Furthermore, similarly to criterion three, a mild pressure exerted by the ultrasound probe or by a contraction of the cervical muscles may alter the diameter of the vein possibly leading to false-positive results. A more correct method would be to calculate the difference of Cabozantinib chemical structure blood flow (CSA × velocity) in the two positions (supine and sitting) as has been recently performed [12], not confirming the hypothesis of Zamboni and co-workers. A very important issue is the cut-off point of these criteria to diagnose CCSVI. In fact, it is unclear how Zamboni decided that two or more of the five ultrasound criteria may be used to diagnose CCSVI. Diagnostic criteria using a new alternative method (i.e. ultrasound) are usually

compared with a validated gold-standard investigation (venography according to Zamboni et al.). However, Zamboni et al.’s comparison of venography in 65 CCSVI ultrasound-positive MS patients was not blinded and is therefore open to bias. There was also see more no validation of the CCSVI-criteria by different and independent observers. Finally, subsequent studies using MR-venography could not confirm differences regarding

cerebrospinal drainage in MS patients and controls [27], [28], [29] and [30]. Ultrasound investigation of intracranial and cervical veins is highly operator dependent owing to the wide anatomic and physiological variability of these vessels. Therefore a study of cerebral venous drainage requires very experienced neurosonographers, but most importantly, blinding algorithms are mandatory in assessing MS patients especially during venographic verification of ultrasound

findings; these were completely omitted in Zamboni’s studies. To this day, a scientifically sound validation of each of the five criteria proposed by Zamboni for the diagnosis of CCSVI is missing, not to mention their combined application. Concurrently, there is growing evidence which rejects the role of CCSVI in the pathogenesis of MS and which suggests that the proposed CCSVI criteria are questionable due to miscitation, manipulation of known data and methodological flaws. Thus, any potentially harmful interventional treatment such as transluminal angioplasty Loperamide and/or stenting should be strongly discouraged, not only for the lack of any evidence, but also for the risk of serious peri-procedural complications. Claudio Baracchini: Conception, organisation and execution of the research project; writing and review of the manuscript. Paolo Gallo: Conception, organisation and execution of the research project; writing and review of the manuscript. Dr. Baracchini serves on the executive committee of the European Society of Neurosonology and Cerebral Hemodynamics; has received funding for travel and speaker honoraria from Pfizer, Sanofi-Aventis, Laboratori Guidotti and Novartis; serves as Associate Editor for BMC Neurology; and has given expert testimony in a medico-legal case. Dr.