Most recently, it has been announced that a clinical trial of balloon angioplasty to treat CCSVI which had commenced at Albany Medical Centre in New York State, USA, has been cancelled due to lack of participants. The trial led by Dr Gary Siskin, was to be a double blind trial in which participants received either balloon angioplasty, or sham surgery. The participants and assessing doctors would be un-aware of which procedure they had received until the end of the trial (view details of the trial here).
The Provincial government of Saskatchewan in Canada had committed funds to the Albany trial to support the participation of people with MS from Saskatchewan. Dr Siskin is quoted in the media as suggesting that the placebo-controlled trial design, plus a lack of referrals by doctors may have contributed to the poor recruitment for the trial.
The very large prevalence study funded by the Italian MS Society, known as CoSMo, examining the prevalence of CCSVI in people with MS, has also just published its results in the journal Multiple Sclerosis. This study used a stringent design including blinding sonographers to the disease status of the subjects, viewing of all sonography results by blinded central readers, involvement of 35 centres from around Italy and a large sample size of 1165 people with MS, 226 people with other neurological diseases and 376 healthy individuals.
The investigators found a low prevalence of CCSVI of 3.26% in MS, 3.10% in other neurologic diseases and 2.13% in healthy controls. There was no statistically significant difference between the three groups.
There was a high level of agreement between the local sonographer findings and the central reader on cases with an absence of CCSVI, however, in cases where sonographers identified CCSVI there was lower agreement. The local centres showed a much higher prevalence than central locations to report positive CCSVI findings, likely due to subjective readings at these locations and the more successful total blinding of the central readers. Despite this the prevalence of CCSVI identified by local sonographers was almost identical in the MS and other neurological disease groups (15.8% versus 15.0%, respectively), with a trend toward lower prevalence in healthy controls (11.9%) that was not statistically significant. The authors conclude that CCSVI is not associated with MS.
For a broad overview of other clinical trials underway or completed, and prevalence studies published in the peer-reviewed scientific literature, please see below.
Please note very small studies, review articles, conference abstracts and general media or online coverage are not included below.
Other clinical trials of CCSVI treatment
The clinical trial funded by the Canadian Institute of Health Research and the Canadian MS Society is continuing to recruit participants. This trial, led by Dr Traboulsee of the University of British Columbia is a double-blind cross-over trial in which participants will first receive either sham surgery or balloon angioplasty and be followed for 48 weeks. At this point they will then receive the opposite treatment and be followed for a further 48 weeks. This way all patients in the trial will receive treatment for CCSVI. Details of this trial can be found here.
The CCSVI treatment trial at the Alfred Hospital in Melbourne, is also a double-blind cross-over design. This trial has commenced, but it is reportedly fully enrolled and also seeking further funding. More details can be found here.
An Italian trial, conducted by Dr Zamboni who originally proposed that CCSVI may play a role in MS, is also ongoing. This trial, known as BRAVE-DREAMS (see details here ) aims to recruit 679 patients with either relapsing remitting or secondary progressive MS. The patients will be randomly assigned to receive balloon angioplasty or sham surgery only. The trial is expected to complete data collection in February 2014.
Another Italian group has published feasibility and adverse event findings from 1219 interventions which included 1205 balloon angioplasties and 14 stent placements. Major complications included one (0.1%) azygous vein rupture, one (0.1%) severe bleeding in the groin, two (0.2%) surgical removal of balloon fragments, and three (0.2%) blood clots in the internal jugular vein. The overall major and minor complication rates at 30 days were 0.6% and 2.5%, respectively. The authors conclude that the procedure is safe and feasible. This study did not include data on clinical outcomes for patients following the procedures. Their conclusions are in contrast to those of Ghezzi and colleagues who cautioned that the risk of adverse events warranted careful consideration of the safety of the procedure.
A study by Serbian researchers of 72 patients followed up after balloon angioplasty treatment for CCSVI reported improvements in EDSS for patients with relapsing remitting MS that persisted to 1 year following treatment. Patients with progressive MS showed improvements at early time points, but these did not persist to later time points. Patient –reported disease status showed improvement in 50% of patients. A significant drawback of this study, however, is the lack of a comparison group of patients receiving placebo, or sham, surgery.
Another Italian study, without placebo treated controls, found no changes to relapse rates and disability status worsened in comparison to baseline measurements following balloon angioplasty. New lesions were found in 29% of patients by MRI. However, patients’ subjective experience, as measured by the validated MS-Qol-52 questionnaire showed a statistically significant improvement in quality of life. Without a placebo control group for comparison, it cannot be determined if this is a placebo effect or a true treatment effect.
Prevalence of CCSVI in MS
Researchers from the University of Kentucky, USA, have conducted, a combined analysis (meta-analysis) of the data from several of the CCSVI prevalence studies conducted to date. Their findings show that there is a higher rate of CCSVI in people with MS in comparison to healthy individuals. However, the authors conclude that their data does not show evidence that CCSVI is a causal factor in MS.
One of the seven major CCSVI studies funded by the USA and Canadian MS societies has now published its findings on the prevalence of CCSVI in children with MS. They used ultrasound to examine the internal jugular, vertebral, and deep cerebral veins of 26 paediatric patients with MS (18 years or younger), 26 age-matched healthy controls, and 13 young adults with paediatric-onset MS. They also used MRI studies to examine cerebral and venous blood flow. 73% of all participants had no abnormalities. 23% of all participants had one of the five Zamboni-defined ultrasound criteria for CCSVI. Two patients with MS and 1 young adult with paediatric-onset MS met chronic cerebrospinal venous insufficiency criteria (2 or more abnormalities). Cerebral blood flow findings showed no difference between the individuals with CCSVI (3 people) and those with no abnormal ultrasound findings. The data analysis indicates that CCSVI is rare in children with MS and the authors conclude that CCSVI is not a causative factor in MS.
Another Canadian study, funded by philanthropic donations, led by Dr Rodgers from McMaster University and published in the open access journal PLOS ONE described the ultrasound and MRI findings in 100 people with MS in comparison with 100 age-matched healthy individuals. The two ultrasonographers involved in the study had received training in the ultrasound technique under the supervision of Dr Zamboni in Italy. Only one person with MS had two ultrasound findings consistent with the definition of CCSVI. Two healthy individuals and two people with MS had ultrasound findings consistent with only one of the CCSVI criteria. The authors conclude that the study ‘provides compelling evidence against the involvement of CCSVI in MS’.
Another study concluded that ultrasound defined CCSVI is more common in MS patients than healthy individuals, but appears to be primarily associated with the patient’s age, and poorly correlated with the clinical course of the disease. (Full article available here). Researchers from the Mayo Clinic, Rochester, USA, concluded that narrowing of the internal jugular vein is common (found in 25%) of patients without any history of MS.
A team from Texas, USA published a small study in which they re-assessed 8 patients who had originally shown CCSVI abnormalities by ultrasound. In the repeat ultrasound the assessors were blinded to the original assessment and found no CCSVI abnormalities. The authors suggest that cerebral venous flow abnormalities may be dynamic and transient (no abstract available).
A study by Zivadinov and colleagues at State University of New York at Buffalo, USA, showed no evidence of an association between the presence and severity of CCSVI with cognitive impairment and depression in patients with MS. Another study reported that fatigue, depressive, bladder/sexual symptoms and self-reported quality of life are not associated with the presence of CCSVI.
The large COSMO study, funded by the Italian MS society, looking at the prevalence of CCSVI in at least 1,200 adults with MS, as well as 400 healthy subjects and 400 subjects with other neurodegenerative diseases, has completed recruitment but patient assessments and data analysis are ongoing (view details of the study here).
MS Australia has been meeting with key CCSVI stakeholders, including CCSVI Australia and key researchers involved in the clinical trial at the Alfred Hospital. More information can be found in the MS Australia Advocacy Update.
For earlier round-ups of research into CCSVI in MS, please view the following news articles:
Australian results published on prevalence of CCSVI in early MS, CCSVI Research Round-up March 2013, Recent CCSVI research findings July 2012 or view a list of previous news articles relating to CCSVI.
