Multiple Sclerosis: Is the Brave Dreams Study a tombstone for CCSVI and Eventual Surgical Procedures? An Open Discussion
Pietro M. Bavera MD
Vascular Surgeon and Diagnostician for Medick-Up Vascular Lab, Milano; Member of the Italian Society for
Angiology and Vascular Medicine (SIAPAV); Member of the Italian Society for Vascular Investigation (SIDV)
The results of a recent article published in JAMA Neurology regarding the conclusions of Brave Dreams (BD) Study (1), “Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis a Randomized Clinical Trial”, disappointed for a multitude of reasons. It was closed after almost five years and missing enrolment of 315 Multiple Sclerosis (MS) patients, out of the initially intended 430, the conclusions could therefore turn out to be a sort of statistical hazard.
All conclusions are significant when numbers are big otherwise the results may be weak. This is mathematical, and it is precisely the case of the Brave Dreams Study.
The Authors affirm some good scientific results that don’t match with JAMA Neurology Editor’s final considerations applied to Chronic Cerebrovascular Vein Insufficiency (CCSVI) treatment in the whole. The Editor’s conclusions lead against jugular Percutaneous Transluminal Angioplasty (PTA) treatment efficacy in Multiple Sclerosis Patients, sustaining uselessness, but they differ from the Clinical Reality that we daily see in our professional practice.
Keywords: CCSVI, Multiple Sclerosis, Jugular Veins, Venous Insufficiency.
Commenting the BD Study, the most obvious limitation related to the sample size is stated properly in the section with a post-hoc analysis of the “power” about what the study could actually find (not much).
Even the use of new, not comparable, functional scores in such an important trial is reported among the limitations, coupled with the fact that patients were generally “not seriously ill” and so maybe unrepresentative for “identifiable improvements”.
In our opinion a mistake comes from the planning of this trial, largely overestimating the ability to reach the number of required patients. It is unclear how the expected results were hypothesized as useful both by means of MRI and a functional score.
The trial moreover seems to have missed the point considering what is reported in the conclusions with the initial target.
Despite the minimalist sample size, the MRI results still manage to be around the threshold of significance. This has positive connotations and is interesting about PTA and its effect on Blood-Brain-Barrier (BBB) perspectives.
It would have been useful to evaluate short-term end points also on the functional scores that are reported only in a period of 12 months.
From a general scientific point of view, there is a considerable shift between what was initially proposed with the final conclusions.
In the introduction the aim was to assess the efficacy and safety of PTA in MS patients with CCSVI. In the conclusion it is affirmed that the PTA is not effective in treating CCSVI since, a year after, only 54% of MS patients had recovered an adequate flow at the Duplex evaluation.
This however was a secondary endpoint and not the primary stated objective.
So we think there are three questions to be answered:
(1) does PTA resolve CCSVI?
(2) does PTA bring benefits in MS?
(3) does the healing of CCSVI give benefits on MS ?
1) Considering how the Study was carried out, PTA doesn’t seem so because 12 months after surgery only slightly more than half of MS patients had benefits on CCSVI. However, the trial was not designed to respond primarily to this question. Still, more than 50% had some benefits without particular side effects due to the procedure.
2) The trial was designed to answer to this question but because of the up-listed limitations (mentioned also in Zamboni’s paper) actually it doesn’t provide sufficient information to respond adequately. In other words, it is ineffective in respect to the initial target.
3) We don’t know because of the negative response in point 1. Probably we should develop a better technique (stenting?) that produces long-lasting effects on CCSVI and, above all, monitoring of a larger number of subjects in a wider lapse of time, at least from 3 to 4 years.
The BD Study was closed with a heavy burden of expectations and, considering the final numbers, still has too many unresolved endpoints. Several published works are now highlighted upon the blood-brain-barrier (BBB) defaults and these realistically can be the future for research in MS (2,3,4).
Chronic Cerebrovascular Venous Insufficiency (CCSVI) is already an acquainted reality (5,6 ) and the description of venous outflow defects are described in several papers and even in University Textbooks of Vascular Surgery (7).
Topics on “CCSVI” and “Duplex exams for CCSVI” have gained a percentage of relevance that few other vascular issues have reached altogether. A recent review on PubMed scores 282 published papers just regarding the two issues, while Google Scholar reaches a score of 37.100 results just for Chronic Cerebrovascular Vein Insufficiency. Numbers will grow when adding CCSVI to more issues, like MRI, Meniere’s Disease or Fatigue Syndrome.
The majority of these published Scientific Papers were released before the BD Study.
Among the Editor’s conclusions of the BD Study we read the statement that says: “Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS”. Furthermore, among the key points of the BD Study, it is stated that “Venous PTA cannot be recommended for patients with relapsing-remitting multiple sclerosis”.
It is an opinion but for many Patients that underwent with success to venous PTA, these conclusions are far away from Clinical Reality.
The BD Study mainly confirms that the vein PTA is a safe procedure if carried out by professionally expert hands. This is quite obvious and is valid for all situations.
Two years ago an independent Study paper edited by Veins and Lymphatics (8) regarding 366 MS patients with a 48 month follow-up was read and appreciated by thousands of people and concluded with an excellent percentage of symptom improvements especially on relapsing-remitting conditions. It is completely opposite to the key point highlighted in the BD Study.
There are too many scientifically proven, published and indexed results that cannot be denied by a statistically weak Study like Brave Dreams that doesn’t answer many questions for which it was intended at the start. Certainly we now know that angioplasty can safely correct some jugular vein issues, but this is too little. Progress in this direction, but not only, must be encouraged and the Brave Dreams Study paper shouldn’t be a tombstone but a spur for research, even in different issues (9), to meet the still pending solutions towards materials and therapeutic methods regarding CCSVI. The Study and, above all the conclusions, are rushed and overestimated (10), certainly not a tombstone.
1- Paolo Zamboni, Luigi Tesio, Stefania Galimberti et al. Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis, a Randomized Clinical Trial. JAMA Neurology November 18, 2017
2- Jonathan I Spencer, Jack S Bell, Gabriele C DeLuca, et al. Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier. J Neurol Neurosurg Psychiatry 2017
3- Berghoff SA, Duking T, Spieth L, et al. Blood-brain barrier hyperpermeability precedes demyelination in the cuprizone model. Acta Neuropathol Commun. 2017 Dec 1;5(1):94.
4- Dulamea A. The contribution of oligodendrocytes and oligodendrocyte progenitor cells to central nervous system repair in multiple sclerosis: perspectives for remyelination therapeutic strategies. Neural Rigen Res. 2017 Dec;12(12):1939-1944.
5- Lee BB, Bergan J, Gloviczki P, et al. Diagnosis and treatment of venous malformations. Consensus document of the International Union of Phlebology (UIP) 2009. International Union of Phlebology (UIP) Int Angiol 2009;28:434-51.
6- Lee BB, Baumgartner I, Berlien P, et al.Diagnosis and Treatment of Venous Malformations Consensus Document of the International Union of Phlebology (IUP): updated 2013. Int Angiol 2015;34:97-149.
7- Paolo Zamboni, Sergio Gianesini, and Erica Menegatti. Chronic cerebrospinal venous insufficiency, in diseases of the veins and lymphatics. Oxford Textbook of Vascular Surgery Edited by Matthew M.Thompson, Robert Fitridge, Jon Boyle et al. Oxford University Press Aug 2016
8- Pietro M. Bavera. May symptoms of chronic cerebrospinal venous insufficiency be improved by venous angioplasty? An independent 4-year follow up on 366 cases.
Veins and Lymphatics 2015; vol.4:5400
9- Dario C. Alpini, Pietro M. Bavera, Federica Di Berardino, et al. Bridging the gap between chronic cerebrospinal venous insufficiency and Ménière disease. Veins and Lymphatics 2016; volume 5:5687
10- Bernhard H.J. Juurlink , Pietro M. Bavera, Salvatore Sclafani, et al. Brave Dreams: An overestimated study, crippled by recruitment failure and misleading conclusions. Veins and Lymphatics 2018; volume 7:7340