Comment

www.thelancet.com Published online October 9, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61912-1 1

Chronic cerebrospinal venous insuffi ciency in multiple sclerosis: the fi nal curtain

In 2009, Zamboni and colleagues1 reintroduced the theory that obstructions of the venous outfl ow from the CNS are associated with multiple sclerosis, and they proposed a link with multiple sclerosis pathogenesis. This hypothesis, originally posed by Putnam in 1947,2 then attracted an enormous amount of attention from patients, physicians, and the media, but also caused sub-stantial uncertainty. In fact, both the theory3 and the ultrasound and catheter venography studies on which the concept of chronic cerebrospinal venous insuf-fi ciency is based have substantial methodological fl aws, as has recently been shown convincingly.4,5 Many studies with ultrasound,6–8 MRI techniques (including fl ow measure ments9), catheter venography,10 or combined methods11 have conclusively disproven a link between multiple sclerosis and fi ndings suggestive of venous out-fl ow obstructions in the head and neck. Nevertheless, the associated treatment for chronic cerebrospinal venous insuffi ciency, in the form of angioplastic inter-ven tions, which was tendentiously termed liberation treatment and proposed as a valid approach to alleviate multiple sclerosis symptoms, earned widespread media coverage and kindled the hopes of desperate patients with the disease.12 Despite the absence of scientifi c evidence, chronic cerebrospinal venous insuffi ciency rapidly entered the multiple sclerosis glossary and there were testimonials of miraculous recoveries following angioplastic procedures. Although most researchers, clinicians, and multiple sclerosis societies urged caution, pressure by advocacy groups and feverish enthusiasm in sections of the media led to the allocation of substantial public funding for interventional trials.

In The Lancet, Anthony Traboulsee and colleagues13 report a multicentre, masked, case-control study of the prevalence of extracranial venous narrowing on both catheter venography and ultrasound in patients with multiple sclerosis, their siblings, and unrelated healthy controls (177 participants in total). The results of this investigation, which was complicated because of the challenging methodology, showed that one of 65 (2%) people with multiple sclerosis fulfi lled catheter venography criteria for chronic cerebrospinal venous insuffi ciency—a percentage comparable to

that of unaff ected siblings (one of 46 [2%]) and unrelated controls (one of 32 [3%]). Greater than 50% narrowing in any major extracranial vein was detected on catheter venography in roughly 70% of participants, with no diff erences between any of the three groups. Ultrasound criteria for chronic cerebrospinal venous insuffi ciency were fulfi lled in 44% of people with multiple sclerosis, 31% of unaff ected siblings, and 45% of unrelated controls.

A highly innovative aspect of this study was the combination of the two most important diagnostic methods in the diagnosis of venous anomalies and pathologies: ultrasound and catheter venography, which is widely regarded as the gold standard for this type of diagnosis. An important fi nding was that the sensitivity and specifi city of ultrasound criteria for detecting greater than 50% narrowing on catheter venography were poor (sensitivity 0·406 [95% CI 0·311–0·508], specifi city 0·643 [0·480–0·780]) in both patients with multiple sclerosis and controls to an equal extent. The study also showed that the proportion of study participants who met the greater than 50% narrowing criterion on catheter venography varied substantially between the participating clinical centres. This fi nding emphasises how crucial masking is in studies of a functional and anatomical system that is as variable and dynamic as is the venous vasculature. Additionally, the study provides evidence that results obtained with one diagnostic modality (eg, ultrasound) do not necessarily correlate with those obtained with another diag nostic procedure (eg, catheter angiography). This fi nding lends further weight to arguments based on pathophysiological and methodological concerns that no indication exists for venous angioplasty in multiple sclerosis.

We believe that the work by Traboulsee and col-leagues13 is a solid and well-balanced study, and, moreover, is one that sounds a death knell for the hypoth esis of chronic cerebrospinal venous insuffi ciency as a disease entity. Chronic cerebrospinal venous insuffi ciency is not highly prevalent in multiple sclerosis. The disorder is neither specifi c to the disease nor does it have a causative role. What has been

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2 www.thelancet.com Published online October 9, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61912-1

described as venous narrowing in about two-thirds of study participants is unlikely to be more than frequent anatomical variants of a complex vascular system that remains poorly understood.4 If chronic cerebrospinal venous insuffi ciency actually existed, the ultrasound fi ndings of this study and previous studies would suggest that up to half of the general and otherwise healthy population should be judged to be seriously ill because of venous insuffi ciency of the cervical veins. The fact that some changes in the venous system have been described in association with multiple sclerosis does not imply causality.14

A lively discussion has emerged recently as to whether funding of chronic cerebrospinal venous insuffi ciency research is, or was, a waste of valuable time, money, and intellectual energy.15 The work by Traboulsee and colleagues13 should be viewed as the defi nitive conclusion to this discussion. Although it is laudable that the Multiple Sclerosis Society of Canada and other sources have funded this seminal study, which would probably not have received funding other wise, now it is absolutely clear that no reason exists to allocate any further resources to chronic cerebrospinal venous insuffi ciency research, be they fi nancial or intellectual.

*Friedemann Paul, Mike P WattjesNeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany (FP); and MS Center Amsterdam, Department of Radiology, Nuclear Medicine, and PET Research, VU University Medical Center, Amsterdam, Netherlands (MPW)friedemann.paul@charite.de

FP is supported by the German Research Council (DFG Exc 257), the German Ministry for Education and Research (Competence Network Multiple Sclerosis), and the EU FP7 programme (www.combims.eu). He has received research support, travel grants, and speaker honoraria from Biogen Idec, Bayer, Merck Serono, Sanofi Genzyme, Teva, and Novartis, and travel reimbursement from the Guthy Jackson Charitable Foundation. FP serves on the steering committee of the OCTIMS study sponsored by Novartis. MPW has received speaker honoraria from Biogen Idec, Novartis, and Janssen Cilag. He serves on advisory boards for Biogen Idec.

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13 Traboulsee AL, Knox KB, Machan L, et al. Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study. Lancet 2013; published online Oct 9. http://dx.doi.org/10.1016/SO140-6736(13)61747-X.

14 Sinnecker T, Bozin I, Dörr J, et al. Periventricular venous density in multiple sclerosis is inversely associated with T2 lesion count: a 7 Tesla MRI study. Mult Scler 2013; 19: 316–25.

15 Hutchinson M. Funding CCSVI research is/was a waste of valuable time, money and intellectual energy: commentary. Mult Scler 2013; 19: 861–62.