In a subsequent lecture to the Royal Society of Medicine, London, in July 2006, Prof. Zamboni then proposed what he termed ?The Big Idea?: that the iron-dependent inflammation seen in venous disease was analogous to the inflammatory plaque formation in MS (Zamboni P. J R Soc Med 2006; 99: 589-593; free download atwww.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/?tool=pubmed).

Briefly stated, he hypothesized  that in chronic venous disease (CVD), leg ulcers arise from increased iron deposition, which triggers WBC recruitment and migration, the expression of adhesion molecules (e.g. ICAM, VCAM), and transmigration of inflammatory cells (macrophages, T-cells) into the tissue. Overexpression of MMPs results in matrix degradation and ulcer onset. Since leg ulcers develop in only a minority of CVD patients, he further suggested that ulcer formation may be genetically determined. A previous case-control study found that the C282Y mutation of the HFE gene, which is associated with hemochromatosis (type 1) in Northern Europeans, significantly increases the risk of ulcers in CVD patients (Zamboni et al. J Vasc Surg 2005; 42: 309-314).

These findings suggested certain parallels with the etiopathology of MS. Acute and chronic MS lesions have been shown to be associated with venulitis  (Adams et al. J Neurol Sci 1985; 69: 269-283). Barkhof and colleagues, in an autopsy study a decade ago, reported that a majority of cortical lesions arose near the principal cortical veins (Kidd et al. Brain 1999; 122(pt 1): 17-26).  Moreover, it has been well established that MS inflammation is associated with adhesion molecule activation  and MMP-mediated degradation of the blood-brain barrier, resulting in the migration of activated immune cells into the CNS.

Prof. Zamboni has suggested that in MS, macrophages with high intracellular iron stores (from phagocytosis of senescent erythrocytes) are able to migrate into the CNS, resulting in the iron overload seen in MS plaques.  Moreover, he notes that the frequency of the C282Y mutation is increased in MS patients of European origin, further underscoring the importance of altered iron metabolism in the pathogenesis of MS.

As to the latter point, published studies of the C282Y mutation in MS patients have reported conflicting results. The Oxford group found no evidence that the frequency of HFE mutations were more common in MS patients, nor that HFE mutations had any effect on the clinical course of MS (Ramagopalan et al. J Neuroimmunol 2008; 203: 104-107).  Similar results were reported in two subsequent studies (Ristic et al. Neurosci Lett 2005; 383: 301-304; Kotze et al. Metab Brain Dis2006; 21: 109-120). In contrast, one study in Australia did report that the C282Y allele was more common in MS patients of northwest European ancestry, however, the presence of this mutation did not appear to be associated with a predisposition to MS (Rubio et al. Hum Genet 2004; 114: 573-580).

The putative role of iron overload in the pathogenesis of MS has been debated for decades and remains controversial. An early autopsy study found positive iron reactions in sections around demyelinated plaques (Craelius et al. Arch Pathol Lab Med 1982; 106: 397-399). A later autopsy study found no evidence of iron overload in MS brain samples (Walton & Kaufmann. Arch Pathol Med 1984; 108: 755-756).

Another approach has been to assess iron metabolism. A Canadian study reported that mean serum ferritin was higher in MS patients versus controls; higher values in one or more test (serum ferritin, red cell ferritin, transferrin saturation) appeared to be associated with disease severity (Valberg et al. Can J Neurol Sci1989; 16: 184-186). Levels of soluble transferrin receptor were reported to be significantly higher in MS patients with active (but not with stable) disease compared to controls, which may represent increased iron turnover (Abo-Krysha et al. Mult Scler 2008; 14: 602-608; Sfagos et al. Mult Scler 2005; 11: 272-275). A separate study found transferrin and ferritin levels in the CSF were comparable in MS patients and controls, although ferritin levels were elevated in chronic progressive patients with active disease (LeVine et al. Brain Res 1999; 82: 511-515).

Imaging studies have reported iron deposition in deep gray matter structures (e.g. basal ganglia, putamen) in patients with MS and clinically isolated syndrome (Khalil et al. Mult Scler 2009; 15: 1048-1054; Ge et al.AJNR Am J Neuroradiol 2007; 28: 1639-1644; Hammond et al. Ann Neurol 2008; 64: 707-713; Ceccarelli et al. Mult Scler 2010; 16: 39-44), although the clinical significance of these findings is unclear. It has been suggested that ?black T2? (T2 hypointensity) in the deep grey matter is caused by abnormal iron deposition; one study observed a correlation between signal intensity in the globus pallidus/caudate nucleus and disability (Zhang et al. Mult Scler 2007; 13: 880-883).

Preclinical and clinical studies have reported mixed results. It has been noted that iron-deficient EAE mice failed to develop EAE symptoms; however, severe EAE also did not develop in iron-overloaded mice (Grant et al. J Nutr 2003; 133: 2635-2638). Iron deficiency is common in MS patients; in a 6-month pilot study, MS patients who received nutritional supplements (including iron) improved neurologically (van Rensburg et al.Metab Brain Dis 2006; 21: 121-137).

Administering an iron chelating agent to EAE mice inhibited T-cell function and suppressed active disease (Mitchell et al. Mult Scler 2007; 13: 1118-1126). However, in the only published trial of iron chelator therapy in MS, 9 patients with chronic progressive disease received desferrioxamine for two years: one patient improved, three remained stable and five worsened by >0.5 EDSS points (Lynch et al. Cell Mol Biol 2000; 46: 865-869).

CCSVI
The putative immunopathological and neurotoxic effects of iron deposition in the CNS, presumed to be due to hemodynamic alterations in MS patients, provide a rationale for surgical intervention to restore normal blood flow (reviewed in Singh & Zamboni. J Cereb Blood Flow Metab 2009; 29: 1867-1878).

Following the observation of reverse blood flow from the chest to the internal jugular vein in an MS patient who coughed, Prof. Zamboni speculated that the development of MS was associated with altered venous hemodynamics. Subsequent studies have assessed blood flow with transcranial colour-coded Doppler sonography (TCCS) and high-resolution echo-colour Doppler (ECD); these noninvasive methods enable the investigation of cerebral venous outflow, although the authors have noted that there are no standard values for normal venous return (Menegatti & Zamboni. Curr Neurovasc Res 2008; 5: 260-265).

A preliminary study in 89 consecutive MS patients and 60 matched controls found that reflux/bidirectional flow rate was higher in MS patients versus controls (Zamboni et al. Curr Neurovasc Res 2007; 4: 252-258; free full text at www.ms-info.net/Intracranial_Venous_Haemodynamics_in_Multiple%20Sclerosis.pdf). Venous reflux directed to the subcortical grey matter was significantly associated with the highest disability scores. A second study of 109 MS patients and 177 controls selected from a larger cohort found a higher number of anomalies of venous return, as assessed by TCCS-ECD, in MS patients (Zamboni et al. J Neurol Sci 2009; 282: 21-27).

A subsequent study performed TCCS-ECD on 65 MS patients and 235 controls (Zamboni et al. J Neurol Neurosurg Psychiatry 2009; 80: 392-399; free full text atwww.ncbi.nlm.nih.gov/pmc/articles/PMC2647682/?tool=pubmed). Controls included healthy age/sex-matched subjects, healthy older subjects, patients with other neurological disorders, and non-neurological patients scheduled for venography for other conditions. TCCS-ECD focused on the detection of abnormalities in five parameters that are absent in normal subjects (e.g. reflux in the internal jugular, vertebral and/or deep cerebral veins, and evidence of stenoses of the internal jugular vein). Patients with evidence of abnormal venous outflow received selective venography.

With TCCS-ECD, none of the controls was positive for more than one of the criteria versus 180 positive criteria and 145 negative criteria in MS patients. The risk of MS was calculated to be increased 43-fold. Venography revealed extracranial venous stenoses in all MS patients who met at least 2 of 5 TCCS-ECD criteria; none of the controls met the criteria for venography. Stenosis was present in the azygous vein in 86% of MS patients, and in the internal jugular vein in 91% of MS patients. The location of the venous obstruction also appeared to influence the clinical course of MS.

Surgical intervention has been evaluated in a prospective open-label study of 65 consecutive MS patients (35 with RRMS, 20 with SPMS, 10 with PPMS) diagnosed with CCSVI (Zamboni et al. J Vasc Surg 2009; 1348-1358). All underwent percutaneous transluminal angioplasty (PTA). Mean follow-up was 18 months.

The proportion of relapse-free RRMS patients increased from 27% at baseline to 50% postoperatively. The annualized relapse rate declined from 0.9 to 0.7; this difference was not statistically significant. The proportion of patients with Gd-enhancing lesions declined from 50% to 12%; however, the authors noted that MRI was not always performed with the same equipment at the same time intervals and did not follow the same protocol. At one year, the MS Functional Composite score significantly improved from baseline in RRMS patients but not in SPMS or PPMS patients. The rate of restenosis was 47% for the internal jugular vein, and 4% for the azygous vein. The authors reported that no relapses have occurred in RRMS patients when venous patency was maintained.

No CCSVI studies have yet been registered at clinicaltrials.gov. A second open-label pilot study of endovascular treatment of MS was announced at ECTRIMS 2009 and will involve Italian and U.S. researchers (Zamboni et al. Abstract P483). An additional 500 patients have reportedly been selected for CCSVI evaluation at the Buffalo Neuroimaging Center, Buffalo, NY. The preliminary results, announced only by press release, are expected to be presented at the AAN annual meeting in April.

In the aftermath of these preliminary results, the National MS Society (NMSS) and the MS Society of Canada have issued a Request for Applications to explore CCSVI, and are expected to begin funding new projects in July 2010. The NMSS has cautioned that surgical treatment of CCSVI should only be performed in the context of a clinical trial since there have been anecdotal reports of adverse events, including one death (www.nationalmssociety.org/news/news-detail/index.aspx?nid=2206).

At least one CCSVI trial is expected to be performed in Canada. To that end, one researcher has created a CCSVI website, and has raised over $62,000 in online donations thus far to fund a proposed trial at McMaster University, Hamilton.

Commentary by Daniel Selchen, MD
Canadian neurologists (and particularly MS specialists) have recently been inundated with patient inquiries related to the concept of CCSVI as a result of national television (W5) and newspaper (Globe and Mail) coverage.  The above report summarizes the background studies and the recent treatment trial by Zamboni et. al.

Prof. Zamboni?s work is of course not news to Canadian MS specialists, who have seen presentations at ECTRIMS, Charcot, and other major meetings.  Prof. Zamboni acknowledges that his research to this point has been almost entirely single-centre and unblinded, with all of the potential problems and biases associated with non-randomized, non-controlled, non-blinded studies.  With regard to the scientific underpinnings of the CCSVI hypothesis ? contrary to the suggestions in the Canadian media ? the published work is highly speculative and begs some obvious questions.  Is iron deposition in MS plaques a cause or a product of inflammation?  If the observation of venous anomalies in MS patients is confirmed, does that necessarily imply causation?

The published study of the clinical efficacy of Dr. Zamboni?s procedure is titled, ?A Prospective Open Label Study of Endovascular Treatment of CCSVI.?  The trial population is a mixed group of 65 patients with RRMS, SPMS and PPMS who meet Zamboni?s venous criteria.  As there is no control group, no one is blinded, including the evaluators.  No primary clinical outcome is actually specified.  The positive outcomes included an increase in relapse-free patients from 27% to 50%, numbers which are very difficult to evaluate as the study gives very little indication of how relapses were defined and evaluated.  The relapse rate itself is a bit unusual for a modern trial, given the median EDSS score of 1.7 in the RRMS group.  In the study, the annualized relapse rate outcome was actually negative.  The other clinical outcome measures were the MSFC, which is very difficult to evaluate without a control group as placebo groups in trials frequently improve on this measure because of a learning effect; and QOL measures, which are notoriously subject to a placebo effect. The MRI measures used were, as pointed out in the paper, difficult to evaluate as ?MRI was not always performed with the same instrument, followed the same protocol, or was at the same intervals?. Given the media fuss, it is noteworthy that progressive patients did not appear to benefit from the procedure in the Zamboni study.

None of these obvious cautions appeared to affect the reporting on W5 and in the Globe and Mail.  MS experts were interviewed and the interviews were not included in the finished pieces.  No hard questions were asked.  If the goal of the media presentations was any kind of objective analysis, it is difficult to understand the timing of the story, which preceded the publication by a week and a half, thus precluding any discussion of the obvious huge methodological issues evident from review of the published paper.

Dr. Zamboni and a number of advocates of his theory held a meeting in Hamilton on the weekend of February 6, 2010, attended by a number of Canadian neurologists.  One of the advocates of the theory, physicist Dr. Mark Haacke, was quoted in The National Post with this gem: ?Not to give penicillin to somebody would not be a good idea once you know you?ve got a drug that works.? ( http://www.nationalpost.com/nationalpost/story.html?id=2538597). The comparison of the ?liberation procedure? to penicillin is an unfortunate illustration of the quality of much of this discussion.

On February 10, 2010, the University of Buffalo group led by Robert Zivadinov presented the results of the first 500 patients in their blinded study of venous insufficiency prevalence in multiple sclerosis.  The incidence of venous anomalies meeting their criteria was 56.4% in MS subjects and 22.4% in controls.  This is a rather long way from Zamboni?s results of virtually 100% in MS and 0% in controls. In a rational universe, one would have expected this to have calmed some of the discussion given that close to 50% of MS patients did not appear to have a condition which is alleged to be causative.  It is also of note that these data have been tossed into the furor by press release, not a peer-reviewed publication.  It is also of interest that the Buffalo group have virtually simultaneously announced a testing service for MS patients at a cost of US$4,500 or $6,000, depending on which package is chosen.

This whole situation has created very significant and unfortunate tensions between MS clinicians and their patients.  It is very difficult to tell a patient who is seeing a ?cure? for MS described in the mainstream media that at this point in time there is no reliable evidence supporting the alleged ?cure? and very little to even demonstrate an association between the vascular condition and the disease.  Many of us have been torn by the conflict between trying not to dash our patients? hopes and trying to prevent them from mortgaging their homes to pursue unproven treatment for a condition which may or may not exist.

Nothing would make MS clinicians happier than another treatment for a disease which is frequently devastating.  It is certainly possible that venous obstruction and other anomalies could be associated with, or even be a contributor to, the development of multiple sclerosis.  Like any other scientific hypothesis with regard to causation and treatment, what is required is good clinical evidence in controlled trials before leaping to conclusions, and before patients are subjected to invasive procedures.  This elementary notion seems to have gotten lost in the media-generated hysteria around this subject.  Our role as clinicians, with CCSVI and every other scientific development, is to try to do the best we can for our patients by explaining the issues involved, and counselling appropriate caution pending real scientific data.  

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