Study Refutes Venous Hypothesis in Multiple Sclerosis, Weakening Argument for Stenting

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Several recently published studies have suggested that perivenous inflammation, a histopathological signature of multiple sclerosis (MS), may be initiated by cerebral venous hypertension or chronic cerebrospinal venous insufficiency (CCSVI), giving rise to the theory that angioplasty with stenting may help alleviate the condition. However, a new study published in the December 2011 issue of Archives of Neurology shoots down the theory by attempting, and failing, to replicate key data on which the CCSVI hypothesis hinges.

The original data came from a study by Paolo Zamboni, MD, of Azienda Ospedaliero-Universitaria di Ferrara (Ferrara, Italy), and colleagues, which reported evidence of CCSVI in patients with MS but not in control subjects. A number of researchers have since been unable to verify the results of either that initial study or another in which Dr. Zamboni reported disease phenotype-specific venous outflow characteristics in MS patients and suggested that correction of the stenosis can have a beneficial effect on MS course.

Despite the lack of replication of these original results, angioplasty with stenting has begun to be used by some clinicians to treat MS.

For the new study, researchers led by Olaf Stüve, MD, PhD, of the VA North Texas Health Care System (Dallas, TX), used gray-scale, color, and spectral Doppler ultrasonography to examine the internal jugular veins, vertebral veins, and deep cerebral veins for stenosis, absence of signal, and reflux in 18 US veterans (3 women and 15 men) with a diagnosis of definite MS. Eleven age- and sex-matched subjects (4 women and 7 men) with migraine headaches or without a neurological diagnosis served as controls and underwent the same imaging. There was no significant difference between the patients with MS and the control subjects with respect to age or sex.

A Failure to Replicate

Using the same methods as Zamboni et al, Dr. Stüve and colleagues looked for evidence of 5 criteria defined by the Zamboni research as necessary for the diagnosis of CCSVI, and which purportedly increase cerebral venous pressure. They include:

  • Reflux more than 88 seconds in the internal jugular veins and/or vertebral veins
  • Reflux in the deep cerebral veins
  • B-mode evidence of proximal internal jugular vein stenosis, defined as local reduction of the cross-sectional area of 50% or more in the supine position
  • Flow not Doppler detectable in both internal jugulars and/or both vertebrals
  • Missing internal jugular diameter decrease in the sitting position, ie, reverted postural control of the main cerebral venous outflow pathways

Of the 18 patients with MS, 4 met 1 definition for CCSVI. Similarly, in the 11 control subjects, 4 met 1 definition for CCSVI. Overall, however, there was no significant difference in the number of ultrasonography abnormalities between patients with MS and controls.

Dr. Stüve and colleagues point out that theirs is not the first study that used the identical methods outlined by Zamboni et al and failed to support the hypothesis that MS patients are significantly more likely to have an impairment in cerebral venous drainage. The study authors say the failure of ultrasound studies to detect a difference suggests that it may not be the best method for the study of CCSVI. However, a method known to be more reliable and validated, venous intraluminal catheter, was used by Zamboni et al in a recent study (Zivadinov R, et al. Neurology. 2011;Epub ahead of print) but found no significant difference in venous pressure between MS patients vs. controls.

Dr. Stüve and colleagues conclude that while “new insights into the disease process and especially the promise of a single effective treatment,” are welcome, the preponderance of evidence “call[s] into question whether CCSVI plays a pathogenic role in a substantial fraction of patients with MS and whether it presents a valid therapeutic target.”

Ethical Responsibility Invoked

In an editorial accompanying the study, Michael A. Williams, MD, of Sinai Hospital of Baltimore (Baltimore, MD), and Arun Venkatesan, MD, PhD, of Johns Hopkins University School of Medicine (Baltimore, MD), agree with the conclusion of Dr. Stüve and colleagues and say there currently is no firm evidence that a scientifically plausible relationship exists between CCSVI and MS.

But the damage may already be done, according to Drs. Williams and Venkatesan, by a 2009 report by Zamboni et al of an unblinded pilot study of angioplasty and stenting of the jugular veins in patients with MS who met the CCSVI criteria. The authors reported that patients had significant improvements in mental and physical quality of life.

“News of this ‘success’ quickly spread in the MS community, and despite the acknowledgment by Zamboni and colleagues of the ‘great possibility that bias could be playing an important role in trying to find hope for the treatment of this chronic disease,’ patients, the public, the media, and politicians have appealed to make endovascular interventions available for these patients,” the editorial notes.

What is now needed, Drs. Williams and Venkatesan say, is for clinicians, researchers, and patients to wait for appropriately designed clinical trials before ushering in a new standard of care.

Hoping Science Will Win Out

“With MS, you have a devastating, untreatable disease,” said Christopher J. White, MD, of Ochsner Medical Center (New Orleans, LA), in a telephone interview with TCTMD. “And then you have people making claims that are not reproducable. This has led to an unwillingness to do a controlled trial, which in turn leads some patients to believe there is this conspiracy out there and that people are suppressing access to therapy. When you have patients who are desperate and will try anything, you are going to get disreputable people offering therapies to them and that is a real problem.”

Dr. White said that while the new study is “solid well-done evidence,” without a randomized trial, patients are still going to be seeking out a physician willing to use stents to treat their MS.

He added that a research group led by Michael D. Dake, MD, of Stanford University Medical School (Stanford, CA), has encountered numerous problems attempting to conduct such a trial. In December 2009, Dr. Dake’s MS stenting program was shut down. According to the Wall Street Journal, the shutdown came after 1 patient died of a brain hemorrhage on the way home from treatment and another required emergency surgery.

But Dr. White said the Stanford program is still attempting to move ahead with a randomized clinical trial.

“They are facing a lot of criticism because people argue there is no basis for the equipoise but their argument is that someone has to do the trial in order to put this to rest,” Dr. White said. “A randomized trial at a reputable center probably won’t end it, but it’s the best we can do to prove there is no reason to keep barking up this tree.”

 


Sources:
1. Marder E, Gupta P, Greenberg BM, et al. No cerebral or cervical venous insufficiency in US veterans with multiple sclerosis. Arch Neurol. 2011;68:1521-1525.

2. Williams MA, Venkatesan A. No endovascular innovation without evaluation in chronic cerebrospinal venous insufficiency: A call for the IDEAL model. Arch Neurol. 2011;68:1510-1512.

3. 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.

4. Burton TM. MS program halted amid controversy [online edition]. Wall Street Journal. March 25, 2010.

 

Disclosures
  • Drs. Stüve, Williams, and Venkatesan report no relevant conflicts of interest.
  • Dr. White reports receiving research support from Boston Scientific.

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