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CCSVI Controversy: A Call for New Research

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Perspective

To say that the relationship between CCSVI and multiple sclerosis is controversial is an understatement. This article introduces both sides of the story and summarizes the current evidence. While many physicians remain understandably skeptical, it is worth remembering that "conventional wisdom" on the pathophysiology of some diseases has turned out to be way off the mark - consider peptic ulcers. Clearly, more objective data is needed before routine interventions for CCSVI can be recommended, and hopefully, ongoing registries and trials will provide that data. In the meantime, those of us involved with the vascular laboratory should be prepared to evaluate patients for the abnormalities described in CCSVI. Detection of reflux and obstruction in the internal jugular and vertebral veins by duplex ultrasound (in both supine and seated positions) is based on the same general principles as the more familiar upper extremity venous and carotid duplex examinations. Ideally, patients should be screened and entered into a clinical study to establish an evidence base for future decision-making. Until then, we will be stuck between the "liberators" and the "nihilists", and our patients will be caught in the middle.

Robert Eugene Zierler, M.D., is professor of surgery, division of vascular surgery, department of surgery, and medical director, Vascular Diagnostic Service, University of Washington School of Medicine, Seattle, Wash. He is also an associate medical editor for Vascular Specialist.


 

Multiple sclerosis patients and endovascular interventionalists were elated when Italian researchers reported in 2009 that they had found evidence of chronic cerebrospinal venous insufficiency in nearly every MS patient they had studied and that in many cases, balloon angioplasty and sometimes stent placement of central thoracic veins reduced or eliminated signs of the disease. Neurologists, on the other hand, suggested that hope might be eclipsing reason in the rush to advocate the vascular procedure, given the single-center study's small sample size and nonrandomized, uncontrolled design.

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

On one side of the debate are the MS patients and endovascular interventionalists, dubbed the "liberators" by Dr. Burks because of their unflappable advocacy for what has become known as the liberation procedure - the endovascular surgery designed to open the lesions causing the venous insufficiency, he said.

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

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

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

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

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

P Researchers at the University of Buffalo found that up to 62% of the 280 patients with MS enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation study - the first randomized clinical trial to evaluate MS patients for CCSVI - had the characteristic narrowing of the extracranial veins compared with approximately 22% of 220 healthy controls. While the results, which were reported at the annual meeting of the American Academy of Neurology, did not establish causation, they showed "that narrowing of the extracranial veins, at the very least, is an important association in multiple sclerosis," principal investigator Dr. Robert Zivadinov said in a statement. He acknowledged that the finding of vascular narrowing in nearly a quarter of the healthy controls warranted additional investigation (www.buffalo.edu/news/fast-execute.cgi/article-page.html?article=109370009).

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

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

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

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

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

P Italian researchers investigating the occurrence of CCSVI in 50 consecutive patients with clinically isolated syndromes suggestive of MS reviewed the patients' extracranial and transcranial venous echo-color Doppler sonographs and compared the findings to those of 50 age- and gender-matched healthy controls as well as those of 60 patients with transient global amnesia (TGA) and 60 healthy controls matched to the TGA patients. They found extracranial Doppler sonographic abnormalities in 52% of patients with possible MS, 68.3% of patients with TGA, and 31.8% of the healthy controls. While eight of the patients with possible MS fulfilled the CCSVI criteria, selective phlebography showed no venous anomalies in seven of them. The authors concluded that there was no evidence of CCSVI at MS onset but recommended further studies to "clarify whether CCSVI is associated with later disease stages and characterizes the progressive forms of MS" (Ann. Neurol. 2011;69:90-9).

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

Additionally, in a commentary on the treatment of CCSVI, representatives of the Cardiovascular and Interventional Radiological Society of Europe acknowledged that although several centers worldwide are promoting and performing balloon dilatation, with or without stenting for CCSVI, "We believe that until real scientific data are available for CCSVI and balloon dilatation, this treatment should not be offered to MS patients outside of a well designed clinical trial" (Cardiovasc. Intervent. Radiol. 2011;34:1-2).

Toward that end, the National Multiple Sclerosis Society of the United States and the MS Society of Canada have pledged $2.4 million in support of seven CCSVI research studies, including projects designed to evaluate venous abnormalities in children and teens with MS, patients with early and late stage MS, and those at risk for MS.

An international review panel comprising radiologists, vascular surgeons, and neurologists evaluated research applications via an expedited review process, according to the societies.

Dr. Burks disclosed relationships with various pharmaceutical companies. Dr. Baracchini had no relevant conflicts.

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