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What is Chronic cerebrospinal venous insufficiency (CCSVI)?

CCSVI Blood Flow Diagram

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

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Abstract

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 Nichol^c

^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)

By 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; salvatore.sclafani@downstate.edu.

   ^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 mddake@stanford.edu.

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 barryk@baptisthealth.net.

   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)

With 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)

A 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)

Researchers 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)

The 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)

A 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)

MS 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)

ABSTRACT

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)

Duncan 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)

Abstract (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)

Georgetown 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)

Rebecca 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."

Source@ AOL News © 2010 AOL Canada Inc All Rights Reserved. (27/04/10)

Chronic 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

by 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)

AIM: 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)

The 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)

AIM: 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)

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)

AIM: 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)

AIM: 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)

AIM: 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)

AIM: 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)

AIM: 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)

AIM: 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)

In 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)

St. 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)

A 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: Claudio.Buffagni@esaote.com

Source: CTV News © 2010 CTVGlobeMedia (03/03/10)

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)

Perez 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)

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
Marian Simka
EuroMedicVascular and Endovascular
Surgery Department Katowice
Poland

http://www.ms-mri.com/docs/Simka-hamilton%20-ccsvi-1.pdf

More 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)

One 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)

Finding 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)

A 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: Claudio.Buffagni@esaote.com

Source: CTV News © 2010 CTV Globe Media (30/01/10)

Investigators 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)

The 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)

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)

Multiple 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)

Possible 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

The 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)

New 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)

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)

Multiple 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)

US 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)

The 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 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)

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 Salvi^2
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