for a proper randomized, blinded clinical trial on the effect of this therapeutic approach," he said.

    The study would look at whether balloon angioplasty to open up blocked neck and chest veins relieves MS symptoms any better than patients given a sham treatment or no treatment.

    "I urge researchers interested in better understanding the linkages between MS and CCSVI to apply to CIHR," Beaudet said, noting the deadline for grant proposals is August.

    "Research into clinical treatment of MS has to be accelerated."

    The U.S. and Canadian MS Societies announced last week the awarding of $2.4 million in research grants to study a vein condition dubbed CCSVI, or chronic cerebrospinal venous insufficiency. Those studies will focus on the prevalence of CCSVI in MS patients, not on treatment.

    Four Canadian universities and three American centres will begin that research later this year.

    Beaudet also told the subcommittee that a special committee of experts has been formed, in collaboration with the MS Society of Canada, to analyze the data available on the theory that venous problems may be linked to some MS symptoms.

    "We are asking the committee of experts to analyze what is out there... (including) contradictions in the literature (and tell us) what is needed in further studies," he said.

    He noted as well a meeting of top international researchers in the field will be held in August to focus on accelerating research into MS, including research on CCSVI.

    The subcommittee also heard video testimony Tuesday from Dr. Marian Simka from Poland.

    Simka said he had diagnosed and treated some 347 MS patients for CCSVI, all of whom paid for their diagnosis with ultrasound and MRV and treatment at his hospital in Katowice.

    He reported the procedure "was safe and well tolerated" with "few complications, no deaths, no hemorrhages, no cerebral strokes, no stent migration" in the patients he is tracking.

    Simka has been using metal stents in some patients to keep veins open. The practice is controversial. One case in the U.S saw the stent fall into the patient's heart, prompting open heart surgery to remove it.

    Simka also reported that 80 to 90 per cent of patients treated -- including those with progressive MS for whom there are no drug treatments -- reported improvements in one to two-month follow-up studies. He expects to publish data on his work this fall.

    Also testifying before the committee was Dr. Paolo Zamboni, the Italian doctor pioneering the treatment for CCSVI. He told MPs the procedure has so far shown promising results.

    The developments come on the heels of a recent study in the Annals of Neurology which found no cases of blood flow problems in the veins of patients with MS tested with ultrasound.

    Source: CTV Winnepeg © 2010 CTVGlobeMedia (16/06/10)

    Study questions vein blockages hypothesis in people with MS
    CCSVI VenogramA study published online today, led by scientists from Barts and The London School of Medicine and Dentistry, part of Queen Mary, University of London, and University Hospital Charité, Humboldt University in Berlin, found no evidence supporting previous claims that blockages in veins play a significant role in MS.

    The 2009 proposal, that people with MS have chronically blocked veins, which lead to a backflow of blood into their brains, was reported by a group of Italian researchers, who coined the term chronic cerebro-spinal venous sufficiency ( CCSVI).

    The research triggered international media interest and caused many people with MS to believe their veins need to be scanned and widened, or “liberated” in the words of the leading author. Treatment attempts based on the theory of CCSVI resulted in two serious adverse events, one of which was fatal.

    Dr Klaus Schmierer, a clinical senior lecturer in neuroimmunology at the Blizard Institute for Cell and Molecular Science at Barts and The London, and co-author of the paper published today, said his research with the University Hospital Charité in Berlin brought CCSVI into question.

    “We used virtually identical ultrasound techniques to try and reproduce the results by Dr Zamboni and his co-researchers but we had quite different outcomes. In the 76 subjects used in our research, the blood flow in the head and neck veins was normal in everyone except for one person with MS,” Dr Schmierer said.

    “Although some people have tried interventional procedures to ‘unblock veins’ we would strongly advise against this until further investigations into CCSVI and its possible role in MS are conducted.”

    Dr Schmierer’s fellow researchers, Florian Doepp, Jose Valdueza and Stephan Schreiber, performed an extracranial and transcranial venous ultrasound analysis of 76 subjects; 56 people with MS and 20 healthy people. None of the subjects fulfilled more than one criterion for CCSVI.

    “Although we didn’t find any evidence to support the theory of CCSVI, the discrepancies between the studies may be due to the inclusion in our study of blood flow analysis. We believe the comprehensive venous blood flow assessment performed in our study provides a strong basis to diagnose obstructions in the veins,” Dr Schmierer said.

    "Further studies to evaluate this theory are underway. Preliminary results from a large study at the University of Buffalo have so far been inconclusive."

    Link to study: http://www3.interscience.wiley.com/journal/123513536/abstract?CRETRY=1&SRETRY=0 (14/06/10)

    North American MS societies to fund seven CCSVI research projects
    CCSVI VenogramMS societies in Canada and the United States have announced they are releasing funds to study the effectiveness of a new, unproven treatment for multiple sclerosis.

    The treatment is based on research by an Italian physician named Paolo Zamboni, who found abnormalities in the veins that drain blood from the brain and spine in people who suffer from MS. He dubbed the condition CCSVI, or chronic cerebrospinal venous insufficiency, and set about alleviating the blockages.

    Zamboni's work was featured in reports on CTV's W5 this year, prompting wider interest in the controversial theory.

    Under pressure from patients eager to receive the new treatment, the MS Society of Canada said Friday it is committing $700,000 to study the link between CCSVI and MS. South of the border, the National MS Society said it will spend $1.7 million for the same purpose.

    Together, the two organizations say they will fund seven research projects on CCSVI.

    "The MS Society of Canada is committed to funding strong science, backed by research goals that move us forward in our pursuit to end MS," Yves Savoie, president and CEO of the MS Society of Canada said in a statement.

    "I am very pleased that grantees, their collaborators and their host institutions will help us play a part in better understanding CCSVI and its relationship to MS."

    One of the studies awarded funds is being conducted by a team of researchers from the University of British Columbia, Vancouver Coastal Health Research Institute and the University of Saskatchewan. They plan to recruit 100 participants with MS as well as 100 people in a control group who don't have the disease.

    "Our goal is to verify the condition itself, and the usefulness of non-invasive techniques that would make it easier to screen for CCSVI," the study's lead researcher, Dr. Anthony Traboulsee at the University of British Columbia, said in a statement.

    Another of the funded studies will be conducted by Dr. Brenda Banwell at the Toronto Hospital for Sick Children's pediatric MS clinic, in the hopes of determining whether vein blockages also occur in young MS patients.

    "We do feel that the kids have the ability to teach us something really important here," Banwell said.

    "I think if it's absent in children, that will add a lot of weight to the concern that this finding is an observation perhaps in selected MS patients, but it's not a fundamental part of MS," she said.

    But if the study finds that CCSVI is more frequent in children with MS, "then I think it adds an enormous weight in the ‘this is important' aspect," she said.

    Two other studies led by Dr. Carlos Torres at the University of Ottawa and Dr. Fiona Costello at the University of Calgary have also earned funding to explore CCSVI.

    The seven new research studies are to pick up on Zamboni's findings, examining whether CCSVI causes MS, hoping to reconcile "conflicting data" from previous studies and possibly paving the way for medical trials to determine whether treating CCSVI improves or changes the condition of MS patients.

    But some say the funding is far less than expected. "For context, over the last two years the MS Society has granted $21.1 million in research grants," said Kate Bahen of Charity Intelligence a group that analyzes charitable organizations.

    Bahen says the CCSVI research accounts for 3 per cent of research spending.

    "This research isn't expected to produce results until June 2012 and will only involve 430 people with MS in the initial scans," Bahen said. "The other estimated 54,500 people with MS will have to wait at least two years."

    Most Canadian research teams interested in CCSVI suggest that funding in the range of $500,000 to $600,000 is needed to properly conduct a trial.

    "CCSVI is a serious legitimate medical theory that requires rigorous research. I am worried that this isn't enough funding to adequately do this work, preferably in a timely manner," Bahen said.

    Surprisingly, the research team from McMaster University and St. Joseph's Hospital in Hamilton, which had applied for funding, and are preparing for a study, were not given any funding from the MS Society. Nor was the research team at University of Buffalo, where Dr. Robert Zivadinov has been conducting pioneering research on CCSVI.

    Others say that the research projects ignore evidence being collected at clinics in Poland, Europe and the U.S.

    "I would note this research, when it is all done and published, will not bring us any notable understanding that we don't already have today," said Ashton Embry, the father of a patient with MS and Member of an MS support group based in Alberta called Direct MS. "This is classic stall research which will delay any real research which will test the efficacy of CCSVI treatment."

    Source: CTV © 2010 CTVGlobeMedia (13/06/10)

    Vascular comorbidity is associated with more rapid disability progression in MS
    Vascular comorbidity in MSABSTRACT

    Background: Vascular comorbidity adversely influences health outcomes in several chronic conditions.

    Vascular comorbidities are common in multiple sclerosis (MS), but their impact on disease severity is unknown. Vascular comorbidities may contribute to the poorly understood heterogeneity in MS disease severity. Treatment of vascular comorbidities may represent an avenue for treating MS.

    Methods: A total of 8,983 patients with MS enrolled in the North American Research Committee on Multiple Sclerosis Registry participated in this cohort study. Time from symptom onset or
    diagnosis until ambulatory disability was compared for patients with or without vascular comorbidities to determine their impact on MS severity. Multivariable proportional hazards models were adjusted for sex, race, age at symptom onset, year of symptom onset,  socioeconomic status, and region of residence.

    Results: Participants reporting one or more vascular comorbidities at diagnosis had an increased risk of ambulatory disability, and risk increased with the number of vascular conditions reported (hazard ratio [HR]/condition for early gait disability 1.51; 95% confidence interval [CI] 1.41–1.61). Vascular comorbidity at any time during the disease course also increased the risk of ambulatory disability (adjusted HR for unilateral walking assistance 1.54; 95% CI 1.44–1.65). The median time between diagnosis and need for ambulatory assistance was 18.8 years in patients without and 12.8 years in patients with vascular comorbidities.

    Conclusions: Vascular comorbidity, whether present at symptom onset, diagnosis, or later in the disease course, is associated with a substantially increased risk of disability progression in multiple
    sclerosis. The impact of treating vascular comorbidities on disease progression deserves investigation.

    R.A. Marrie, R. Rudick, R. Horwitz, G. Cutter, T. Tyry, D. Campagnolo and T. Vollmer

    Source: Neurology® 2010;74:1041–1047 (17/05/10)

    Canadian trials to examine 'liberation procedure' for multiple sclerosis
    CCSVI VenographyDuncan Thornton is still getting used to enjoying the small things that most Canadians take for granted.

    “I do laundry spontaneously,” says the 47-year-old resident of Winnipeg, Manitoba. Diagnosed with multiple sclerosis in August 2009, Thornton figures he’s had the disease for at least two decades.  Fatigue was always the most disabling aspect of my illness.  … For the last 20 years, anytime I stood for more than five minutes I began looking for a chair.”

    Duncan and his brother, 49-year-old Evan of Ottawa, Ontario, who also has MS, made headlines in March after travelling to a clinic in Poland for surgery nicknamed the “liberation procedure.”

    The operation is based on research by Paolo Zamboni, a professor of medicine at the University of Ferrara in Italy. He suspects multiple sclerosis is not, as is widely believed, an auto-immune disease, but rather, a vascular condition he dubbed chronic cerebrospinal venous insufficiency, or CCSVI.

    Zamboni discovered that in about 90% of people with multiple sclerosis, the veins draining blood from the brain are blocked or malformed, causing a build-up of iron in the brain. Zamboni believes that build-up causes the neurological symptoms of multiple sclerosis.

    It is not a new hypothesis, according to Dr. Ian Rodger, vice-president of research at St. Joseph’s Healthcare Hamilton, in Ontario.

    But it remains clinically untested, Rodger says. “The idea that blood vessels are involved in MS goes back over 100 years. But it rises to the surface and fades away. For the last 50 years, at least, the auto-immune theory has been somewhat dominant.”

    Researchers at St. Joseph’s Healthcare will test Zamboni’s proposition. “I have no doubt that there is an auto-immune component to MS. But what Zamboni has done is he has raised the awareness again that the vascular component could be real,” Rodger says. “So it could be auto-immune with a vascular component. And who knows what else? We don’t know.”

    Rodger says his team is looking to establish the prevalence of CCSVI by comparing subjects who have multiple sclerosis and with age- and gender-matched healthy people. Those 100 people will be put in four categories: primary progressive, secondary progressive, relapsing-remitting, and benign.

    “Specifically, we are going to measure by ultrasound and try to mimic almost exactly, if not exactly, what Zamboni has done. We’re also going to use MR [magnetic resonance] imaging to look at the architecture of the veins,” Rodger says. “We’re trying to see whether MR is superior to ultrasound. It’s obviously a lot more expensive. But you see different things with MR than you see with ultrasound. So really, we’re going to do a comparison.”

    The University of British Columbia and Vancouver Coastal Health has partnered with the University of Saskatchewan to undertake a similar research project.

    “A lot of people are anxious to have a test done and surgery without having the validation done first,” says Dr. Anthony Traboulsee, the medical director of UBC’s MS clinic. “Our feeling is that the validation of Zamboni’s original findings needs to be done first before people run off to have surgery.”

    “So far, that hasn’t been replicated and we think that is the most important first step before going on to treatment trials,” Traboulsee adds.

    The UBC-led team will compare the use of catheter venography with ultrasound and magnetic resonance venography as methods of validating the presence or absence of venous abnormalities in people with multiple sclerosis, compared with those who do not.

    “We’re also looking to see if it’s real,” Traboulsee says. “That’s what the whole community is waiting for. Is this real or is this fantasy? If results have only come out of one group, then that is interesting but not proof in itself. So a completely independent research group needs to reproduce what somebody else did to prove it’s a valid abnormality.”

    “The first step is to reproduce Zamboni’s findings,” he adds. “The second step is to find what test is good enough to find the abnormality, so we’re doing both of those in one study. Then the third step would be to show if treatment is beneficial. Unless we do the proper studies, a lot of people are going to be exposed to surgery for this potential abnormality and may get a risk from the surgery without getting a clear sustainable benefit.”

    Source CMAJ Copyright 1995-2010, Canadian Medical Association (05/05/10)

    Custom CGH array profiling of copy number variations (CNVs) on chromosome 6p21.32 (HLA locus) in patients with venous malformations associated with multiple sclerosis
    CCSVI GeneticsAbstract (provisional)

    Background
    Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance.

    Methods
    In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate.

    Results
    In total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r=0.6590, p=0.0104; linear regression analysis r=0.6577, p=0.0106). The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype.

    Conclusions
    The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region.

    Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.

    Alessandra Ferlini , Matteo Bovolenta , Marcella Neri , Francesca Gualandi , Alessandra Balboni , Anton Yuryev , Fabrizio Salvi , Donato Gemmati , Alberto Liboni  and Paolo Zamboni

    BMC Medical Genetics 2010, 11:64doi:10.1186/1471-2350-11-64 © 1999-2010 BioMed Central Ltd (29/04/10)

    Multiple Sclerosis patients at Georgetown screened for blood flow abnormality called CCSVI
    CCSVI VenographGeorgetown University Hospital has begun screening some Multiple Sclerosis (MS)patients for a condition that causes abnormal blood drainage from the brain that some research is suggesting might exacerbate their MS symptoms.

    “We are proceeding very cautiously and slowly with this. It might work or it might be a dead end, but we need to see where the science takes us without risking patient safety,” said Carlo Tornatore, MD neurologist and head of Georgetown’s Multiple Sclerosis Clinic. With 2,000 patients, Georgetown’s MS clinic is the largest in the DC area.

    The test is a screening diagnostic ultrasound performed in the Non-invasive Vascular Laboratory that evaluates the central venous circulation for abnormal flow patterns that may indicate chronic cerebrospinal venous insufficiency (CCSVI), essentially a blockage that can cause a backup of blood into the brain. The screening is an ultrasound of the veins in the neck and carries no risk to the patient. It may or may not be covered by insurance. “The theory is that when the blood backs up into the brain or the spinal cord, the blood vessels break open a little bit and iron deposits from the blood get into the brain. In response, white blood cells attack the myelin sheath of the nerves and cause a breakdown of the myelin sheath that we see in patients with MS,” said Dr. Tornatore.

    Multiple sclerosis is a chronic, often disabling disease that attacks the central nervous system, which is made up of the brain, spinal cord, and optic nerves. MS symptoms can be mild like numbness in the limbs, or they can be severe, including loss of vision, paralysis and difficulty breathing. The progression and severity of symptoms vary from person to person. The National Multiple Sclerosis Society reports an estimated 400,000 people in the United States have MS, with 200 more people diagnosed each week. Around the world, MS is estimated to affect more than 2.1 million people and more women than men.

    If the patient’s ultrasound finds certain abnormal flow patterns, then they are referred on for a venogram to be performed by Richard Neville, MD, chief of Vascular Surgery at Georgetown. “The venogram confirms and assesses the extent of the blockage or abnormal flow. The procedure involves placing a catheter into the veins and obtaining pictures of the blood flow in the veins. If we find a blockage, then we can then perform an angioplasty, by inflating a balloon inside the vein to open the blockage. Venous angioplasty is a procedure we perform often in other situations and we believe is a fairly safe option. We are not using stents to prop open the veins.”

    Dr. Neville and Tornatore have applied for a clinical trial under IRB protocol which will allow the supervised collection and analysis of data from the diagnostic and therapeutic procedures. “We are hoping to evaluate this new modality in a thoughtful and scientific way,” said Dr. Neville.

    Dr. Tornatore will be following up with his MS patients who receive angioplasty. “After the procedure, I will be following the patients with a battery of tests, including follow-up ultrasounds to determine whether the veins have re-stenosed, or re-clogged.”

    So far, GUH has screened 40 MS patients for the condition and half have been found to have it. Those approximately 20 patients will go on to have a venogram and angioplasty, if indicated. To date, five MS patients have had venograms with angioplasty.

    “I’ll be shocked if this is the total answer to MS; it’s a very complicated disease,” said Dr. Tornatore. “But the whole concept of the veins being too narrow is interesting and something we feel we can’t ignore. We owe it to our patients to explore this.”

    Source Georgetown University Hospital © Georgetown University Hospital (27/04/10)

    Networking power of the web shifting power balance between doctors and patients
    The InternetRebecca Cooney may have a debilitating, degenerative disease, but that doesn't mean she's ready to automatically defer to the authority of the medical community.

    "I've never been a person who thinks somebody else can make decisions for me. Even my doctors - they're the experts, I take what they say, but I have my own mind and my own information," says Cooney, 42, who has been living with multiple sclerosis for the past 18 years.

    "I'm not one that believes the Pope is the only one who can speak to God. I can speak to God myself."

    There have always been patients with Cooney's independent bent. But these days there seems to be hordes of them, due in large measure to the extraordinary reach of the Internet.

    A technology that makes a pioneering or profiteering clinic somewhere overseas a mere Google search away, the Internet is changing the nature of patient advocacy. It's amping up the activism.

    And those more activist patients, who share information and strategies through email, discussion boards and Facebook, are actually in some cases altering the research agenda in fields such as cancer, alternative medicine and now multiple sclerosis.

    Some want access to experimental drugs or therapies before science has proven that they are safe or useful. In other cases, they are agitating for a say in which theories, techniques or treatments get research funding.

    Patients like Cooney are thrilled about what she describes as the huge power shift she has seen in the years since she was first diagnosed.

    "The Internet - email - has really allowed me and most of the MS patients to really work in conjunction with the doctors, which we've never been able to do," she says.

    "It used to be almost what your neurologist said or what your doctor said was God. You couldn't really debate it. You couldn't say anything. Because you didn't know."

    "Now, I'm empowered. I can find out information."

    Other players are not so enthusiastic, saying the change is fostering tension within disease advocacy organizations and between doctors and their patients.

    Such is the case with multiple sclerosis, where the patient community is aflame with hope about a new and as-yet unproven claim by Dr. Paolo Zamboni that clogged neck veins may be triggering the disease or contributing to the destruction it wreaks. The condition has been dubbed chronic cerebrospinal venous insufficiency or CCSVI.

    Individually, a number of MS patients have already flown to clinics in places like Poland to undergo a vein opening operation that has been given the hope-inspiring name "the liberation procedure."

    Collectively many MS patients are pushing the MS Society of Canada and the National Multiple Sclerosis Society in the U.S. to fast-track funding for CCSVI research.

    The societies have jointly issued a special call for research proposals and will review them next month. The first funding awards are due to be announced in June. Donors - the societies get the bulk of their funding from the patient community - are even being allowed to earmark donations specifically to CCSVI work.

    Dr. Aaron Miller is a neurologist and head of the MS clinic at New York's Mount Sinai Medical Center. As the chief medical officer of the National Multiple Sclerosis Society, he tries to keep an open mind towards new claims about MS, noting that there are times when ideas from out of left field propel scientific advances.

    He points to the example of stomach ulcers, which were long thought to be the product of stress. Then Barry Marshall and Robin Warren, two Australian researchers, proved they are caused by a bacterium, Helicobacter pylori and are treatable with antibiotics.

    Marshall and Warren won the 2005 Nobel Prize for Medicine. Still, those kinds of paradigm shifting successes aren't everyday occurrences. Miller suspects CCSVI isn't going to join that list but he fears that answer won't be arrived at quickly or cheaply.

    "We know that research dollars are extremely scarce, especially these days. And when you have to divert large sums of money to investigate something that's probably going to be barking up the wrong tree, it certainly is distressing," Miller says.

    He points out that the MS community has seen other provocative claims in the past, prior to the Internet's emergence as a communications tool for the masses. In the early 1990s, for instance, the TV newsmagazine "60 Minutes" aired a piece advancing the notion dental amalgam might be the cause of MS. Patients flocked to dentists to have old-fashioned fillings removed.

    "But the pace at which this happens now and the numbers of people to whom these stories and the information reaches is astronomical compared to what it once was," says Miller, who notes that Internet counselling has become a part of his routine interactions with patients.

    "It's a real challenge in how to interact with patients on issues like this," he admits.

    The scenario is unfolding in other subspecialties of medicine too.

    Dr. Maurie Markman, vice-president for clinical research at the University of Texas M.D. Anderson Cancer Center, says the advocacy community has long been vocal in cancer care and research.

    Some bristle when they are told putative treatments need to be tested in staged clinical trials, he says.

    "Online, the New England Journal of Medicine has no more authority than Mr. Smith's or Mrs. Smith's website telling you that 'Here's the cure for cancer,"' Markman says.

    He explains the kind of pushback those insisting on proper trials sometimes encounter: "Five thousand people who are online say it's correct. So who are you ... Dr. Scientist, to tell me I'm wrong?"

    What's the answer? "It's not confrontation," Markman continues. "It's discussion and an awful lot more effort to explain."

    Still, a confrontational dynamic can emerge.

    The hesitancy of MS specialists towards CCSVI has frustrated and angered some patients. Some doctors who are viewed as impeding access to the treatment have received abusive hate mail. People on both sides of the divide say the situation has given rise to an us-versus-them mentality.

    "I do think the Internet has created an us-and-them thing," admits Cooney, who has co-founded a group called MS Liberation that is lobbying for the procedure to be available in Canada.

    "I don't like it. I wish it would stop. But ... I don't think it will until both people (parties) acknowledge that the playing field has changed."

    "I think the patients are not giving the neurologists and the doctors the time to really learn about this and to investigate it properly. But I also think the neurologists don't acknowledge that it's a different ball game."

    "They're used to holding back information from the patients. And what's happening is they can't do that anymore."

    [email protected] AOL News © 2010 AOL Canada Inc All Rights Reserved. (27/04/10)

    Chronic cerebrospinal venous insufficiency (CCSVI) in Multiple Sclerosis patients - Kuwait study initial results

    Kuwait CCSVI Study LogoChronic cerebrospinal venous insufficiency (CCSVI) in Multiple Sclerosis patients - Kuwait study

    Intial Samples
     
    CCSVI: To establish the link to M.S.

     Started colour Doppler screening of neck veins
    62 M.S. patients ( 32 F,  30 M)
    Age group (22-57)
    22 controlled group ( 15 F,  7 M)
    Age (20- 59)
    Dublex studies (Zamboni protocol)
    Results: 62 M.S. ( 50pt , 81% positive)
    22 controlled (no positive)
    MRV Of neck veins
    50 M.S. Patients (age, 20 – 54) Done
    48 M.S. patients (96% positive)
    No control group ( 50 will be enrolled)
    Matched for age and sex.
    Comparison of results will be made
     
    CCSVI: Link to M.S. (Conclusion)

     Our results so far shows strong link between CCSVI and M.S.
    CCSVI leads to iron deposition which may trigger the inflammatory reaction leading to M.S. or at least worsen the pathology.
    CCSVI may not necessary be the cause, however there is clinical relation to M.S.
     
    CCSVI: The treatment

      Pilot study. 50 pt - Started March 2010.
    10 (6 F, 4 M) Volunteers with M.S.
    Inclusion Criteria:
    Proven M.S.
    Positive (duplex study and MRV)
    Not wheel chair bound or bed redden
    Sign informed consent and agree to be part of experimental study.
     
    CCSVI: The treatment 2

    Venography of neck veins and Azygos  in normal breathing and Valsava maneuver
    All narrowing where dilated with balloon
    Patients where covered with 3000 I.U. Heparin during procedure.
    Discharged next day on Clexaine, Aspirin and Warfarin 
    Close follow up for INR, Clinical symptoms


    CCSVI: The treatment results 

    All successful Angioplasty with satisfactory post balloon dilatation
    No complications
    All patients reported improvement ( 1 month) :
    Improvement or disappearance of Numbness
    Loss of Fatigue and increased energy
    Improvement of power (foot drop)
    Improvement visual acuity (No blurred vision)
    Reduced electrical sensation
    Memory improvement


     Conclusion of CCSVI and Venous Angioplasty
     
    It a prospective study 
    Try to stop the progression of MS ( it is not a cure)
    Finally will audit our result with respect to
    Diagnostic modality
    Clinical improvement
    Radiological improvement i.e. MRI
    Neurological correlation

    Funding trials of CCSVI: Can the MS Society do better?
    CCSVI Venogramby Dr. Lorne Brandes

    The good news emanating from this week’s American Academy of Neurology (AAN) meeting in Toronto was that, although skepticism abounded, Dr. Paulo Zamboni and CCSVI were not ignored by “the establishment”. Far from it, judging by the conference’s special session devoted to debating and discussing his controversial new theory that MS is primarily a disease caused by blocked neck or chest veins.

    In addition to Dr. Zamboni, a panel of MS experts, a large crowd of neurologists, and more than 4,000 patients from around the world attended the event on line... surely a first for any medical meeting, and indicative of the pivotal role that the Internet has played in galvanizing an MS community enthralled with the Zamboni hypothesis and unhappy with currently-available immunosuppressive therapies.

    Now the bad news: despite a willingness of investigators to move forward, there appears to be a major stumbling block in obtaining the monies required to fund the human clinical trials needed to learn whether blocked neck and chest veins cause MS, and whether unblocking them will truly benefit patients with the disease.

    For example, in the absence of public funding, Dr. Robert Zivadinov, head of the largest CCSVI study at the University of Buffalo, requires patients to pay several thousand dollars to be tested.

    In Canada, ambitious clinical trials planned at UBC, McMaster and the University of Saskatchewan have been delayed for lack of funds. They remain on hold pending the results, expected in June, of a special MS Society-sponsored grant competition. But, as reiterated in a report on CTV’s W5, successful applicants will receive a maximum grant of only $200,000 over two years.

    "I am quite convinced as a result of the excitement, the mobilization, the media attention, the process of discovery is going to be much accelerated," Yves Savoie, the president of the Canadian MS Society, told W5.

    Much accelerated? By awarding each needy centre (how many, we do not yet know) a total of $200,000 to carry out these sophisticated, expensive and highly important studies? Is he kidding?

    As one involved in laboratory and clinical cancer research for over 35 years, I must tell you that, given the costs required for any type of human investigation,  especially one as complex as a study of the potential relationship between CCSVI and MS, this is a paltry sum, by any standard. A strategy that spreads small amounts of money among many investigators will accomplish very little at the end of the day.

    Can’t the MSS do a lot better than this? Indeed, how much of the money they raise each year actually goes to funding research?

    To answer this question, I obtained a copy of the Society’s most recent financial statement, audited by Price, Waterhouse, Coopers, LLP.

    Here is the bottom line: for the year ended August 31, 2009, the Canadian MSS took in revenue of $33,677,000. Of that amount, $28,503,000 came from donations (including $1,197,000 from the United Way) and fundraising events. 

    The amount spent on research? Twenty-two cents out of every dollar collected, for a total of $7,324,000.

    As for how the rest was allocated:

    $10,495,000 was spent on services to patients
    $889,000 to help fund MS clinics
    $2,806,000 for chapter and volunteer support and development
    $4,086,000 for public awareness and education
    $1,570,000 to cover “government and community relations”.
    So here is my question to the Canadian MSS: could you not spend less money educating people about a disease of which they are already well aware, and stop spending over $1.5 million on government and community relations (whatever form that may take)?

    By making those specific budget cuts, you might easily free up several million dollars to help Canadian centres move ahead with their CCSVI trials without jeopardizing patient care, or taking away from other funded research projects.

    Given the importance of this issue, I hope you will give serious thought to this suggestion.

    Source: CTV © Copyright 2010 CTVglobemedia Publishing Inc (17/04/10)

    Hemodynamic patterns of chronic cerebrospinal venous insufficiency in multiple sclerosis. Correlation with symptoms at onset and clinical course
    CCSVI VenographAIM: Chronic Cerebrospinal Venous Insufficiency (CCSVI) is associated with multiple sclerosis (MS). CCSVI is detected by transcranial and extracranial color-Doppler high-resolution examination (TCCS-ECD) and venography that permit to identify five types of venous malformations and four major (A-D) hemodynamic patterns of anomalous extracranial-extravertebral venous outflow.

    We investigated possible correlation between such hemodynamic patterns and both the symptoms at onset and clinical course in patients with MS and CCSVI.

    METHODS: TCCS-ECD, selective venography and clinical records of 65 patients affected by definite MS and CCSVI were reviewed.

    RESULTS: The four hemodynamic patterns of CCSVI were unevenly (P<0.0001) distributed with respect to the types of clinical presentation and course. In particular the Type A or B patterns were common in patients with onset of optic neuritis, but rare in patients presenting with spinal cord symptoms who typically showed a type D pattern. As well, the type A or type B hemodynamic were more common in patients with relapsing-remitting course than in patients with secondary progressive course and rare in patients with primary progressive course. The C hemodynamic pattern was not observed in patients with primary progressive course who showed a remarkable prevalence of the type D pattern.

    CONCLUSION: The distribution of venous malformations and the resulting hemodynamic pattern show correlation with symptoms at onset and clinical course in patients with MS and CCSVI.

    Bartolomei I, Salvi F, Galeotti R, Salviato E, Alcanterini M, Menegatti E, Mascalchi M, Zamboni P.

    Center for Rare and Neuroimmunitary Diseases, Department of Neurological Science, Bellaria Hospital, Bologna, Italy

    Source: Pubmed PMID: 20351674 (06/04/10)

    Chronic cerebro-spinal venous insufficiency: report of transcranial magnetic stimulation follow-up study in a patient with multiple sclerosis

    CCSVI VenographThe pyramidal pathway is frequently affected early on in multiple sclerosis (MS) and impaired motor performance is a major cause of disability. Pyramidal tract function can be assessed using transcranial magnetic stimulation (TMS).

    TMS supports the diagnosis of MS, detecting corticospinal tract involvement and monitoring its course with or without treatment.

    It has been never investigated whether any relationship exists between the TMS outcome measure and minimally invasive treatment of multiple severe extracranial stenosis, affecting the principal ce rebrospinal venous segments in MS patients.

    We report the clinical and transcranial magnetic stimulation follow-up of a patient during a relapse in relapsing-remitting MS. She underwent percutaneous balloon angioplasty of the associated chronic cerebrospinal venous insufficiency (CCSVI), due to membranous obstruction of the proximal azygous vein, with severe stenosis of the left internal jugular vein.

    Treatment of the associated CCSVI made a parallel improvement in both clinical and neurophysiological parameters, allowing us to avoid high dose steroid therapy.

    The relationship between the clinical and neurophysiological course on the one hand, and haemodynamic correction of the associated CCSVI on the other, calls for further exploration on a wider number of patients.

    The impact of CCSVI on the different neuro-physiological parameters has not been fully estimated, but the intriguing case here reported suggests that it may be greater than previously assumed.

    The demonstration of a modification of the cerebrovenous function with both clinical manifestation and via TMS suggests that the hampered cerebral venous return may contribute to the clinical course of MS.

    Plasmati R, Pastorelli F, Fini N, Salvi F, Galeotti R, Zamboni P.

    Department of Neurology, Bellaria Hospital, Bologna, Italy2 Vascular Diseases Centre, University of Ferrara, Italy

    Source: Pubmed PMID: 20351675 (01/04/10)

    Is chronic fatigue the symptom of venous insufficiency associated with multiple sclerosis? A longitudinal pilot study

    CCSVI VenographAIM: Chronic fatigue (CF) severely affects patients with multiple sclerosis (MS), but its pathogenesis remains elusive and the effectiveness of available treatments is modest. We aimed to evaluate the effect on CF of the balloon dilatation of stenosing lesions affecting the main extracranial veins configuring the chronic cerebrospinal venous insufficiency (CCSVI), a condition strongly associated with MS.

    METHODS: Thirty-one MS consecutive patients (16 males, age 46.2+/-9.4 years) with associated CCSVI and CF underwent the endovascular procedure. Fatigue was assessed using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) at baseline (T0) and one (T1), six (T6) and twelve (T12) months after the procedure. In ambulatory patients (N.=28), mobility was evaluated using the 6-min walking test at T0 and T1.

    RESULTS: and MFIS scores significantly improved from preoperative values, and the positive trend was maintained at one year (FSS: T0=5.1+/-1.0 to T12=3.5+/-1.8, P<0.001; MFIS-total score: T0=34.9+/-14.8 to T12=22.5+/-13.7, P<0.001; MFIS-Physical subscale: T0=21.2+/-8.0 to T12=13.5+/-9.7 P<0.001; MFIS-Cognitive subscale: T0=9.2+/-9.5 to T12=6.0+/-6.3, P=0.03; MFIS-Psychosocial subscale: T0=4.5+/-2.1 to T12=2.5+/-2.1, P<0.001). Six-min walking distance (6MWD) at T1 improved significantly (332+/-190m to 378+/-200m, P=0.0002). In addition, an inverted correlation between 6MWD and MFIS-physical subscale variations was found in the subgroup of patients (N.=8) with no lower limb motor impairment (r=-0.74, P=0.035).

    CONCLUSION: The reestablishment of cerebral venous return dramatically reduced CF perception in a group of MS patients with associated CCSVI, suggesting that CF is likely the symptom of CCSVI.

    Malagoni AM, Galeotti R, Menegatti E, Manfredini F, Basaglia N, Salvi F, Zamboni P.

    Vascular Diseases Center, University of Ferrara, Ferrara, Italy

    Source: Pubmed PMID: 20351673 (01/04/10)

    Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control study
    CCSVI VenographAIM: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular phenomenon recently described in multiple sclerosis (MS) that is characterized by stenoses affecting the main extracranial venous outflow pathways and by a high rate of cerebral venous reflux that may lead to increased iron deposition in the brain.

    Aim of this study was to investigate the relationship between CCSVI and iron deposition in the brain of MS patients by correlating venous hemodynamic (VH) parameters and iron concentration in deep-gray matter structures and lesions, as measured by susceptibility-weighted imaging (SWI), and to preliminarily define the relationship between iron measures and clinical and other magnetic resonance imaging (MRI) outcomes.

    METHODS: Sixteen (16) consecutive relapsing-remitting MS patients and 8 age- and sex-matched healthy controls (HC) were scanned on a GE 3T scanner, using SWI.

    RESULTS: All 16 MS patients fulfilled the diagnosis of CCSVI (median VH=4), compared to none of the HC. In MS patients, the higher iron concentration in the pulvinar nucleus of the thalamus, thalamus, globus pallidus, and hippocampus was related to a higher number of VH criteria (P<0.05). There was also a significant association between a higher number of VH criteria and higher iron concentration of overlapping T2 (r=-0.64, P=0.007) and T1 (r=-0.56, P=0.023) phase lesions. Iron concentration measures were related to longer disease duration and increased disability as measured by EDSS and MSFC, and to increased MRI lesion burden and decreased brain volume.

    CONCLUSION: The findings from this pilot study suggest that CCSVI may be an important mechanism related to iron deposition in the brain parenchyma of MS patients. In turn, iron deposition, as measured by SWI, is a modest-to-strong predictor of disability progression, lesion volume accumulation and atrophy development in patients with MS.

    Zivadinov R, Schirda C, Dwyer MG, Haacke ME, Weinstock-Guttman B, Menegatti E, Heininen-Brown M, Magnano C, Malagoni AM, Wack DS, Hojnacki D, Kennedy C, Carl E, Bergsland N, Hussein S, Poloni G, Bartolomei I, Salvi F, Zamboni P.

    Buffalo Neuroimaging Analysis Center, University at Buffalo, Buffalo, NY, USA

    Source: Pubmed PMID: 20351672 (01/04/10)

    Iron stores and cerebral veins in MS studied by susceptibility weighted imaging

    CCSVI VenographAIM: In this paper, we seek to determine whether the iron deposition as seen by susceptibility weighted imaging (SWI) in the basal ganglia and thalamus of patients with multiple sclerosis is greater than the iron content measured in normal subjects (individuals unaffected by multiple sclerosis). As increased iron content may result from increased venous pressure, such information would add credence to the concept of Zamboni et al (1) that MS is caused by chronic cerebrospinal venous insufficiency.

    METHODS: Fourteen MS patients were recruited for this study with a mean age of 38 years ranging from 19 to 66 year-old. A velocity compensated 3D gradient echo sequence was used to generate SW images with a high sensitivity to iron content. We evaluated iron in the following structures: substantia nigra, red nucleus, globus pallidus, putamen, caudate nucleus, thalamus and pulvinar thalamus. Each structure was broken into two parts, a high iron content region and a low iron content region. The measured values were compared to previously established baseline iron content in these structures as a function of age.

    RESULTS: Twelve of fourteen patients had an increase in iron above normal levels and with a particular pattern of iron deposition in the medial venous drainage system that was associated with the confluence of the veins draining that structure.

    CONCLUSION: Iron may serve as a biomarker of venous vascular damage in multiple sclerosis. The backward iron accumulation pattern seen in the basal ganglia and thalamus of most MS patients is consistent with the hypothesis of venous hypertension.

    Haacke EM, Garbern J, Miao Y, Habib C, Liu M.

    Department of Radiology, Wayne State University, Detroit, MI, USA2 Department of Radiology, the First Affiliated Hospital, Dalian Medical University, Dalian, China

    Source: Pubmed PMID: 20351671  (01/04/10)

    CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies: a pilot study

    CCSVI VenographAIM: We previously reported unexpectedly robust associations between vascular haemodynamic (VH) anomalies in the principal extracranial cerebral veins, causing chronic cerebrospinal venous insufficiency (CCSVI), and multiple sclerosis (MS). Aim of this study was to investigate the relationship between the VH changes and MRI measures of MS disease severity in a cross sectional survey.

    METHODS: The number of anomalous VH criteria were measured using an echo-color Doppler, whereas CSF flow, atrophy and lesion measures were obtained from quantitative magnetic resonance imaging (MRI) analysis in sixteen consecutive relapsing-remitting MS patients, (mean age: 36.1+/-SD 7.3 years, disease duration: 7.5+/-1.9 years and median EDSS: 2.5) and in 8 healthy controls (HC) with similar age and sex distributions.

    RESULTS: All 16 MS patients investigated and none of the HCs met the VH criteria for CCSVI (P<0.0001). MS patients showed significantly lower net CSF flow compared to the HC (P=0.038) that was associated with number of anomalous VH criteria present (r=0.79, P<0.001). Moreover, increases in the number of anomalous VH criteria present were negatively associated with lower whole brain volume (Spearman R=-0.5, P=0.05).

    CONCLUSION: VH changes occur more frequently in MS patients than controls. Altered VH is associated with abnormal CSF flow dynamics and decreased brain volume.

    Zamboni P, Menegatti E, Weinstock-Guttman B, Schirda C, Cox JL, Malagoni AM, Hojnacki D, Kennedy C, Carl E, Dwyer MG, Bergsland N, Galeotti R, Hussein S, Bartolomei I, Salvi F, Ramanathan M, Zivadinov R.

    Vascular Diseases Center, University of Ferrara-Bellaria Neurosciences, Ferrara and Bologna, Italy

    Source: Pubmed PMID: 20351670 (01/04/10)

    Use of neck magnetic resonance venography, Doppler sonography and selective venography for diagnosis of chronic cerebrospinal venous insufficiency: a pilot study in multiple sclerosis patients and healthy controls

    CCSVI VenographyAIM: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of primary veins outside the skull that restrict normal outflow of blood from the brain. CCSVI was recently described as highly prevalent in patients with multiple sclerosis (MS), and can be non-invasively diagnosed by Doppler sonography (DS) and invasively by selective venography (SV).

    The aim of this paper was to investigate the value of neck magnetic resonance venography (MRV) for the diagnosis of CCSVI compared to DS and SV in patients with MS and in healthy controls (HC).

    METHODS: Ten MS patients and 7 HC underwent DS, 2D-Time-Of-Flight venography (TOF) and 3D-Time Resolved Imaging of Contrast Kinetics angiography (TRICKS). MS patients also underwent SV. The internal jugular veins (IJVs) and the vertebral veins (VVs) were assessed by both MRV sequences, and the findings were validated against SV and DS. SV has been considered the diagnostic gold standard for MS patients.

    RESULTS: All MS patients and none of the HC presented CCSVI, according to the DS criteria. This was confirmed by SV. For CCSVI diagnosis, DS showed sensitivity, specificity, accuracy, PPV and NPV of 100%, whereas the figures were 40%, 85%, 58%, 80% and 50% for 3D-TRICKS, and 30%, 85%, 52%, 75% and 46% for 2D-TOF in the IJVs. In MS patients, compared to SV, DS showed sensitivity, specificity, accuracy, PPV and NPV of 100%, 75%, 95%, 94% and 100%, whereas the figures were 31%, 100%, 45%, 100% and 26% for 3D-TRICKS and 25%, 100%, 40%, 100% and 25% for 2D-TOF in the IJVs.

    CONCLUSION: The use of MRV for diagnosis of CCSVI in MS patients has limited value, and the findings should be interpreted with caution and confirmed by other imaging techniques such as DS and SV.

    Hojnacki D, Zamboni P, Lopez-Soriano A, Galleotti R, Menegatti E, Weinstock-Guttman B, Schirda C, Magnano C, Malagoni AM, Kennedy C, Bartolomei I, Salvi F, Zivadinov R.

    The Jacobs Neurological Institute, State University of New York, Buffalo, NY, USA

    Source: Pubmed PMID: 20351669 (01/04/10)

    The reproducibility of colour Doppler in chronic cerebrospinal venous insufficiency associated with multiple sclerosis

    CCSVI VenogramAIM: Chronic cerebrospinal venous insufficiency (CCSVI) is a syndrome described in multiple sclerosis (MS) patients, characterized by stenosis of the main extracranial veins with hampered cerebral venous outflow. In the original description echo-colour Doppler demonstrated to be an ideal non invasive tool for screening CCSVI patients, but the reproducibility was not assessed. Aim of this study is to assess the variability coefficient between trained and in not trained echo-colour Doppler operators.

    METHODS: Thirty-six (36) subjects, matched for age and gender, were subset in 3 groups (group A, 12 healthy controls, HC; group B, 12 multiple sclerosis patients, MS; group C, 12 patients with other neurological disease, OND) underwent echo-colour Doppler screening for CCSVI according to an original protocol previously described. The inter observer variability rate was assessed by comparing respectively trained vs not trained operators, and trained vs trained operators, by using the same echo-colour Doppler equipment. In addition, by scanning 15 subjects after one month from the first session, intra observer coefficient was also assessed in trained operator.

    RESULTS: The inter observer variability rate between trained and not trained echo-colour Doppler operators, were not completely satisfactory (K coefficient 0.47 95% CI 0.27-0.68). To the contrary the inter observer agreement between trained operators was much more reliable (K coefficient 0.80 95% CI 0.59-1.01). Finally, the intra observer variability rate in trained operators was 0.93, (95% CI 0.80-1.06) confirming a highly satisfactory agreement.

    CONCLUSION: Echo-colour Doppler is a powerful, non-invasive and reproducible tool for screening CCSVI-MS but it needs special training.

    Menegatti E, Genova V, Tessari M, Malagoni AM, Bartolomei I, Zuolo M, Galeotti R, Salvi F, Zamboni P.

    Vascular Diseases Centre, University of Ferrara, Italy

    Source: Pubmed PMID: 20351668 (01/04/10)

    Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis

    CCSVI VenogramAIM: The aim of this study is to compare the hemodynamics and the morphology of the internal jugular veins using Colour-Doppler and B-mode sonongraphy in multiple sclerosis patients (MS) and in controls.

    METHODS: The internal jugular veins of 25 MS patients and 25 controls were examined using colour Doppler and B-mode ultrasound in sitting and supine positions, recording the changes in hemodynamics and the presence or absence of morphological changes. The presence of at least two of the extracranial Zamboni criteria in the same individual was considered positive for evidence of chronic cerebrospinal venous insufficiency (CCSVI).

    RESULTS: According to the described criteria, 92% of the MS patients showed abnormal findings and 84% of them showed evidence of CCSVI, however; only 24% of controls showed abnormal findings, but none of them showed evidence of CCSVI (OR=7.25, 95% CI 2.92-18.01, P<0.0001).

    CONCLUSION: Hemodynamic abnormalities and morphological changes involving the internal jugular vein are strongly associated with MS. These findings can be demonstrated by a non-invasive, cost effective Doppler ultrasound criteria.

    Al-Omari MH, Rousan LA.

    Radiology Department, King Abdullah University Hospital, Jordan University of Science and Technology, Jordan.

    Source: Pubmed PMID: 20351667 (01/04/10)

    Extracranial Doppler sonographic criteria of chronic cerebrospinal venous insufficiency in the patients with multiple sclerosis.
    CCSVI VenographAIM: The aim of this open-label study was to assess extracranial Doppler criteria of chronic cerebrospinal venous insufficiency in multiple sclerosis patients.

    METHODS: Seventy patients were assessed: 49 with relapsing-remitting, 5 with primary progressive and 16 with secondary progressive multiple sclerosis. The patients were aged 15-58 years and they suffered from multiple sclerosis for 0.5-40 years. Sonographic signs of abnormal venous outflow were detected in 64 patients (91.4%).

    RESULTS: We found at least two of four extracranial criteria in 63 patients (90.0%), confirming that multiple sclerosis is strongly associated with chronic cerebrospinal venous insufficiency.

    Additional transcranial investigations may increase the rate of patients found positive in our survey. Reflux in internal jugular and/or vertebral veins was present in 31 cases (42.8%), stenosis of internal jugular veins in 61 cases (87.1%), not detectable flow in internal jugular and/or vertebral veins in 37 cases (52.9%) and negative difference in cross-sectional area of the internal jugular vein assessed in the supine vs. sitting position in 28 cases (40.0%).

    Flow abnormalities in the vertebral veins were found in 8 patients (11.4%). Pathologic structures (membranaceous or netlike septa, or inverted valves) in the junction of internal jugular vein with brachiocephalic vein were found in 41 patients (58.6%), in 15 patients (21.4%) on one side only and in 26 patients (37.1%) bilaterally.

    CONCLUSION: Multiple sclerosis is highly correlated with chronic cerebrospinal venous insufficiency. These abnormalities in the extracranial veins draining the central nervous system can exist in various combinations. The most common pathology in our patients was the presence of an inverted valve or another pathologic structure (like membranaceous or netlike septum) in the area of junction of the IJV with the brachiocephalic vein.

    Simka M, Kostecki J, Zaniewski M, Majewski E, Hartel M.
    Department of Angiology, Private Healthcare Institution SANA, Pszczyna, Poland

    Source: Pubmed PMID: 20351666 (01/04/10)

    Saskatoon researchers to test MS/CCSVI findings of Italian doctor
    CCSVI VenographIn light of work done by an Italian researcher into the cause of multiple sclerosis, Dr. Katherine Knox and her team of researchers announced they will put a controversial hypothesis to the test.

    Knox, director of the MS Clinic, located at City Hospital, and members of her research team outlined their plans during an educational session on Tuesday. They also fielded questions from patients and health officials from around Saskatchewan.

    Dr. Paolo Zamboni, of the University of Ferrara in Italy, has hypothesized there's a connection between MS and Chronic Cerebrospinal Venous Insufficiency (CCSVI) -- impaired blood drainage through the veins from the brain.

    Knox said Zamboni hypothesized that CCSVI occurs when the veins that drain the spinal cord as well as the brain are blocked and obstruct the normal flow of blood. She said Zamboni's theory assumes the obstruction causes back pressure and a leakage of red blood cells from the vessels. Iron is released from the red blood cells, which stimulates an inflammation in the brain or spinal cord.

    Zamboni and his colleagues have published a study that proposes

    CCSVI might be corrected by endovascular surgery. Symptoms of MS disappeared in most patients when he cleared blockages and got the blood flowing again.

    Zamboni's hypothesis helped Knox and her team identify specific areas of research and allowed them to set out their goals.

    "We would like to know how common (CCSVI) is or is not in MS," Knox said. "We would like to know if it's a risk factor in MS and how to look for it."

    Knox said they are launching a pilot project that will test 35 subjects with MS symptoms and a separate study that will test people who are at a high risk for MS.

    Knox and her team studied the work of Zamboni, including tests he ran on 65 people with MS and 235 people without the disease.

    "He concluded that obstructions may be causative of MS rather than a coincidental finding," Knox said. "He said the hypothesis of venous malformations of congenital development origin associated with MS seems to be plausible, but that additional longitudinal studies are necessary to confirm this hypothesis."

    Knox pointed out several problems with both the research conducted by Zamboni and his final hypothesis.

    "We can say that maybe it's not clear what we should call normal and abnormal," she said. "We don't know exactly how those criteria were developed and what we should label as normal and abnormal."

    Knox said there were problems with the tests done on the group without MS as well as the logical error of assuming abnormalities in blood flow is a cause of MS. She said she will avoid these problems when conducting her own studies.

    Knox and her team are just as anxious as MS patients are in testing Zamboni's hypothesis. However, she said they are not at the stage where they can safely and effectively treat someone with MS.

    "Unproven treatments are associated with high cost, high risk and unknown benefit and a public funded system on its own cannot support the right to unproven treatment," Knox said.

    Source: The StarPhoenix © The StarPhoenix (31/03/10)

    100 MS patients will get special CCSVI investigation in new study

    CCSVI VenogramSt. Joseph’s is holding the equivalent of a big-jackpot lottery for area multiple sclerosis patients when it randomly selects 100 of them to take part in its study of a radical new theory that the disease is vascular.

    More than 22,000 MS patients from all over the world have vied for one of the spots in the Hamilton research testing the theory of Italian Dr. Paolo Zamboni that is expected to start this summer.

    But in the end, only area patients will take part.

    Researchers Dr. Ian Rodger and Dr. Mark Haacke will randomly choose from 1,200 patients who have been treated by Hamilton’s MS Clinic located at McMaster University Medical Centre.

    They will do ultrasounds and MRI scans to determine if there is any difference in the veins draining blood from the head in MS patients compared to 100 similar healthy people.

    Zamboni believes the veins draining blood from the brain are blocked and leaking in MS patients. This allows iron to leak into brain tissue and he thinks the buildup causes many symptoms of MS. Zamboni found those veins blocked or malformed in more than 90 per cent of MS patients he studied -- including his wife.

    It’s a radical departure from current thinking that MS is an autoimmune disease with few treatments.

    St. Joseph’s is one of only two centres in Canada studying the theory. The other is in British Columbia.

    Rodger and his staff are hoping to personally contact each of the more than 22,000 patients who have asked to be part of the study.

     “We feel an obligation to get back to these people,” said Rodger. “A lot of patients would love to be part of the study, but from the standpoint of scientific rigor you have to do the selection randomly otherwise bias can come into the data you may generate.”

    Source: thespec.com  Copyright Metroland 2010 (28/03/10)

    UBC researchers planning to study Multiple Sclerosis vein theory

    Venous system of head and neckA medical centre in British Columbia says it wants to become the first in the country to test the controversial theory that multiple sclerosis patients have blocked veins, preventing proper blood flow from the brain.

    "There's a large demand for us to look into this," Dr. Anthony Traboulsee told CTV News. "Patients are very excited. We are very interested ourselves, and we want to meet the demand of our patients."

    A group of researchers at the University of British Columbia MS Clinic, part of the Vancouver Coastal Health Authority, are planning to study the theory, using a variety of imaging techniques. If it gets approval and funding, it appears to be the most comprehensive examination of this novel theory in the world.

    They will be studying the findings of Italian researcher Dr. Paolo Zamboni, who believes that blocked veins in the neck and chest of MS patients lead to blood drainage problems and triggers the immune responses that mark the disease.

    Zamboni contends that angioplasty surgery on these blocked veins, a procedure he calls the Liberation Treatment, can then open them. A preliminary study of the treatment in 65 patients showed it improved the quality of life for many patients, and as long as the veins remained open, symptoms of MS were reduced and new attacks were halted.

    The BC team envisions a study that begins with MS patients being scanned for abnormalities, likely using the ultrasound test pioneered in Italy. They would also be given MRI scans, to see how the different tests detect possible problems. The prevalence of vein problems would also be assessed in MS patients and in normal healthy control patients. Data would also be blinded to minimize the risk for bias in the research.

    Once these non-invasive scans have been done, test patients would proceed to the angiography suite. There they would undergo a venogram. That's where a probe is inserted, from the groin, into the vein system that travels through the chest and into the neck. Doctors inject a dye and watch the blood-flow. This is also, according the University of Ferrara team, the definitive way of seeing blockages in the jugular veins in the neck and the azygos vein in the chest.

    And if there are blocked or narrowed veins, the UBC researchers want to open them up to see what happens.

    "Not only do we want to see if we can detect these abnormalities, we also want to see, if we change them, does it improve peoples' lives?" said Traboulsee.

    The B.C. researchers, who include radiologists, vascular specialists, and physicists working on new imaging technologies, say they had heard about the theory before CTV's W5 aired a story describing the theory, and were investigating the possibility of a study.

    But interest in the theory in Canada has exploded since the episode aired.

    A professor of neurosurgery at the University of Buffalo, Dr. Robert Zivadinov, who worked on an early study with Zamboni, says his office was contacted by 8,000 MS patients in the three weeks after the W5 episode aired.

    The Vancouver researchers want to determine the prevalence of the vein abnormality, which Zamboni has dubbed CCSVI -- or chronic cerebrospinal venous insufficiency. They also want to know how easily it can be detected with ultrasound and MRI testing.

    Joining the study will be Alex Rauscher, a physicist. He hopes to look at MRI scans of patients to search for evidence of iron deposits in the brain, since some research has suggested that iron in the brain may contribute to the inflammation and the immune system attacks that mark MS.

    "It is our duty to find the answers," said Rauscher.

    The Vancouver Coastal Health researchers say they have applied for funding from the MS Society of Canada to fund research to determine the most practical and reliable test for CCSVI. But because of the size and scope of the study -- and their desire to begin quickly -- they are also accepting funding from other agencies and private donations.

    Donations should be directed to: VGH and UBC Hospital Foundation  - UBC Faculty of Medicine (funds can be specified for CCSVI research)

    The researchers note that their study is not accepting patients yet and likely won't for a few months until they acquire funding, obtain ethical approval, and develop an MRI and ultrasound testing protocol.

    Patients are asked to refrain from contacting the clinics until they are ready to proceed with the study.

    Meanwhile in Italy, one of the companies that manufactures the ultrasound machines used in the testing for CCSVI, is beginning to hold training sessions for doctors and technicians who want to learn the novel technique for scanning the neck and head.

    One training program is being held this week at the University of Ferrara with technicians who developed the tests, and with Zamboni. A second session is planned for March.

    Contact information for the course is available through: [email protected]

    Source: CTV News © 2010 CTVGlobeMedia (03/03/10)

    Blood brain barrier compromise with endothelial inflammation may lead to autoimmune loss of myelin during multiple sclerosis

    Endothelial Inflammation in the brain
    Multiple sclerosis is an autoimmune disease characterized by multifocal areas of inflammation and demyelination within the central nervous system.

    The mechanism that triggers the disease remains elusive. However, recent findings may indicate that multiple sclerosis, at its source, could be a hemodynamic disorder.

    It has been found that multiple sclerosis patients exhibit significant stenoses in extracranial veins draining the central nervous system (in azygous and internal jugular veins), which are associated with significant pressure gradients measured across strictures. Such anatomic venous abnormalities were not found in the control group of healthy subjects.

    In this review, it is hypothesized that pathological refluxing venous flow in the cerebral and spinal veins increases the expression of adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), by the cerebrovascular endothelium. This, in turn, could lead to the increased permeability of the blood-brain barrier.

    Inflamed and activated endothelium could secrete proinflammatory cytokines, including GM-CSF and TGF-beta In these settings, monocytes could transform into antigen-presenting cells and initiate an autoimmune attack against myelin-containing cells.

    Consequently, a potential therapeutic option for multiple sclerosis could be pharmacotherapy with either substances that strengthen the tight-junctions barrier, or with agents that reduce the expression of adhesion molecules. In addition, surgical correction could be an option in some anatomical variants of pathologic venous outflow.

    We are optimistic that a hemodynamic approach to the multiple sclerosis pathogenesis can open a new chapter of investigations and treatment of this debilitating neurologic disease.

    Simka M.

    Department of Angiology, Private Healthcare Institution SANA, Pszczyna, Poland.

    Source: PMID: 19442163 (01/03/10)

    Iron leads to memory impairment that is associated with a decrease in acetylcholinesterase pathways

    Iron deposits in brainPerez VP, de Lima MN, da Silva RS, Dornelles AS, Vedana G, Bogo MR, Bonan CD, Schröder N.

    Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University, Av. Ipiranga, 6681 Prédio 12C, Sala 340, 90619-900 Porto Alegre, RS, Brazil.

    Increasing evidence indicates that excessive iron in selective regions of the brain may be involved in the etiology of neurodegenerative disorders. Accordingly, increased levels of iron have been described in brain regions of patients in Parkinson's and Alzheimer's diseases.

    We have characterized neonatal iron loading in rodents as a novel experimental model that mimics the brain iron accumulation observed in patients with neurodegenerative diseases and produces severe cognitive impairment in the adulthood.

    In the present study we have investigated the involvement of the cholinergic system on iron-induced memory impairment.

    The effects of a single administration of the acetylcholinesterase (AChE) inhibitor galantamine or the muscarinic receptor agonist oxotremorine on iron-induced memory deficits in rats were examined.

    Male Wistar rats received vehicle or iron (10.0 mg/kg) orally at postnatal days 12 to 14. At the age of 2-3 months, animals were trained in a novel object recognition task.

    Iron-treated rats showed long-term impairments in recognition memory. The impairing effect was reversed by systemic administration of galantamine (1 mg/kg) immediately after training.

    In addition, iron-treated rats that received oxotremorine (0.5 mg/kg) showed enhanced memory retention. Rats given iron showed a decreased AChE activity in the striatum when compared to controls.

    The results suggest that, at least in part, iron-induced cognitive deficits are related to a dysfunction of cholinergic neural transmission in the brain.

    These findings might have implications for the development of novel therapeutic strategies aimed at ameliorating cognitive decline associated with neurodegenerative disorders.

    Source: Pubmed PMID: 20158466 (01/03/10)

    The severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics
    CCSVI Chronic cerebrospinal venous insufficiency(CCSVI) is a vascular picture that shows a strong association with multiple sclerosis (MS).

    The aim of this study was to investigate the relationship between a Doppler cerebral venous hemodynamic insufficiency severity score (VHISS) and cerebrospinal fluid (CSF) flow dynamics in 16 patients presenting with CCSVI and relapsing-remitting MS (CCSVI-MS) and in eight healthy controls (HCs).

    The two groups (patients and controls) were evaluated using validated echo-Doppler and advanced 3T-MRI CSF flow measures. Compared with the HCs, the CCSVI-MS patients showed a significantly lower net CSF flow (p=0.027) which was highly associated with the VHISS (r=0.8280, r2=0.6855; p=0.0001).

    This study demonstrates that venous outflow disturbances in the form of CCSVI significantly impact on CSF pathophysiology in patients with MS.

    Zamboni P, Menegatti E, Weinstock-Guttman B, Schirda C, Cox JL, Malagoni AM, Hojanacki D, Kennedy C, Carl E, Dwyer MG, Bergsland N, Galeotti R, Hussein S, Bartolomei I, Salvi F, Zivadinov R.

    Source: Pubmed PMID: 20018140 (28/02/10)

    Preliminary results of preoperative diagnostics and endovascular treatment for CCSVI
    Preliminary results of preoperative diagnostics and endovascular treatment for CCSVI
    Marian Simka
    EuroMedicVascular and Endovascular
    Surgery Department Katowice
    Poland

    http://www.ms-mri.com/docs/Simka-hamilton%20-ccsvi-1.pdf

    First blinded study of venous insufficiency prevalence in MS shows promising results
    CCSVI Blood FlowMore than 55 percent of multiple sclerosis patients participating in the initial phase of the first randomized clinical study to determine if persons with MS exhibit narrowing of the extracranial veins, causing restriction of normal outflow of blood from the brain, were found to have the abnormality.

    The results were reported today by neurology researchers at the University at Buffalo.

    When the 10.2 percent of subjects in which results were border line were excluded, the percentage of affected MS patients rose to 62.5 percent, preliminary results show, compared to 25.9 percent of healthy controls.

    These preliminary results are based on the first 500 participants in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study, which began at UB in April 2009. Investigators are planning to examine 500 additional subjects, who will be assessed in the second phase of the study with more advanced diagnostic tools. Complete data on the first 500 will be presented at the American Academy of Neurology meeting in April.

    Robert Zivadinov, MD, PhD, UB associate professor of neurology and principal investigator on the study, says he is "cautiously optimistic and excited" about the preliminary data. Zivadinov directs the Buffalo Neuroimaging Analysis Center (BNAC), located in Kaleida Health's Buffalo General Hospital, where the study is being conducted.

    "The data encourage us to continue on the same course," he says. "They show that narrowing of the extracranial veins, at the very least, is an important association in multiple sclerosis. We will know more when the MRI and other data collected in the CTEVD study are available." The analyses are being conducted by an independent statistician.

    The investigation is the first step in determining if a condition called chronic cerebrospinal venous insufficiency (CCSVI) is a major risk factor for MS. CCSVI is a complex vascular condition discovered and described by Paolo Zamboni, MD, from Italy's University of Ferrara. Zamboni's original investigation in a group of 65 patients and 235 controls showed CCSVI to be associated strongly with MS, increasing the risk of having MS by 43 fold.

    Zamboni and Zivadinov hypothesize that this narrowing restricts the normal outflow of blood from the brain, resulting in alterations in the blood flow patterns within the brain that eventually cause injury to brain tissue and degeneration of neurons.

    The first 500 patients, both adults and children, were grouped based on their diagnosis: MS, clinically isolated syndrome (CIS) and "other neurologic diseases" (OND), in addition to healthy controls.

    All participants in the first phase underwent ultrasound (Doppler) scans of the head and neck in different body postures to view the direction of venous blood flow. MS subjects also underwent MRI scans of the brain to measure iron deposits in lesions and surrounding areas of the brain, using a method called susceptibility-weighted imaging. Iron findings on these images will be related to subjects' disability and neuropsychological symptoms.

    Of the total participants, 97.2 percent were adults, with the 280 MS patients comprising the largest disease cohort examined in the study to date. The majority of MS subjects were diagnosed with the relapsing-remitting form of MS. There were 161 healthy controls. Doppler scan results were reported on five specific criteria that affect venous blood flow. Patients who met at least two of the criteria were considered to have CCSVI. More detailed analysis of specific Doppler criteria and their association to disease status is underway.

    When the 10.2 percent borderline subjects were included in the "normal" category (no venous insufficiency), the CCSVI prevalence was 56.4 percent in MS subjects and 22.4 percent in healthy controls.

    In this large MS cohort, the presence of CCSVI did suggest an association with disease progression, a finding that was not shown in Zamboni's smaller cohort, Zivadinov notes.

    The finding that 22.4 percent of healthy controls also met two CCSVI criteria requires continuing investigation, he says.

    Bianca Weinstock-Guttman, MD, UB associate professor of neurology in the UB School of Medicine and Biomedical Sciences and a co-principal investigator on the study, notes that the results of the CTEVD research will pose new and provocative questions about the CCSVI theory.

    Murali Ramanathan, PhD, associate professor in the Department of Pharmaceutical Sciences, UB School of Pharmacy and Pharmaceutical Sciences, and Ralph Benedict, PhD, UB professor of neurology and psychiatry, also are major contributors to the study.

    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: The University at Buffalo © 2010 University at Buffalo (10/02/10)

    Centre to test for Chronic Cerebrospinal Venous Insufficiency (CCSVI) and it's possible link to MS
    CCSVI Blood FlowOne of the first clinics in North America devoted to testing for a vascular condition that some experts believe is linked to multiple sclerosis is set to open later this month in Buffalo, just as scientists are to release more findings on the controversial theory.

    The Buffalo Neuroimaging Analysis Center (BNAC) has announced that it will begin to offer testing for the newly discovered condition, called chronic cerebrospinal venous insufficiency (CCSVI), in mid-February due to overwhelming demand from MS patients.

    Italian scientist Dr. Paolo Zamboni believes that CCSVI causes veins in the neck and upper chest to twist, narrow or become blocked; in some cases, these veins never form at all. The result is poor blood drainage from the brain.

    Zamboni has found that more than 90 per cent of patients with MS have these malformed veins, and improper blood flow from the brain.

    Due to the overwhelming response to Zamboni's research and to its own study on the condition, the BNAC said it will begin offering diagnostic venous testing to patients beginning in mid-February 2010.

    Testing will include:

    • An MRI of the brain to measure the level of iron deposits
    • An MRI of the neck to study the jugular, vertebral and other collateral veins
    • A Doppler exam of the head and neck to determine blood flow
    • A follow-up visit with a doctor to discuss the findings

    News of the findings comes days before scientists from the BNAC release data from their study that includes 500 MS patients who were tested for CCSVI.

    "What I can tell you today is that the preliminary results are exciting scientifically and will generate a great deal of discussion among our colleagues, the worldwide press, and individuals like you who are following very closely any developments about CCSVI," Dr. Robert Zivadinov said in the BNAC newsletter.

    Zivadinov said the second phase of the study will include another 500 patients and will "pose new and provocative questions about the CCSVI theory."

    Scientist welcomes scepticism

    Zamboni told CTV's Canada AM Monday that he welcomes skepticism about his findings.

    "This is normal when there is a new finding in science," Zamboni said. "I think that this is positive because it stimulates debate."

    Zamboni was in Hamilton, Ont., Sunday for a scientific workshop looking into the relationship between MS and CCSVI. Scientists from the United States, Europe and the Middle East reported that they had found CCSVI in more than 95 per cent of MS patients.

    "The meeting yesterday was quite successful because we met a lot of colleagues from all over the world that are actually working on our theory," said Zamboni, who is a professor of medicine at the University of Ferrara in Italy.

    According to Zamboni, a surgical procedure to restore proper blood flow, which he dubbed the "Liberation treatment," can reduce MS symptoms.

    In a study of 65 patients who underwent the procedure, released in the Journal of Vascular Surgery, Zamboni says that 50 per cent of patients with the most common form of MS were relapse-free for at least 18 months.

    In a control group of MS patients who did not undergo the procedure, only 27 per cent went 18 months without an MS attack.

    Additionally, only 12 per cent of patients in the surgery group had brain lesions -- a sign of active disease -- compared to 50 per cent in the control group.

    Research will take time

    Dr. Mark Haacke, director of the imaging division in the school of biomedical engineering at McMaster University, organized the weekend conference and said "no one is claiming it's a cure."

    "It's a cardiovascular problem first, it may be related to MS, it may cause MS -- but we don't know all those answers yet," he told CTV.ca. "That's going to take time to do very careful research to evaluate those MS patients that do get the operation.

    "Do they get better? Do they stay the same? Do their lesions go away? Or do they at least not get worse. (It) may take years and years to really determine the effectiveness of this surgery."

    MS societies around the world have responded with funding for research into CCSVI. The Italian Multiple Sclerosis Foundation has allocated up to $4.5 million for research and the MS Society of Canada has called for applications for grants for those studying Zamboni's findings.

    Charity Intelligence Canada, a group that provides donors with research and information, called for additional research and funding into Zamboni's findings on Monday.

    The group said Canadians donated $62 million to MS-related charities in 2009, and said "supporting CCSVI research presents an opportunity for donors to have high impact in their giving."

    "Donors wanting to support CCSVI research in Canada should donate directly to St. Joseph's Healthcare and McMaster University in Hamilton, Ontario and University of British Columbia, designating their donations to CCSVI research," the group said in a statement.

    However, experts have warned that the findings are far from being validated and those with MS should continue with their current treatment.

    "Although the early data are of great interest, it is important to acknowledge that the concept of CCSVI as a cause of MS and the use of stents or balloons to widen veins as treatments, are ideas that are far from being accepted by most researchers in the field," the MS Society of Canada says on its website.

    Experts have expressed concern that the initial excitement over the new procedure was leading some to drop their current treatment.

    "To people with MS we say: don't abandon the course of treatment that you have started," Yves Savoie, the president and CEO of the MS Society of Canada told CTV News in November.

    "Those treatments have been proven in large trials to be effective in reducing the burden of disability that comes with MS."

    Haacke says that since most MS patients have MR scans performed, clinicians should consider performing additional scans for CCSVI.

    "It's important for clinicians to begin to realize that they should be taking some time clinically – not on the research side – to scan their patients and find out if this is a problem," he said.

    Canada has one of the highest rates of MS in the world, affecting between 44,000 to 78,000 in the country.

    Source: CTV News © 2010 CTVGlobeMedia (09/02/10)

    Test of CCSVI - Multiple Sclerosis theory 'watershed moment' for St. Joe's
    Prof. ZamboniFinding a treatment for multiple sclerosis holds as much promise for Hamilton as it does for patients.

    St. Joseph's Hospital is one of just two places in Canada testing Italian vascular surgeon Dr. Paolo Zamboni's controversial theory that MS is a vascular disease -- a radical departure from long-held beliefs that it's an autoimmune condition. The University of British Columbia is the other place.

    It has brought Hamilton to the attention of the world with about 22,000 MS patients from Asia to Africa to South America to all over the United States and Canada vying to be one of the 100 chosen for the study. It will also recruit 100 healthy people to take part.

    "This is a watershed moment," said Dr. Ian Rodger, vice-president of research at St. Joseph's Healthcare. "Opportunities like this don't come along very often."

    Hamilton has the chance because of McMaster's affiliation with Detroit imaging expert Dr. Mark Haacke, who met Zamboni in September when the Italian doctor held a conference about his theory.

    Zamboni believes the veins draining blood from the brain are blocked and leaking in MS patients. This allows iron to leak into brain tissue and he thinks the buildup causes many symptoms of MS. Zamboni found those veins blocked or malformed in more than 90 per cent of MS patients he studied -- including his wife.

    Haacke has long researched the role iron plays in MS and is eager to test Zamboni's theory. His main lab is in Detroit but he's also an adjunct professor at McMaster. With eight other Hamilton doctors, he plans to use St. Joseph's MRI, which is twice as strong as traditional machines, to look at the veins in the brains of MS patients and healthy people to see whether there is a difference.

    Haacke says there has been a lot of resistance to Zamboni's theory -- Chronic Cerebrospinal Venous Insufficiency (CCSVI) -- from medical professionals, particularly neurologists.

    "It was just so flabbergasting to them," he said.

    But the idea can't be ignored.

    "We're going to have 10 years of fascinating research."

    St. Joseph's, McMaster and Hamilton Health Sciences want to play a big role in that. They don't have funding yet, but are together putting in a proposal to the MS Society of Canada Tuesday for $100,000 a year for two years.

    Rodger is leading the research and hoping other funders will come forward so that they can do a much bigger study that would produce results in 12 to 15 months instead of two years or longer. Philanthropists and/or their advisors are expected to be at the workshop Zamboni and Haacke are presenting in Hamilton tomorrow.

    The stakes are high for MS patients, as there are few treatment options. Zamboni performs an experimental surgery similar to angioplasty to unclog the veins and improve blood flow. He says it has worked for his wife and others.

    Hamilton MS patient Vasilios "Bill" Smyrnios wants to know if that surgery could help him. The 50-year-old who was diagnosed 10 years ago can't walk anymore and has to live in supportive housing.

    "This disease is relentless," he said. "It keeps getting worse. It has amazed me. I never expected to get like this."

    He has newfound hope since researching Zamboni's theory.

    "It was the first thing I've read in a long time that made sense."

    While St. Joseph's is studying the theory and hosting the conference, it is a long way from endorsing it.

    "There's a great deal of skepticism about the observational study (that Zamboni did)," said Kevin Smith, CEO of St. Joseph's Healthcare. "A lot of the scientific community has already rejected the view. But it resonates profoundly with patients and families so it's our responsibility to determine if this is more than unusual observation."

    Source: Thespec.com © Copyright Metroland 2010 (07/02/10)

    UBC researchers planning to study Multiple Sclerosis vein theory
    CCSVI Blood FlowA medical centre in British Columbia says it wants to become the first in the country to test the controversial theory that multiple sclerosis patients have blocked veins, preventing proper blood flow from the brain.

    "There's a large demand for us to look into this," Dr. Anthony Traboulsee told CTV News. "Patients are very excited. We are very interested ourselves, and we want to meet the demand of our patients."

    A group of researchers at the University of British Columbia MS Clinic, part of the Vancouver Coastal Health Authority, are planning to study the theory, using a variety of imaging techniques. If it gets approval and funding, it appears to be the most comprehensive examination of this novel theory in the world.

    They will be studying the findings of Italian researcher Dr. Paolo Zamboni, who believes that blocked veins in the neck and chest of MS patients lead to blood drainage problems and triggers the immune responses that mark the disease.

    Zamboni contends that angioplasty surgery on these blocked veins, a procedure he calls the Liberation Treatment, can then open them. A preliminary study of the treatment in 65 patients showed it improved the quality of life for many patients, and as long as the veins remained open, symptoms of MS were reduced and new attacks were halted.

    The BC team envisions a study that begins with MS patients being scanned for abnormalities, likely using the ultrasound test pioneered in Italy. They would also be given MRI scans, to see how the different tests detect possible problems. The prevalence of vein problems would also be assessed in MS patients and in normal healthy control patients. Data would also be blinded to minimize the risk for bias in the research.

    Once these non-invasive scans have been done, test patients would proceed to the angiography suite. There they would undergo a venogram. That's where a probe is inserted, from the groin, into the vein system that travels through the chest and into the neck. Doctors inject a dye and watch the blood-flow. This is also, according the University of Ferrara team, the definitive way of seeing blockages in the jugular veins in the neck and the azygos vein in the chest.

    And if there are blocked or narrowed veins, the UBC researchers want to open them up to see what happens.

    "Not only do we want to see if we can detect these abnormalities, we also want to see, if we change them, does it improve peoples' lives?" said Traboulsee.

    The B.C. researchers, who include radiologists, vascular specialists, and physicists working on new imaging technologies, say they had heard about the theory before CTV's W5 aired a story describing the theory, and were investigating the possibility of a study.

    But interest in the theory in Canada has exploded since the episode aired.

    A professor of neurosurgery at the University of Buffalo, Dr. Robert Zivadinov, who worked on an early study with Zamboni, says his office was contacted by 8,000 MS patients in the three weeks after the W5 episode aired.

    The Vancouver researchers want to determine the prevalence of the vein abnormality, which Zamboni has dubbed CCSVI -- or chronic cerebrospinal venous insufficiency. They also want to know how easily it can be detected with ultrasound and MRI testing.

    Joining the study will be Alex Rauscher, a physicist. He hopes to look at MRI scans of patients to search for evidence of iron deposits in the brain, since some research has suggested that iron in the brain may contribute to the inflammation and the immune system attacks that mark MS.

    "It is our duty to find the answers," said Rauscher.

    The Vancouver Coastal Health researchers say they have applied for funding from the MS Society of Canada to fund research to determine the most practical and reliable test for CCSVI. But because of the size and scope of the study -- and their desire to begin quickly -- they are also accepting funding from other agencies and private donations.

    Donations should be directed to: VGH and UBC Hospital Foundation , UBC Faculty of Medicine (funds can be specified for CCSVI research)

    The researchers note that their study is not accepting patients yet and likely won't for a few months until they acquire funding, obtain ethical approval, and develop an MRI and ultrasound testing protocol.

    Patients are asked to refrain from contacting the clinics until they are ready to proceed with the study.

    Meanwhile in Italy, one of the companies that manufactures the ultrasound machines used in the testing for CCSVI, is beginning to hold training sessions for doctors and technicians who want to learn the novel technique for scanning the neck and head.

    One training program is being held this week at the University of Ferrara with technicians who developed the tests, and with Zamboni. A second session is planned for March.

    Contact information for the course is available through: [email protected]

    Source: CTV News © 2010 CTV Globe Media (30/01/10)

    Australian study questions established concepts of early disease events in MS
    T CellsInvestigators at the University of Sydney have published a study suggesting that the earliest activity seen in the brain in MS is the destruction of cells that make myelin (oligodendrocytes), occurring before the onset of immune activity usually blamed for triggering the disease.

    This provocative study, co-funded by many sources including the National MS Society, opens up new possibilities for finding the cause of the disease and developing new treatments. The study is authored by Drs. John W. Prineas, Andrew P.D. Henderson and colleagues, and is published in the December issue of Annals of Neurology (2009;66:739–753).

    Background: Multiple sclerosis has long been thought to be triggered by immune attacks in the brain and spinal cord, causing a spectrum of neurological symptoms. Extensive research has been underway to better understand what triggers the immune attacks and which immune cells are involved, and to better understand the damage to the central nervous system that occurs during the course of MS. In addition to studies of immune activity underlying what has been considered an autoimmune process, another important approach has centered on pathology studies involving microscopic explorations of MS lesions (damaged areas, also called plaques) in the brains of people with MS.

    The lead author of the current study, John W. Prineas, MB, BS, FRCP, was the 2001 winner of the John Dystel Prize for MS Research, an award given jointly by the National MS Society and the American Academy of Neurology. He was recognized for being the investigator who first described how myelin, the substance that insulates nerve fibers, is broken down in MS, and he was the first to demonstrate that myelin repair occurs during the course of MS through the body’s natural repair processes.

    Current Study: For this study, the team used brain specimens from 11 people who had died early in the course of their MS, and the team also used comparison specimens from people with other disorders including stroke. Some of the tests focused on subsets of specimens from seven people who had lesions showing active myelin destruction. To get a sense of immune cell activity in the brain and at what stage it was occurring, the team examined newly active and resolved lesions, as well as nearby blood vessels, surrounding areas showing some disease activity and surrounding areas that appeared normal, and areas that were farther away from the lesions of interest.

    Results: In tissues surrounding newly forming lesions, the investigators found evidence of the loss of oligodendrocytes with an absence of immune T or B cells that would normally be held responsible for launching the immune attack against oligodendrocytes and the myelin they produce. These and other immune cells, including scavenger cells (macrophages and microglia), were more numerous in lesions and surrounding tissues at apparently later stages of destruction and sometimes in lesions that were in the process of repair. In specimens from two very early cases of clinical onset of disease, they found few immune cells within the lesions and no evidence of activation of scavenger cells.

    These and other unexpected findings from this study led the investigators to propose that the early immune activity seen in active lesions is that of macrophages and microglia, whose job it is to clean up and remove damaged myelin. They propose that lesion formation is caused by something other than destructive immune activity led by inflammatory cells against a component of myelin or oligodendrocytes.

    Comment: This study is a significant addition to a small but growing body of evidence that highlights the question of what triggers MS and whether there is something other than, or in addition to, the immune attacks that lead to tissue damage in the brain and spinal cord of people with MS. Further research, which is ongoing by investigators around the world, should shed further light on this question and may offer novel treatment approaches.

    Note: The availability of donor brain specimens was crucial to this and other studies focusing on disease pathology

    Source: US National Multiple Sclerosis Society (30/01/10)

    A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency
    A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency (Journal Of Vascular Surgery © 2009 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved)

    Italian Multiple Sclerosis group offers $4.5M to fund new MS research
    CCSVIThe Italian Multiple Sclerosis Foundation today announced it will allocate up to $4.5 million to fund ongoing research into CCSVI -- a condition linked to Multiple Sclerosis.

    The foundation says it is accepting research proposals until March 8 from scientists interested in studying CCSVI -- a condition discovered by a team at the University of Ferrara in Italy and lead scientist Dr. Paolo Zamboni.

    “We await proposals from groups of Italian researchers, in particular by the research groups that are already active with Prof. Zamboni,” said in a press release.

    The condition causes veins in the neck and upper chest to twist, narrow or become blocked. In some cases these veins never form at all. The result is poor blood drainage from the brain. Dr. Zamboni has found that more than 90 per cent of patients with MS have these malformed veins, and improper blood flow from the brain.

    Roberta Amaedo, President of the Italian Association for Multiple Sclerosis, said in the release: "We need certainty about the relationship between MS and CCSVI and on the clinical course that this can cause, and on that clinical trials will make an important contribution.”

    The association also cautioned patients against seeking endovascular or surgical procedures to open these blocked veins outside of controlled research studies.

    In another development, an international group of doctors who specialize in disorders of the veins has issued a consensus document, on the diagnosis and treatment of these problems, including CCSVI.

    The international Union of Phlebology officially classified CCSVI as a congenital vascular malformation, outlining official guidelines for diagnosis and treatment.

    Dr. James Laredo, a vascular surgeon at Georgetown University Hospital, and one of the authors of the statement, said the members of the group voted unanimously in favour of including CCSVI as a venous malformation.

    The statement also says the origins of this novel condition appear to take root during development in the uterus, before birth. Dr. Zamboni, who first identified the condition, is also part of this group.

    Dr. Laredo told CTV News that his hospital is now planning to begin a study in a month with neurologists to screen MS patients for these abnormal veins and determine if there is a link between CCSVI and multiple sclerosis. They will be treating MS patients who are found to have CCSVI.

    "In Dr. Zamboni's group of MS patients, I feel that he has demonstrated proof of concept. Furthermore, I feel that his findings are significant enough that it requires further investigation and that is why we at Georgetown University Medical Center have begun our investigation into CCSVI," said Dr. Laredo.

    Source: CTV News © 2010 CTVGlobeMedia (28/01/10)

    Diagnosis and treatment of venous malformations - Consensus document of the international union of phlebology (IUP)-2009
    Venous Malformations
    A Consensus Conference on Venous Malformations - headed by Prof. Byung B Lee from Georgetown - and experts from 47 countries studied the evidence and unanimously voted in favour of officially including the stenosing lesions found in CCSVI in the new
    Consensus document and Guidelines. Now published- http://tinyurl.com/yh8qgq3

    This paper can be brought to interventional radiologists and vascular surgeons. CCSVI lesions are classified as a truncular
    venous malformations - which means that vascular doctors have now classified this disease, CCSVI, as congenital- and
    preceding MS lesions.

    Vascular doctors have agreed. CCSVI comes first.

    Dr. Zamboni has been speaking to medical panels around the world. Yesterday was a "4 hour machine gunning of questions"
    by the Italian, Canadian and US MS Societies in Milan- Dr. Zamboni said he was able to answer all the questions with scientific
    evidence, and was quite pleased with the meeting's outcome. He'll be in North American soon.

    Source: ThisisMS CCSVI Forum (26/01/10)

    Wedge-shaped medullary lesions in multiple sclerosis suggestive of an impairment of venous drainage
    CCSVI in MSMultiple sclerosis (MS) is a heterogeneous disease with variable clinical features and magnetic resonance imaging (MRI) findings.

    We report four MS cases with unusual wedge-shaped lesions in the paramedian ventral medulla oblongata demonstrated on MRI.

    The clinical features and MRI characteristics of the medullary lesions suggest an impairment of venous drainage.

    We propose that the formation of these wedge-shaped lesions may be related to the pattern of venous drainage in the ventral medulla and raised venous pressure due to chronic cerebrospinal venous insufficiency which has recently been described in MS.

    Qiu W, Raven S, Wu JS, Carroll WM, Mastaglia FL, Kermode AG.

    Centre for Neuromuscular and Neurological disorders, University of Western Australia, Australia; Department of Neurology, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia; Department of Neurology, the Third Affiliated Hospital of Sun yat-sen University, Guangzhou, China.

    Copyright © 2010 Elsevier B.V. All rights reserved.

    Source: PubmedPMID: 20056253 (11/01/10)

    Epstein-Barr virus may cause Multiple Sclerosis through involvement of the venous system
    Epstein-Barr virusPossible connection to Chronic Cerebrospinal Venous Insufficiency - CCSVI explained.

    Re: Epstein–Barr virus is associated with grey matter atrophy in multiple sclerosis
    R Zivadinov, M Zorzon, B Weinstock-Guttman, M Serafin, A Bosco, A Bratina, C Maggiore, A Grop, M A Tommasi, B Srinivasaraghavan, M Ramanathan
    J Neurol Neurosurg Psychiatry 2009;80:620-625 Published Online First: 23 January 2009 doi:10.1136/jnnp.2008.154906

    Dear Editor,

    I read the article by Zivadinov (1) with reference to the association of Epstein-Barr virus (EBV) to gray matter atrophy in multiple sclerosis (MS) patients.

    Accumulation of EBV infected B cells in meninges and perivascular regions of MS lesions in 21 or 22 patients with MS (2) was noted as well, indicating direct involvement of the brain and perivascular spaces by EBV in MS patients..

    A recent study has indicated chronic cerebrospinal venous insufficiency with multiple extracranial venous strictures in MS patients (3).

    EBV appears to infect endothelial cells (4), and may be important in the pathology of EBV virus.

    EBV virus has been found to cause deep venous thrombosis in a patient with hereditary thrombophilia (5).

    EBV may infect the venous endothelium causing venous thromboses and strictures in the cranial and spinal venous drainage system and perivascular regions of MS lesions in patients with MS.

    Such venous involvement may be implicated in MS disease involvement.

    Chronic EBV infection may involve the venous system with secondary effects on the brain and spinal cord in MS.

    References

    1.Zivadinov R, Zorzon M, Weinstock-Guttman B, Serafin M, Bosco A, Bratina A, et al.
    Epstein-Barr virus is associated with grey matter atrophy in multiple sclerosis
    J Neurol Neurosurg Psychiatry 2009; 80: 620 -625.

    2.Serafani B, Rosicarelli B, Franciotta D, et al.
    Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain.
    J Exp Med 2007; 204:2899-2912.

    3. Zamboni P, Galeotti P, Menegatti E, Malagoni AM, Tacconi G, et al.
    Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.
    J Neurol Neurosurg Psychiatry 2009: 80: 392-398.

    4. Jones K, Rivera C, Sgadari C, Franklin J, Max EE, et al.
    Infection of human endothelial cells with Epstein-Barr virus.
    J Exp Med. 1995; 182: 1213-1221.

    5. Mashav N, Saar N, Chundadze T, Steinvil.
    Epstein-Barr virus associated thromboembolism: A case report and review of the literature.
    Thromb Res. 2008; 122: 570-571.

    No conflict of interest.

    Steven R Brenner, Neurologist
    St. Louis VA Medical Center and Dept Neurology and Psychiatry at St. Louis University

    Source: J Neurol Neurosurg Psychiatry © 2009 by the BMJ Publishing Group Ltd

    University of British Columbia plans to test potentially groundbreaking MS treatment

    CCSVIThe University of British Columbia has announced plans to begin patient trials to test a potentially groundbreaking method of diagnosing and treating multiple sclerosis, a disease that afflicts up to 75,000 Canadians.

    Researchers have proposed launching a study involving 100 patients to test a theory that MS is a vascular disease that can be treated with surgery. It's the first research proposal in Canada to suggest evaluating the findings of an Italian doctor whose early studies indicate that multiple sclerosis might be caused by vein blockages that lead to a buildup of iron in the brain.

    The findings of Paolo Zamboni have generated a great deal of interest among researchers and those with MS. Earlier this year, the Multiple Sclerosis Society of Canada appealed to scientists to follow up Dr. Zamboni's theories.

    The proposed UBC trial, which would be done in collaboration with researchers at the University of Saskatchewan, is an answer to that appeal, said Anthony Traboulsee, medical director of the UBC MS Clinic.

    Dr. Traboulsee said Dr. Zamboni's studies have caused both hope and anxiety among people with MS. They are hungry for a breakthrough, but realize the Italian doctor's findings are preliminary.

    “They are very anxious about this,” Dr. Traboulsee said Tuesday in an interview. “MS is a lifelong disease. Young people are hungry for hope.” Because of the intense interest in the new findings, Dr. Traboulsee said the proposed patient trials must “take a careful” approach.

    Unlike Dr. Zamboni's earlier studies, the UBC research plan will include a control group – which gives more heft to a study's findings – and will take place over a longer period.

    In Dr. Taboulsee's proposed trial, researchers would closely examine participants' neck and stomach veins. The study group will include people with and without MS. Each participant will undergo three tests, including an ultrasound, a magnetic resonance imaging test and the insertion of a catheter. In that test, dye is injected to give researchers a closer look at the veins.

    Only MS participants with blocked or narrowed veins will move on to the second stage of the trials.

    Half that group will undergo a vein dilation procedure – similar to an angioplasty – to expand the vein, the other half won't.

    The purpose of UBC's proposed research trial is to build on the knowledge uncovered by Dr. Zamboni, a professor of medicine at the University of Ferrara in Italy. His theory is that a condition that he dubbed chronic cerebrospinal venous insufficiency causes MS. The current thinking is that MS is an autoimmune condition in which the immune system attacks myelin, a fatty substance that coats nerve cells.

    Dr. Zamboni found that, in about 90 per cent of people with multiple sclerosis, the veins draining blood from the brain were malformed or blocked, which led to a buildup of iron in the brain, which he theorized causes the neurological symptoms of MS.

    Dr. Zamboni had 65 of his patients undergo an angioplasty to clear the blockage. Of those, 50 per cent reported no attacks in the next 18 months. In a group that did not have surgery, that rate was 27 per cent.

    Multiple sclerosis is a degenerative condition that can cause loss of balance, heat sensitivity, impaired speech, double vision and paralysis.

    UBC's trial still needs funding and approval from an ethics committee. The researchers will apply for funds from the MS Society of Canada, private donors and the Canadian Institutes of Health Research. Dr. Taboulsee said the study will cost nearly $1-million for equipment and staff.

    Researchers including some at UBC have already been studying links between MS and iron in the brain, Dr. Taboulsee said. He said the latest findings are like another piece to a jigsaw puzzle. Previous studies have linked MS to, among other things, a Vitamin D deficiency and cold climates.

    Source: The Globe And Mail © 2009 CTVglobemedia Publishing Inc. (16/12/09)

    Endovascular treatment of cerebrospinal venous insufficiency safe, may provide benefit in MS
    CCSVINew data from a pilot open-label study suggest that endovascular treatment of strictures in extracranial cerebrospinal veins is safe in patients with multiple sclerosis (MS) and may provide some neurological benefit for these patients, researchers conclude.

    The controversial approach, which has recently been making headlines in consumer media outlets, proposes that narrowing in the veins draining the brain, called chronic cerebrospinal venous insufficiency (CCVI), may be an early step in the disease process causing MS, and further, this narrowing may respond to simple angioplasty.

    Lead author Paolo Zamboni, MD, director of the Vascular Diseases Center at the University of Ferrara, Italy, emphasized that the current report should be viewed as an interesting finding that urgently requires replication by other groups.

    "What we know is that MS is very complex and multifactorial," Dr. Zamboni told Medscape Neurology. "We have identified an unknown factor and possible treatment for this factor."

    The study is published as an online article in the December issue of the Journal of Vascular Surgery.

    CCVI and MS

    In a previous study published online in December 2008, Dr. Zamboni and colleagues assessed venous outflow routes in 65 patients with clinically definite MS (CDMS) and 235 control patients using a combined transcranial and extracranial color Doppler high-resolution examination. They reported that CDMS and venous outflow abnormalities were "dramatically" associated, with an odds ratio of 43 (95% confidence interval, 29 - 65; P < .0001).

    Venography showed the presence of multiple severe extracranial stenoses affecting the principal venous segments in the patients with MS but not the control patients. "This provides a picture of chronic cerebrospinal venous insufficiency with 4 different patterns of distribution of stenosis and substitute circle," the authors write. "Moreover, relapsing-remitting and secondary progressive courses were associated with CCVI patterns significantly different from those of primary progressive (P < .0001)" (Zamboni P, et al. J Neurol Neurosurg Psychiatry 2009;80:392-399).

    In an editorial accompanying that publication, Claude Franceschi, MD, from Saint Joseph and Pitié-Salpétrière Hospitals in Paris wrote that, "in light of the association between such a previously overlooked vascular picture and MS, a further stimulating research field is opened by this article. This should be addressed in understanding the contribution of venous drainage to the different aspects of inflammation, autoimmunity and neurodegeneration characterising the intriguing puzzle of MS" (Franceschi C. J Neurol Neurosurg Psychiatry 2009;80:358).

    Dr. Zamboni stressed that this association between venous stenoses in main extracranial veins and MS is not contradictory to what is already known about the disease. "What I've found is a previously unknown factor, widely diffuse in my MS population, which could trigger or facilitate both immune reaction and inflammation," he told Medscape Neurology. "If you have elevated pressure and difficulty of drainage in the brain, you have the possibility of extravasation of blood components crossing the blood–brain barrier, and this could trigger inflammation and also immune reaction."

    Restenosis a Problem

    In the current report, the researchers describe the safety and early outcomes in these same patients after endovascular treatment of stenoses in the internal jugular vein and the azygous vein.

    Of the 65 patients, 35 had relapsing-remitting disease, 20 had secondary-progressive disease, and 10 had primary progressive MS. All underwent percutaneous transluminal angioplasty to address strictures in these veins. All procedures were done as day surgery under local anesthesia, and no operative or postoperative complications were seen, including vessel rupture, thrombosis, or adverse effects from contrast.

    Postoperative headache was reported in 6 patients, which resolved spontaneously, and minor hemorrhages with hematoma occurred at vascular access sites "occasionally," the authors report.

    After the procedure, venous pressure was significantly lower in the internal jugular and azygous veins (P < .001). Stenoses in these venous pathways "were never found to be isolated," the researchers note, but always combined in the internal jugular, azygous veins, or lumbar system in 4 main patterns of distribution.

    At a mean follow-up of 18 months, the risk for restenosis after intervention was higher in the internal jugular vein, Dr. Zamboni noted, with a patency rate of 53% compared with 96% in azygous veins (95% confidence interval, 3.5 - 72.5; P < .0001).

    Patency at follow-up depended on the type of obstruction faced, including membranous obstructions, twisting, and hypoplasia. A stent was placed in 1 patient to resolve a twisted vein, but a second case not treated with a stent retwisted, the authors note.

    Using the patients as their own control, the researchers found improvement with treatment on some clinical outcome measures after the intervention, particularly for the relapsing-remitting patients. In this group, 27% were relapse-free before surgery and 50% were so after treatment (P < .001). Gadolinium-enhancing lesions on magnetic resonance imaging (MRI) fell from 50% to 12% on a blinded assessment (P < .001).

    Significant improvement over the preoperative assessment was seen at 1 year on the Multiple Sclerosis Functional Composite again for relapsing-remitting patients (P < .008), but not among those with a secondary or primary progressive course.

    Physical quality-of-life measures also improved significantly in relapsing-remitting MS patients and in primary-progressive patients, with a positive trend among those with secondary progressive disease. Mental quality of life also was significantly improved for the relapsing-remitting and primary progressive groups, but not for those with secondary progressive MS.

    The authors conclude that although improved endovascular techniques are needed to approach the internal jugular vein, "the results of this pilot study warrant a subsequent randomized control study."

    It is possible that the addition of stents to this endovascular approach that he calls the "liberation procedure" may improve outcomes, Dr. Zamboni noted. "However, the results are really interesting, if you think that all treated patients were already under the best treatment for MS and had adjunctive neurological benefits from the liberation procedure compared to the previous 2 years."

    Mixed Response From Neurology Community

    Asked for comment on these findings, Lily Jung, MD, from the Swedish Neuroscience Institute, Seattle, Washington, speaking on behalf of the American Academy of Neurology, was cautious in her assessment. She feels some of the strong claims in the current report are not supported by the data.

    For example, the number of patients in the report is small, "and to make the correlation between the patterns of venous obstruction and the categories of MS is a real stretch," Dr. Jung said. Assessment was done by unblinded neurologists, which is "not ideal." She also noted that the MRI results used different techniques, different protocols, and different study intervals.

    "The bottom line is that my colleagues and I have been flooded by calls and emails from patients who have been led by the publicity around this article to believe that there is a cure for MS, and to make such a claim with such preliminary results is premature," Dr. Jung said. "We would welcome some randomized, controlled, double-blinded studies to look at the issue, but before then would not be encouraging our patients to jump in with both feet to do this procedure, which has significant risks and has not been proven to be safe."

    As a vascular interventionalist, Dr. Zamboni says he is keen to collaborate with neurologists in the setting of MS, but acknowledged that his work has had a mixed response from the neurology community. Some, he says, have been excited and at least curious, which in his view is important in research. Researchers from institutions including Stanford, Harvard, SUNY Buffalo, and others have asked to discuss the technique so that they may attempt to reproduce these findings in their own populations.

    "To the contrary, of course, I've also found big opposition, but I think that probably it is a prejudgement, and they have not read the paper carefully," he said. "But it's not important. What is important is to have other people interested in doing the research and understanding more."

    The first step will be to understand how widespread the presence of CCVI is among patients with MS, he said. "We need to test patients very rapidly to have the epidemiological data, which are very important."

    Already, Dr. Zamboni is collaborating with Robert Zivadinov, MD, and colleagues at Buffalo General Hospital in New York on an open-label, MRI-blinded study of 16 relapsing-remitting patients with MS with confirmed strictures in the cerebrospinal venous outflow routes. Half — 4 randomly selected patients in Italy and 4 in New York — will undergo early intervention to address the blockages at 3 months, and 8 patients will have a delayed procedure at 6 months of follow-up.

    Safety and preliminary efficacy will be monitored using MRI and clinical examination, and outcomes will be compared at 1 year. Dr. Zamboni and Dr. Zivadinov presented their protocol at the 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis earlier this year in Düsseldorf, Germany.

    In Buffalo, Dr. Zivadinov is also conducting a larger epidemiological study aimed at determining the prevalence of CCVI among their MS patients.

    Dizzying Excitement, Desperate Hope

    Although Dr. Zamboni has published previously on this procedure, a news report by a national Canadian news organization with an associated documentary on the same network recently profiled this work, generating a dizzying excitement for many patients in Canada, where MS rates are among the highest in the world. Their subsequent comments on various Internet news and patient sites reflect a desperate hope that this new approach may provide those with MS a possible alternative to lifelong drug therapy and the steady encroachment of disability.

    In a public statement issued December 1, the National Multiple Sclerosis Society cautioned that the findings are preliminary. "Many questions remain about how and when this phenomenon [CCVI] might play a role in nervous system damage seen in MS, and at the present time there is insufficient evidence to prove that this phenomenon is the cause of MS."

    However, the society also notes that it is very interested in seeing more data on this procedure and is prepared to put its money where its mouth is, calling for research proposals to generate that data.

    "If confirmed, these findings may open up new research avenues into the underlying pathology of MS, as well as potential new approaches to therapy," the statement notes. "The National MS Society has invited research proposals to investigate this lead, and is in active discussions with the MS Society of Canada about the possibility of collaborative funding of [CCVI] research."

    The authors have disclosed no relevant financial relationships.

    Source: Medscape Today © 1994-2009 by Medscape (07/12/09)

    A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency
    CCSVI Scans

    Objective
    Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by combined stenoses of the principal pathways of extracranial venous drainage, including the internal jugular veins (IJVs) and the azygous (AZY) vein, with development of collateral circles and insufficient drainage shown by increased mean transit time in cerebral magnetic resonance (MR) perfusion studies. CCSVI is strongly associated with multiple sclerosis (MS). This study evaluated the safety of CCSVI endovascular treatment and its influence on the clinical outcome of the associated MS.

    Methods
    Sixty-five consecutive patients with CCSVI, subdivided by MS clinical course into 35 with relapsing-remitting (RR), 20 with secondary progressive (SP), and 10 with primary progressive (PP) MS, underwent percutaneous transluminal angioplasty (PTA). Mean follow-up was 18 months. Vascular outcome measures were postoperative complications, venous pressure, and patency rate. Neurologic outcome measures were cognitive and motor function assessment, rate of MS relapse, rate of MR active positive-enhanced gadolinium MS lesions (Gad+), and quality of life (QOL) MS questionnaire.

    Results
    Outpatient endovascular treatment of CCSVI was feasible, with a minor and negligible complication rate. Postoperative venous pressure was significantly lower in the IJVs and AZY (P < .001). The risk of restenosis was higher in the IJVs compared with the AZY (patency rate: IJV, 53%; AZY, 96%; odds ratio, 16; 95% confidence interval, 3.5-72.5; P < .0001). CCSVI endovascular treatment significantly improved MS clinical outcome measures, especially in the RR group: the rate of relapse-free patients changed from 27% to 50% postoperatively (P < .001) and of MR Gad+ lesions from 50% to 12% (P < .0001). The Multiple Sclerosis Functional Composite at 1 year improved significantly in RR patients (P < .008) but not in PP or SP. Physical QOL improved significantly in RR (P < .01) and in PP patients (P < .03), with a positive trend in SP (P < .08). Mental QOL showed significant improvement in RR (P < .003) and in PP (P < .01), but not in SP.

    Conclusions
    PTA of venous strictures in patients with CCSVI is safe, and especially in patients with RR, the clinical course positively influenced clinical and QOL parameters of the associated MS compared with the preoperative assessment. Restenosis rates are elevated in the IJVs but very promising in the AZY, suggesting the need to improve endovascular techniques in the former. The results of this pilot study warrant a subsequent randomized control study.

    This work was presented at the Thirty-first Charing Cross Symposium, London, United Kingdom, Apr 3-7, 2009.

    Paolo Zamboni, MDa, Roberto Galeotti, MDa, Erica Menegatti, RVTa, Anna Maria Malagoni, MDa, Sergio Gianesini, MDa, Ilaria Bartolomei, MDb, Francesco Mascoli, MDa, Fabrizio Salvi, MDb

    a Vascular Diseases Center, University of Ferrara, Ferrara, Italy

    b Department of Neurology, Bellaria Hospital, Bologna, Italy

    Source: Journal Of Vascular Surgery © 2009 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.(02/12/09)

    Anomalous venous blood flow and iron deposition in multiple sclerosis
    Venous Reflux In The BrainMultiple sclerosis (MS) is primarily an autoimmune disorder of unknown origin.

     This review focuses iron overload and oxidative stress as surrounding cause that leads to immunomodulation in chronic MS. Iron overload has been demonstrated in MS lesions, as a feature common with other neurodegenerative disorders.

    However, the recent description of chronic cerebrospinal venous insufficiency (CCSVI) associated to MS, with significant anomalies in cerebral venous outflow hemodynamics, permit to propose a parallel with chronic venous disorders (CVDs) in the mechanism of iron deposition.

    Abnormal cerebral venous reflux is peculiar to MS, and was not found in a miscellaneous of patients affected by other neurodegenerative disorders characterized by iron stores, such as Parkinson's, Alzheimer's, amyotrophic lateral sclerosis. Several recently published studies support the hypothesis that MS progresses along the venous vasculature.

    The peculiarity of CCSVI-related cerebral venous blood flow disturbances, together with the histology of the perivenous spaces and recent findings from advanced magnetic resonance imaging techniques, support the hypothesis that iron deposits in MS are a consequence of altered cerebral venous return and chronic insufficient venous drainage.

    Full Paper - http://www.nature.com/jcbfm/journal/v29/n12/full/jcbfm2009180a.html

    Ajay Vikram Singh1 and Paolo Zamboni2

    1Department of Physics, European School of Molecular Medicine (SEMM), IFOM-IEO Campus, Centro Interdisciplinare Materiali e Interfacce Nanostrutturati (CIMAINA), University of Milan, Milan, Italy
    2Vascular Diseases Center, University of Ferrara, Ferrara, Italy

    Source: Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1867–1878; doi:10.1038/jcbfm.2009.180 (30/11/09)

    Report on the CCSVI clinical trial being run in Buffalo, New York

    Multiple sclerosis 'blood blockage theory' tested
    CCSVI and MSUS scientists are testing a radical new theory that multiple sclerosis (MS) is caused by blockages in the veins that drain the brain.

    The University of Buffalo team were intrigued by the work of Italian researcher Dr Paolo Zamboni who claims 90% of MS is caused by narrowed veins.

    He says the restricted drainage, visible on scans, injures the brain leading to MS.

    He has already widened the blockages in a handful of patients.

    The US team want to replicate his earlier work before treating patients.

    Experts welcomed the research saying it was important to confirm the basic science before evaluating any therapy.

    MS is a long-term inflammatory condition of the central nervous system which affects the transfer of messages from the nervous system to the rest of the body.

    The Buffalo team, led by Dr Robert Zivadinov, plan to recruit 1,100 patients with MS and 600 other volunteers as controls who are either healthy or have neurological diseases other than MS.

    Using Doppler ultrasound, they will scan the patients to see if they can find any blockages within the veins of the neck and brain.

    If they can prove Dr Zamboni's theory of " chronic cerebrospinal venous insufficiency", they say it will change our understanding of MS.

    Rewriting science

    Margaret Paroski, who is chief medical officer at Kaleida Health, where the Buffalo researchers are based, said the work could overturn prevailing wisdom that the damage in MS is predominantly the result of abnormal immune responses.

    "When I was in medical school, we thought peptic ulcer disease was due to stress. We now know that 80% of cases are due to a bacterial infection.

    "Dr Zivadinov's work may lead to a whole different way of thinking about MS."

    Dr Zamboni, of the University of Ferrara, believes the blockages are the cause rather than the consequence of MS and that they allow iron from the blood to leak into the brain tissue, where it causes damage.

    He has performed procedures similar to angioplasty to unblock the veins and get the blood flowing normally again.

    He claims this "liberation procedure" can alleviate many of the symptoms of MS and is due to publish his findings in the Journal of Vascular Surgery.

    In an interview with CTV News in Canada he said: "I found the evidence of narrowing - narrowing of the veins just in MS patients.

    "I'm fully convinced that this is very, very important for people."

    Early days

    Kevin Lipp, an MS patient from the US, has been symptom-free since being treated by Dr Zamboni.

    He said: "It's only been 10 months. If nothing happens in the next two to three years, we'll know it's working."

    The BBC has heard anecdotally of other surgeons in Europe testing out the same treatment.

    The MS Society said more research was needed to see if this was an avenue that should be explored further.

    "This is not something patients can expect as a treatment now. This is experimental work and is being tested. We need to know more about its safety and effectiveness."

    Helen Yates, of the MS Resource Centre (MSRC), said: "There is no doubt that this area warrants a great deal more study.

    "This could represent a completely novel approach to MS research which, if proven to be relevant, could be a "sea change" in the understanding of the mechanisms involved in the condition."

    Source: BBC News © British Broadcasting Corporation 2009 (27/11/09)

    MS Society of Canada announces request for research operating grants related to CCSVI and MS
    MS Society Canada LogoThe Multiple Sclerosis Society of Canada announced it will request research operating grants related to chronic cerebrospinal venous insufficiency (CCSVI) and MS.

    A recent study released by Dr. Paulo Zamboni, University of Ferrara, Italy, describes CCSVI as a disruption of blood flow in which the venous system is not able to efficiently remove blood from the central nervous system resulting in increased pressure in the veins of the brain and spinal cord which in turn results in damage to these areas.

    “These early results are encouraging and show that this warrants more study,” said Yves Savoie, MS Society President and CEO.  “This is truly a new avenue to explore in MS research, and we want to be a part of furthering this investigation.”

    The MS Society of Canada will issue an invitation for research operating grant proposals on CCSVI related to multiple sclerosis from qualified investigators based in Canadian institutions. Proposals will be evaluated for their scientific merit and relevance to the field of MS.

    The competition will open on December 9, 2009, and the deadline for applications will be January 22, 2010.

    “There has been tremendous interest and excitement about this study from people with MS, supporters, volunteers and staff across the country. While we acknowledge that the concept of CCSVI as a cause of MS needs to be replicated and validated in larger well-designed studies, the Society looks forward to contributing to this body of work,” said Savoie.

    While excited about the potential of the CCSVI study, the findings are preliminary. Thus the MS Society advises that while further research is underway people follow their physician's recommendations and continue their current course of therapies.

    Source: Multiple Sclerosis Society of Canada (24/11/09)

    Neurologists investigate possible new underlying cause of Multiple Sclerosis
    Chronic cerebrospinal venous insufficiencyNeurologists at the University at Buffalo are beginning a research study that could overturn the prevailing wisdom on the cause of multiple sclerosis (MS).

    The researchers will test the possibility that the symptoms of MS result from narrowing of the primary veins outside the skull, a condition called "chronic cerebrospinal venous insufficiency," or CCSVI.

    CCSVI is a complex vascular condition discovered and described by Paolo Zamboni, M.D., from Italy's University of Ferrara. In the original Italian patients, CCSVI was found to be strongly associated with MS, increasing the risk of developing MS by 43 fold.

    This narrowing restricts the normal outflow of blood from the brain, causing alterations in the blood flow patterns within the brain that eventually causes injury to brain tissue and degeneration of neurons.

    "If we can prove our hypothesis, that cerebrospinal venous insufficiency is the underlying cause of MS," said Robert Zivadinov, M.D., Ph.D., UB associate professor of neurology, director of the Buffalo Neuroimaging Analysis Center (BNAC) and principal investigator on the study, "it is going to change the face of how we understand MS."

    Michael Cain, M.D., professor and dean of the UB School of Medicine and Biomedical Sciences, said a positive outcome from this trial would have enormous implications for the treatment of MS. "Being able to identify those at risk of developing MS before symptoms take their toll could change the lives of millions of persons who now face inevitable lifestyle restrictions."

    Margaret Paroski, M.D., executive vice president and chief medical officer of Kaleida Health, parent of Buffalo General Hospital where the BNAC is located, commented: "Will Rogers once said, 'It isn't what we don't know that gives us trouble, it's what we do know that ain't so'. Challenging basic assumptions about diseases has lead to some very important discoveries.

    "When I was in medical school, we thought peptic ulcer disease was due to stress. We now know that 80 percent of cases are due to a bacterial infection. Dr. Zivadinov's work may lead to a whole different way of thinking about multiple sclerosis."

    The preliminary findings were based on a pilot study at the BNAC headed by Zivadinov, and at the Universities of Ferrara and Bologna, Italy, directed by Zamboni and Fabrizio Salvi, M.D, respectively. The study showed that several abnormalities affecting the predominant pathways that return venous blood from the brain to the heart occurred more frequently in MS patients than in controls.

    This research, supported by the Hilarescere Foundation of Italy and the BNAC, was conducted to replicate the findings of the Italian investigators.

    "Results of this preliminary study, which involved 16 relapsing-remitting MS patients and eight age-and-sex-matched healthy controls, showed that all the MS patients, but none of the controls, had chronic insufficient blood flow out of the brain," said Zivadinov.

    Bianca Weinstock-Guttman, M.D., UB associate professor of neurology and a co-principal investigator on the pilot study, added: "The images from this study were acquired using a method called Doppler ultrasound. The method identified anomalies in the venous blood flow associated with strictures, malformed valves and peculiar webs within the large veins of the neck and brain"

    Weinstock-Guttman directs the Baird Multiple Sclerosis Center at the Jacobs Neurological Institute (JNI), UB's Department of Neurology. The JNI and BNAC are located in Buffalo General Hospital of Kaleida Health.

    Advanced magnetic resonance imaging scanning (MRI) of the MS study patients conducted at the BNAC also identified distinct areas of iron deposits in the brain, and showed that those deposits may be associated with the location of MS lesions and sites of impaired drainage. The scans also revealed increased brain atrophy and changes in the flow of cerebrospinal fluid in the MS patients.

    These results, which form the basis of the current larger investigation, were presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis held in September in Dusseldorf, Germany

    The new study will involve 1,600 adults and 100 children. The cohort will be comprised of 1,100 patients who were diagnosed with possible or definite MS, 300 age-and-sex matched normal controls, and 300 patients with other autoimmune and neurodegenerative diseases. Enrollment in the study has begun and will continue for two years. MS patients from across the U.S. are eligible to participate in the study.

    "The prevailing wisdom that central nervous system damage in MS is predominantly the result of abnormal immune responses against the patient's nervous tissue has been challenged by research findings, which have demonstrated a significant neurodegenerative component in MS and the progressive loss of neurons" said Zivadinov.

    "However, these inflammatory and neurodegenerative processes occur concurrently in MS and vary considerably among patients, making it difficult to identify the cause, or causes of the disease. Consequently, the origin and development of MS remains poorly understood, and its cause remains elusive."

    To determine if these preliminary findings can be repeated, Zivadinov and Weinstock-Guttman organized the present study, which will evaluate both the velocity of blood flow through both the brain's blood vessels and the extracranial veins, using Doppler ultrasound.

    The technical name of the study is "combined transcranial and extracranial venous Doppler (CTEVD) evaluation in MS and related diseases".

    All study subjects will undergo a general clinical examination and a Doppler scan of the head and neck to acquire images of the direction of venous blood flow in different body postures. Participants also will provide blood samples, and complete an extensive environmental questionnaire to identify potential MS risk factors.

    All MS patients will undergo MRI of the brain to measure iron deposits in lesions and surrounding areas of the brain using a method called susceptibility-weighted imaging. Iron findings on these images will be related to neuropsychological symptoms. The neuropsychological part of the study will be conducted by Ralph Benedict, Ph.D., professor of neurology and psychiatry at the JNI, UB's Department of Neurology.

    A sub-cohort of 250 consecutive patients and controls will undergo MRI of the veins of the neck to confirm diagnosis of CCSVI.

    Murali Ramanathan, Ph.D., associate professor in the Department of Pharmaceutical Sciences, UB School of Pharmacy and Pharmaceutical Sciences, will analyze blood samples for proteins and soluble factors associated with central nervous system injury. He also will be looking for other factors of interest in MS research, such as vitamin D metabolites and cigarette smoking, which have been linked to increased risk for developing MS as well as MS disease progression.

    The data will be unblinded at three predetermined time-points, with the initial unblinding scheduled for November 2009.

    Zivadinov said results of the study may lead to a larger multicenter North-American trial that will evaluate the occurrence of CCSVI in MS.

    Commenting on the study, Helen Yates, Multiple Sclerosis Resource Centre Chief Executive said, “CCSVI is a very recent “discovery” in the field of MS and any work that can further Paolo Zamboni’s research and hypothesis is very welcome indeed.  As Robert Zivadinov,MD says, if CCSVI is proven to be the underlying cause of MS this would be a major sea change in the understanding of the disease, its cause and will open up new areas of research towards a potential cure”

    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: University at Buffalo © 2009 University at Buffalo. All rights reserved and MSRC (15/10/09)

    Chronic cerebrospinal venous insufficiency (CCSVI) a new model of Multiple Sclerosis
    Extracranial venous outflow

    Background:
    The extracranial venous outflow routes in clinically defined multiple sclerosis (CDMS) have not previously been investigated.

    Methods:
    Sixty-five patients affected by CDMS, and 235 controls composed, respectively, of healthy subjects, healthy subjects older than CDMS patients, patients affected by other neurological diseases and older controls not affected by neurological diseases but scheduled for venography (HAV-C) blindly underwent a combined transcranial and extracranial colour-Doppler high-resolution examination (TCCS-ECD) aimed at detecting at least two of five parameters of anomalous venous outflow. According to the TCCS-ECD screening, patients and HAV-C further underwent selective venography of the azygous and jugular venous system with venous pressure measurement.

    Results:
    CDMS and TCCS-ECD venous outflow anomalies were dramatically associated (OR 43, 95% CI 29 to 65, p<0.0001). Subsequently, venography demonstrated in CDMS, and not in controls, the presence of multiple severe extracranial stenosis, affecting the principal cerebrospinal venous segments; this provides a picture of chronic cerebrospinal venous insufficiency (CCSVI) with four different patterns of distribution of stenosis and substitute circle. Moreover, relapsing-remitting and secondary progressive courses were associated with CCSVI patterns significantly different from those of primary progressive (p<0.0001). Finally, the pressure gradient measured across the venous stenosies was slightly but significantly higher.

    Conclusion:
    CDMS is strongly associated with CCSVI, a scenario that has not previously been described, characterised by abnormal venous haemodynamics determined by extracranial multiple venous strictures of unknown origin. The location of venous obstructions plays a key role in determining the clinical course of the disease.

    P Zamboni,1 R Galeotti,1 E Menegatti,1 A M Malagoni,1 G Tacconi,1 S Dall’Ara,1 I Bartolomei,2 and F Salvi2
    1
    Vascular Diseases Center, University of Ferrara, Ferrara, Italy
    2 Department of Neurology, Bellaria Hospital, Bologna, Italy

    Source: J Neurol Neurosurg Psychiatry. 2009 April; 80(4): 392–399. (03/07/09)

    © Multiple Sclerosis Resource Centre

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