The controversial theory that multiple sclerosis is caused by obstructed craniocervical veins -- and that angioplasty might help -- once again failed to stand up to another case-control study.
MRI scans in 21 patients and 20 healthy controls revealed "no differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux," according to Peter Sundström, MD, PhD, of Umeå University in Sweden, and colleagues.
"We were not able to reproduce the findings reported to be associated with the suggested vascular MS hypothesis" known as chronic cerebrospinal venous insufficiency or CCSVI, the researchers wrote in the August issue of Annals of Neurology.
In an accompanying editorial, a group of North American researchers led by Omar Khan, MD, of Wayne State University in Detroit, urged physicians to refrain from treating MS patients with angioplasty or stenting "until there is conclusive evidence to justify their indication in MS."
The Swedish report was accompanied by the print publication of similar results from German researchers that had previously been released online.
The findings directly contradict results reported last year and in 2007 by Paolo Zamboni, MD, of the University of Ferrara in Italy, and colleagues from a 300-participant ultrasound study, in which nearly all the MS patients but few controls had CCSVI.
Zamboni and colleagues theorized that abnormal flow through the azygous and jugular venous systems results in a build-up of iron in the brain. The excess iron damages blood vessels and allows the metal, as well as other substances, to cross the blood-brain barrier, eventually leading to MS, they argued.
They also reported highly favorable results with cerebrospinal venous angioplasty in MS patients, including stent placement in some cases. Zamboni and colleagues reported reversal of MS symptoms was common with the procedure.
But neurologists in the mainstream have been skeptical, and the study by Sundström and colleagues will surely reinforce their doubts.
Median age of the Swedish patients was 31 (range 19 to 56) with median disease duration of five years (range 1 to 25). Median scores on the Expanded Disability Status Scale when last assessed was 2.0 (range 0 to 3.5)
The healthy controls were of similar age but included more men (60% versus 38%). Controls were believed to be neurologically healthy and were acquaintances of the investigators.
Phase-contrast MRI was performed in both patients and controls, and patients also underwent contrast enhanced magnetic resonance angiography.
The closest thing to a significant difference between patients and controls in the findings was in total cerebral blood flow, Sundström and colleagues found. The mean in cases was 723 mL/min (SD 123), compared with 813 mL/min (SD 184) in controls (P=0.073).
For other measures -- total jugular blood flow and the ratios of total, right, and left jugular blood to total cerebral blood flow -- there were no differences approaching statistical significance.
On the other hand, Sundström and colleagues identified a trend (P=0.14) toward larger mean stroke volume in cerebrospinal fluid among patients relative to controls.
MR angiography in the patients disclosed that just three of the 21 had internal jugular vein stenoses, all in the vein's middle portion.
In contrast, the initial studies by Zamboni and colleagues had suggested that most MS patients had stenoses as well as signs of venous reflux.
The phase-contrast MRI data reported by Sundström and colleagues indicated that five patients had venous reflux, as did five controls.
In these individuals, there was "markedly decreased internal jugular flow" on the same side as the detected reflux, typically with increased flow on the other side.
"If CCSVI is an entity associated with MS, the association is likely to be weaker than previously reported, and, most importantly, we found no support for a treatment rationale of endovascular procedures like angioplasty or stenting," Sundström and colleagues wrote.
Khan and colleagues agreed in their editorial, noting that -- even apart from the Annals papers directly contradicting the results reported by Zamboni and colleagues -- numerous previous studies had findings inconsistent with the proposed MS-CCSVI mechanism.
For example, transient global amnesia is known to be common with chronic jugular venous insufficiency, yet is rarely seen in MS patients, Khan and colleagues pointed out.
Also, radical neck dissection as cancer therapy results in cerebrovenous insufficiency, but MS has never been reported as a complication.
Khan and colleagues suggested that, if venous obstructions do correlate with MS in some way, perhaps they are secondary to MS rather than the other way around.
They called for additional studies, preferably conducted in multiple centers using MR venography and using "carefully selected" control groups.
In the meantime, they wrote, "it is critical not to compromise patient safety during the conduct of these research endeavors."
They noted disapprovingly that some physicians have already started performing venous angioplasties and stenting as clinical procedures, "in some cases [leading] to serious injury."
The work was funded by Swedish Research Council, Vinnova, the Foundation for Strategic Research, and Objective 2 Norra Norrland–European Union Structural Fund.
Sundstrom and colleagues and Khan and colleagues declared no financial conflicts of interest.
- Reviewed by Michael J. Olek, DO Director, Newport Doctors Multiple Sclerosis Clinic and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Annals of NeurologySource Reference: Sundström P, et al "Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study" Ann Neurol 2010; 68: 255-259.
Annals of NeurologySource Reference: Khan O, et al "Chronic cerebrospinal venous insufficiency and multiple sclerosis" Ann Neurol 2010; 68: 286-290.