LYON, France — A new study looking at the association between the presence of chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS) shows the incidence of CCSVI was low and did not differ among groups of patients with MS, other neurologic diseases, or healthy controls.
The researchers, representing centers across Italy, where the theory of CCSVI was first developed, say that their findings should end once and for all the controversy about whether venous insufficiency has any role in the MS disease process, concluded lead author Giancarlo Comi, MD, director of the Department of Neurology and Institute of Experimental Neurology at the Scientific Institute and University Vita-Salute San Raffaele in Milan, Italy.
"I think that I do really hope that this is the last time I have to talk about this topic," Dr. Comi concluded.
Another observational study suggests that the use of venoplasty to address CCSVI is not without risk, with serious adverse events occurring in about 3% of patients who elected to be treated.
The papers were presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The COSMO Study
Paolo Zamboni, MD, director of the Vascular Diseases Center at the University of Ferrara, Italy, first described this potential relationship, that patients with MS had more abnormalities in the internal jugular and other veins than those without MS. He reasoned that addressing these lesions with venoplasty might improve symptoms in MS.
Since he published his initial results in 2009, however, the CCSVI theory has become a hot button topic in this field. Observational studies have had wildly divergent results, leading to controversy about what constitutes CCSVI and how to detect it on imaging. In the meantime, many patients have paid out of their own pockets to be assessed and undergo venoplasty in hopes of improving their symptoms, often traveling to other countries and not receiving much in the way of follow-up care.
At the meeting here, several new studies were presented with the aim of investigating the correlation between the presence of CCSVI and MS, established by using the criteria proposed by Dr. Zamboni.
The COSMO trial was a case-control observational study. Fundamental to the approach, said Dr. Comi, was the use of local blinded evaluation as well as blinded central evaluation of scans.
The scans were assessed by the peripheral and central reader, and if the diagnosis (presence or absence of CCSVI) matched, that diagnosis was considered final. If there was disagreement, the exam was sent to the other 2 central sonologists. The agreement of 2 of the 3 central sonologists was considered final.
"The criteria we used were exactly those described by Zamboni," Dr. Comi noted, calling for 2 of 5 possible criteria to be present for a diagnosis of CCSVI. "All the sonologists, in order to be accepted for the study, had to perform an applicant training and a final exam, again to prevent the objection that…only some few are able to pick up this condition."
Three groups were included: healthy controls; patients with other neurologic diseases; and patients with various courses of MS, including clinically isolated syndrome, relapsing-remitting MS, and primary progressive and secondary progressive MS, to see whether, in the case of a positive association, that it might be related to the phase of disease, he noted.
Thirty-five centers across Italy participated, and the study was supported by the Italian Association of Multiple Sclerosis.
Some patients were excluded for protocol violations or because image quality was not acceptable, leaving 1767 patients or healthy participants.
The prevalence of CCSVI seen in patients with MS, healthy controls, and patients with other neurologic disorders was low and did different among the groups in this study, Dr. Comi reported.
The odds ratios for the prevalence of CCSVI were 1.55 (95% confidence interval [CI], 0.72 - 3.36; P = .30) for patients with MS vs healthy controls and .05 (95% CI, 0.47 - 2.39; P = .99) for patients with MS vs other those with neurologic diseases.
CCSVI prevalence in clinically isolated syndrome was 3.46% in patients with relapsing-remitting MS, 3.77% in those with secondary progressive MS, and 4.76% in those with primary progressive MS (P for heterogeneity = .24; P for trend = .10).
The major risk factor for the presence of CCSVI was the sonologic center (P = .013), said Dr. Comi. "There are believers in life, there are the non-believers," he said, referring to the divisive controversy that has arisen around this issue.
CCSVI was diagnosed more often in the local centers, but again, the prevalence did not significantly differ among the groups: CCSVI was diagnosed in 15.88% of patients with MS but also in 11.97% of healthy controls and 15.04% of patients with other neurologic diseases.
The agreement between local and central readers was high for negative diagnoses of CCSVI, at 92%, but much lower for positivity, at only 18%.
"So I think the conclusion is very easy — at least for us; I'm not convinced that everybody will be of the same view, but at least in this room — I think that using the scientific approach, you will agree that this study indicates that CCSVI is not associated with multiple sclerosis, and also is not associated to other neurological diseases," Dr. Comi concluded.
After the presentation, Jerry Wolinsky, MD, from the University of Texas Health Science Center, Houston, pointed out that in a separate presentation here, their group reported that CCSVI criteria put forward by Dr. Zamboni were met on neurosonography in 3.88% of their smaller group of patients with MS, also with use of blinded readers, he said, similar to the value found by the COSMO group.
"I was always worried that we were finding a value that was too low, but I don't think I'm alone anymore," Dr. Wolinsky told Medscape Medical News. "So our conclusions are if [CCSVI] exists it's very uncommon, and we really don't find anything in our data that would be highly supportive of this being a) specific to MS, or b) likely being of pathophysiologic consequence for anyone."
Dr. Zamboni Responds
During a press conference on these findings, Dr. Comi noted that Dr. Zamboni was part of the group that launched the COSMO trial but had withdrawn from participation on the basis of objection to the methods.
Asked for comment on the findings, Dr. Zamboni confirmed that he was not happy with the COSMO study design.
"Our seminal paper published in 2009 in JNNP compared Doppler sonography with catheter venography, and found 90% and 75% abnormalities respectively in the jugular and in the azygous veins of MS patients," he told Medscape Medical News. "COSMO trial was initially aimed to verify my data in a wide sample and in a multicenter setting."
"Unfortunately," he said, the study compared Doppler sonography with the agreement of 3 central readers. "This design is not [as] solid of course as comparing ultrasound with venography," Dr. Zamboni added. Moreover, 90% of CCSVI cases discovered in peripheral centers were over-ruled by the central readers, and classified as false positive.
"To me, this study mainly confirms the absence of reproducibility of Doppler sonography in the absence of good CCSVI training, and further suggests to assess patients via [multimodal] diagnostic techniques."
Procedure Not Without Risk
In a separate paper presented here, researchers with the MS Study Group–Italian Society of Neurology, which included some of the COSMO investigators, reported results of an observational study with the aim of defining efficacy and safety outcomes among patients with MS who had elected to have endovascular treatment to address CCSVI.
Included in the study were 462 patients from 33 Italian MS centers. At a mean follow-up of 30 weeks, there was no statistical difference between baseline and follow-up Expanded Disability Status Scale (EDSS) scores, said Angelo Ghezzi, MD, from Ospedale S. Antonio Abate in Gallarate, Italy, who presented the findings here.
"In spite of the fact that the clinical evolution was unchanged after the treatment, many subjects reported an improvement of their clinical conditions," Dr. Ghezzi noted. He acknowledged, though, that any improvements in fatigue or energy levels, for example, would not be picked up by the EDSS.
Table 2. EDSS Scores and Subjective Patient Evaluation Group EDSS Scores at Baseline EDSS Scores at Follow-up Evaluation Improved (%) Evaluation Stable (%) Evaluation Worsened (%) Whole cohort 4.9 + 2.0 5.2 + 2.0 52.5 36.5 11.0
Relapses were seen in 21% of patients. Among 171 who underwent magnetic resonance imaging, 35.7% of these had new lesions and 26.3% had new gadolinium-enhancing lesions. There was a nonsignificant increase in relapses among patients who stopped immunomodulatory therapy after the procedure, he noted.
Mild adverse events, including asthenia, headache, cutaneous rash after the procedure, and hematoma at the site of catheter insertion, were seen in 7.5% of patients.
However, serious adverse events occurred in 3.2% or 15 patients within 3 months of the procedure, he noted. One patient died of myocardial infarction. Jugular thrombosis occurred in 7 patients, hydrocephalus requiring shunting in 1, stroke in 1, paroxysmal atrial fibrillation in 1, status epilepticus in 1, aspiration pneumonia in 1, hypertension and tachycardia in 1, and severe bleeding from a bed sore in 1 who was receiving an anticoagulant after the procedure.
Dr. Ghezzi pointed to the recent warning issued to patients and healthcare providers by the US Food and Drug Administration about the safety of the procedure.
"To conclude, we did not observe a clear beneficial effect of endovascular treatment," Dr. Ghezzi said. "The mean EDSS was unchanged. Many patients continued to develop relapses, but it is important to stress that serious adverse events occurred in a number of patients."
"Many patients reported an improvement, but we have also to consider the possible placebo effect, considering this kind of intervention is called 'liberation,' and this produces very high expectations in people affected by multiple sclerosis," he concluded.
"And it is a matter of discussion if it is justified to propose a controlled study," Dr. Ghezzi added, "given the lack of evidence that there is a clear demonstration of the association between CCSVI and multiple sclerosis, and also the occurrence — in a small number of patients — of serious adverse events."
Dr. Comi told Medscape Medical News that in this study, the disease process continues to evolve after the treatment, "so at the end, we have risks and no positive effects, which is to me, too much to continue."
He says he initially had an open mind about this concept, "but many have jumped immediately from an idea to an action." And the risk of intervention appears to be double, not only with the risk for adverse events but also from the fact that many patients stop treatment with disease-modifying drugs. "I think it's the duty of the national societies, international societies, to inform patients about these types of risks."
Further Trials Ethical?
After presentation of the COSMO results, Dr. Comi was asked whether it is ethical, given these results, to recruit patients into trials of angioplasty for CCSVI.
"We made some jokes this morning because we feel really 'liberated' by this study from a difficult problem, but in reality, we have the problem here that some patients — many patients — decide to have these type of procedures and as we heard yesterday, some of them had a very severe prognosis," he replied. "And I think that because there is no rationale for a trial exploring the efficacy of liberation therapy, I personally think it's absolutely inappropriate that the government finances any type of investigation or research."
The release of these data comes hard on the heels of the recent announcement of a new study of CCSVI funded by the Canadian government. The MS community in Canada has been very vocal in advocating for such a trial, and on September 28, such a study was announced: "a collaborative initiative between the Government of Canada, the provinces and territories and the MS Society of Canada," a press release from the Canadian Institutes of Health Research notes.
Recruitment is set to begin November 1, 2012, with principal investigator Anthony Traboulsee, MD, medical director of the UBC Hospital MS Clinic. The phase 1/2 double-blind, controlled trial will include 100 patients, with a planned 2-year follow-up.
Paul O'Connor, MD, director of the Multiple Sclerosis Clinic and MS Research at St. Michael's Hospital in Toronto and professor of neurology at the University of Toronto, Ontario, Canada, was a session moderator during Dr. Comi's presentation here.
Although he is not involved personally in the planned Canadian trial, he is the national scientific and clinical advisor for the Multiple Sclerosis Society of Canada and has been involved in developing guidance for neurologists providing after-care for their patients who have left the country to obtain venoplasty or stenting to address CCSVI.
Asked for comment on this current situation and Dr. Comi's assessment about the ethics of continued investigation of the association of CCSVI with MS, Dr. O'Connor was circumspect.
"Well, I think that's his opinion," he told Medscape Medical News. "I think we need time to think through the implications of this finding, so I wouldn't be prepared to say at this point if I agree or disagree with him."
However, he was impressed with the quality of the COSMO data. "The study seemed to be very carefully done, with the appropriate attention to detail in terms of establishing the presence or not of CCSVI, and I was very impressed with the methodological rigor of the study. I think there's no reason to doubt that the findings are accurate, and would seem to indicate that the entity of CCSVI appears to be present in only a minority of people, whether or not they have MS or other neurological disease, or are healthy."
He said the key to the reliability in this study was the blinding of the central readers. "It was shown that those who may have been less blinded, the local readers, tended to find this condition more frequently, but equally in all 3 groups, but when you had people who were blinded, they found it less, and the experts found it less frequently than the local readers."
The British Columbia group with senior author Dr. Traboulsee also presented here at the meeting, a poster reviewing an observational study now underway, funded by the British Columbia Ministry of Health. The British Columbia CCSVI Registry is following patients with MS who have elected to have angioplasty or stenting to address the presence of CCSVI in order to ascertain some pre- and post-procedure health outcomes, as well as compile data on complications. All data are self-reported during telephone interview, noted Lucas Kipp, MD, from the Division of Neurology at the University of British Columbia, Vancouver, who presented the data here.
To date, 80 patients have been enrolled, he said. About 10% have reported complications in the month after the procedure, and 11% in the month thereafter. Approximately 50% said they were somewhat or much better, and 50% said they were the same or worse in terms of function after the procedure.
"The plan is to re-interview them at 6 months, 12 months, and 24 months, and go from there," he toldMedscape Medical News. They hope to follow up these patients and capture changes in their functional abilities using EDSS scores, information that will require access to their medical records, he noted.
