Alessandro Rasman

Reflections on the Canadian study by Traboulsee 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

Sandro Mandolesi,1 Aldo d’Alessandro,2 Tarcisio Niglio,3 Michele Rossi 4

1 Department of Cardio-vascular and Respiratory Sciences, La Sapienza University, Rome;
2 Department of Neuroscience, Imaging and Clinical Sciences, G. d’Annunzio University, Chieti-Pescara;
3 Istituto Superiore di Sanità, Rome;
4 Radiology Department Sant’Andrea, La Sapienza University, Rome, Italy.

Correspondence: Sandro Mandolesi, e-mail: s.mandolesi@email.it

Acknowledgments: the authors wish to thank doctor Alessandro Rasman for his collaboration.

Preface by P. Zamboni

The Editorial How to objectively assess primary venous obstruction published in the last 2014 issue of Veins and Lymphatics (http://dx.doi.org/10.4081/vl.2014.4195) stimulates an intense scientific debate even involving the social networks. Strictly correlated to such an open scientific discussion we herein receive a Letter condensing thoughts again about the Traboulsee et al.’s paper published on the Lancet. 1

Letter

1. There is a conflict of interest as the first sponsor is the Multiple Sclerosis Society of Canada and other foundations, we do not know who they represent is also not reported how much it cost the study;
2. If as it appears on the paper the doctors or technicians ultrasonographers who carried out the ultrasound were trained by Zamboni, why they found 0% of reflux and 0% of stenosis in the jugular of patients with MS?? No paper, even the most deductive in literature, reports such as it is statistically impossible;
3. Zamboni can confirm attendance and technical preparation of all sonographers of the three structures that examined the MS patients?? They never speak of hemodynamic stenosis or total compressions of jugular veins (present in our statistics, respectively, in 13% and 48% of patients). 2
4. Why they discarded the radiographic evaluation of the patients studied in orthostatic position by saying that the internal jugular veins usually collapse in the upright position, with blood redirected to the azygous vein and vertebral veins. It must be inferred that they did not show narrowings; it is a motivation not clear as they could evaluate all other hemodynamic parameters (reflux, stasis and compensatory circles). In addition to what sample, healthy or pathological, the vessels were collapsed and what correspondence was between venography and the results of the ultrasound in orthostatic? A vessel collapsed indicates that does not pass the blood in its interior how has been explained this anti-physiological event throughout the sample? Because it would mean that normally in orthostatic we have the internal jugular closed;
5. Why are not reported the venographic results of the azygos vein? They have not even found one lesion on this vessel?
6. The abnormal collaterals were not to our knowledge still encoded by a consensus (they identify the number and caliber: if one is present must be of a size at least 50% greater than the vessel near, if two or more even if they have a smaller caliber vessel near side are pathological;
7. They do not relate the amount of contrast medium injected, but only the pump flow ml/sec (missing for many seconds is the duration of infusion), do not say if this amount was the same in subjects with MS and in those of control or if it is changed in the same subject or in different spots and possibly why;
8. Given the very high position of the catheter should be discarded as parameters of the study both collateral circulation and reflux otherwise always visible if the pressure and the amount of contrast is higher than the pressure of the outflow known in the sample examined, the one studied in supine position, is almost 0;
9. At what stage of respiration was injected contrast after inspiration or expiratiion and was performed at the same stage in all patients?
10. In which position of the head were performed contrastographic spots? In the same position on all vessels? And if rotation of the head in which, intra or extra rotation, with respect to the vessel in question? See our publication on the compression of the jugular veins; 2
11. What radiographic have used the anteroposterior, lateral, both etc?;
12. Why were not reported pressure measurements? They do not report as have been performed, even monitoring during the inspiratory-expiratory cycle?
13. This paper takes account of the hemodynamic events of phlebographic examination narrowing with abnormal flow and those morphological narrowing unreliable because not yet defined for venography. Also the narrowing >50% can go from 51 to 99% with a completely different hemodynamic impact. In the paper have not been stratified ranges for example up to 80% and over 80%. The altered discharge of the contrast medium with a delay time greater than 4 seconds is present on an internal jugular in 89% of patients with MS and in only 5% of the controls. 3 Furthermore, in the recent study from Manconi on the respiratory index (ROC curve 97%) positive test (which corresponds to a hindered discharge vessel) is 4 times greater in subjects with MS compared to healthy ones); 4
14. We judged on haemodynamically significant narrowing to be present if at least one of the following was recorded: reflux persistent retrograde flow of most of the contrast bolus after injection was completed); stasis (contrast was present 4s after the injection); or abnormal collaterals (one or blackberries vessels >50% the size of the adjacent primary vessel, or two or will more collateral vessels present at <50% the size of the adjacent primary vessel).
In this study were placed on the same level three completely different hemodynamic conditions and were not differentiated in the statistical evaluation. Making this soup a normal subject with reflux was equated to one that has both stasis, both reflux and collateral circulation!!!!! See Table 2;
15. The results of table 6 indicate that stenosis >50% is an unusable data as always present in equal measure (74%) in subjects positive at ultrasound (CCSVI present) than negative (CCSVI absent); the serious thing of this unification that are grouped in CCSVI positive subjects with MS, siblings and normal subjects that have almost the same percentage of 40% (see Table 4) and the same is done to form the negative group: this is a pretty tricksy! Statistically;
16. Where were detected stenosis in J1, J2 or J3?
17. There have been differentiated anatomical stenosis from those compressive extravascular?
18. With a mean disease duration of 13 years is statistically impossible to have an EDSS of 2.7 (in our sample of about 1000 patients with a mean duration of 12.6 years, we have 4.5 of EDSS);
19. The criteria used to evaluate the CCSVI score appear to be those of 2009; why they have not used up to date versions of the International Consensus of 2011? 5
20. The literature data tell us that the morphological lesions stenosis venographic (not those US because do not find?!?!?!) examined and evaluated have no value if they are not associated with a hemodynamic effect of contextual obstacle at vessel outflow (delay time greater than 4 sec). Also there can be many false negatives because analyzing habitually anteroposterior if the vessel is compressed on this plane contrast fills equally around the lumen and stenosis is undetectable and only the annular stenosis are always visible;
21. They claim that venography is the gold standard, however, after discarding those orthostatic;
22. They have detected a significant inter-observer variability between centers involved in the study also took good for all data;
23. They preliminary matter that the study was done on three centers except merge two together in the final examination of the data; what would change from statistical point of view, keeping it separate?
24. Where they found all these healthy and asymptomatic who have come to make a venography? They paid and who paid for them has a conflict of interest?

Statistical considerations

25. Given the multiplicity of variables (and the inherent variability of the individual variables), the sample should be larger. At least twice that used;
26. There is no study of the quality of the data collected in most centers. It is not specified whether the equipment were the same and as they were calibrated. In a study of such structure would have to apply a meta-analysis and not simple tests of analysis of variance after forced amalgamation of data from different centers;
27. There is no study on the proper randomization before the study. Changes related to sex and age alone suffice to require such analysis;

Ratings on the Abstract

28. Interpretation at the end of the abstract that Chronic cerebrospinal venous insufficiency occurs rarely in both patients with multiple sclerosis and in healthy people is false!!! because in table 3 is present in 44% in those with MS and 37% in healthy people. That narrowing >50% is very frequent (74%) both in patients with sclerosis and in healthy only indicates that it is not a valid criterion to differentiate the two groups and was not to be used as discriminating. They have missed the aim of the study who wanted to investigate whether the blocking of the veins was specific to the Multiple Sclerosis as it has not been studied blocking of the venous drainage with ultrasound (found in 8%) and the one with venography in the two groups, but rather the stenosis that in ultrasound was never identified as such but simply as anomalies within the vessel and in venography as stenosis >50% which as we have previously reported is not a hemodynamic parameter, but morphological and frequently reflected in both healthy subjects and multiple sclerosis. Moreover stenosis >50% associated with hemodynamic abnormalities reported in the study was a soup of three hemodynamic conditions of which the one valid definition to be used by itself (delay time >4 sec) was not considered.


References

  1. Traboulsee AL, Knox KB, Machan L, et al. Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their sibilings, and unrelated healthy controls: a blinded, case control study. Lancet 2014;383:138-45.[Crossref] [Pubmed]
  2. Mandolesi S, Manconi E, Niglio T, et al. Incidence of anatomical compressions of the internal jugular veins with full block of their flow in patients with chronic cerebro-spinal venous insufficiency and multiple sclerosis. In: Allegra C, Antignani PL, eds. Proc. 21st EUROCHAP-IUA - European Chapter Congress of the International Union of Angiology. Sept 28-Oct 1, 2013, Rome, Italy. Turin: Ed. Minerva Medica; 2013. pp 12-17. Available from: http://wm7.email.it/webmail/wm_5/redir.php?http://filesformailing.minervamedica.it/volumi/EUROCHAP.pdf
  3. Veroux P, Giaquinta A, Perricone D, et al. Internal jugular veins out flow in patients with multiple sclerosis: a catheter venography study. J Vasc Interv Radiol 2013;24:1790-7.[Pubmed]
  4. Cadeddu F. Fisiologia e fisiopatologia della insufficienza venosa cerebrospinale: proposta di nuovi criteri diagnostici. Tesi di dottorato. Università di Cagliari; 2014. Available from: http://veprints.unica.it/960/1/PhD_Thesis_Cadeddu.pdf
  5. Zamboni P, Morovic S, Menegatti E, et al. Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound-recommendations for a protocol. Int Angiol 2011;30:571-97. Erratum in: Int Angiol. 2012;31:201.[Abstract] [Pubmed]

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