ECTRIMS Cleveland Autopsy Study-jugular VMs in pwMS

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Re: ECTRIMS Cleveland Autopsy Study-jugular VMs in pwMS

Postby Cece » Fri Oct 28, 2011 4:58 pm

http://www.nejm.org/doi/full/10.1056/NE ... 5243442106
We found little evidence in general that placebos had powerful clinical effects. Although placebos had no significant effects on objective or binary outcomes, they had possible small benefits in studies with continuous subjective outcomes and for the treatment of pain. Outside the setting of clinical trials, there is no justification for the use of placebos.
A meta-analysis of 114 trials found little evidence of placebo effect.

The powerful placebo effect: fact or fiction?

Henry Beecher, who invented the placebo effect, has had his own studies reanalyzed years later, to the conclusion that there was no placebo effect in Beecher's studies.
http://www.ncbi.nlm.nih.gov/sites/entre ... xed=google

And in MS studies, the patients chosen tend to be those with very active disease, who are then likely to "regress to the mean." This regression, which is a reduction in number of lesions to the more usual number, gets counted as placebo when it is a result of the design of the study.
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Re: ECTRIMS Cleveland Autopsy Study-jugular VMs in pwMS

Postby Cece » Sun Dec 04, 2011 8:37 pm

Wheelchair Kamikaze offers his analysis on what the Cleveland Clinic autopsy study findings might mean ...
http://www.wheelchairkamikaze.com/2011/ ... s-and.html

The unique aspect of this study is that investigators were actually able to hold and examine the veins in question, the only imaging technology utilized being the ever trusty human eye (presumably aided by some type of optical magnification).

Although quite small, limited to only 13 subjects, the study hints at some rather dramatic trends (click here). The researchers looked at the veins of 7 MS and 6 non-MS subjects, and found a variety of structural abnormalities and anatomic variations. Interestingly, vein wall stenosis (narrowing) occurred in equal numbers among the MS and non-MS samples. More prevalent in the MS veins, though, were abnormalities involving malformed valves and anomalous membranes (structures such as webs and septums that shouldn't be there) which could lead to disrupted blood flow. These types of abnormalities would be difficult to spot using noninvasive imaging methods, casting further doubt on studies reliant strictly on traditional MRV in particular, and also Doppler sonography unless the operators were well-versed in protocols specifically designed reveal such anatomic irregularities.

The findings of this study, if borne out by future, larger investigations, could shed light on the wide disparity in benefit (or, often, lack of benefit) experienced by those who have undergone CCSVI venoplasty (click here for a terrific discussion of this, written by Julie Stachowiak of about.com). Many CCSVI treatment procedures, especially those done within the first year or so after knowledge of CCSVI hit the mainstream MS population, concentrated primarily on areas of venous narrowing, which the Cleveland Clinic findings suggest are not as abnormal as first thought. Since these narrowings were seen in equal numbers among MS and non-MS subjects, they may fall within the parameters of normal anatomic variation, and have little actual significance.

The high prevalence of malformed or misplaced valves and other anatomic structures within the veins of MS patients, on the other hand, could very well prove to have considerable import. Although the goal of CCSVI treatment has in large part shifted away from simply expanding narrowed veins and moved more towards clearing malformed or otherwise broken valves, aberrant membranes would in many cases be difficult to treat using the balloon venoplasty techniques currently employed to address CCSVI. In theory, some of these treatments may have coincidentally alleviated the effects of such abnormal membranes by disrupting them and compressing them against the vein walls of treated patients. If this were the case, and these membranes eventually returned to their original form, this might explain the far too common phenomenon of restenosis experienced by patients treated for CCSVI. The failure to properly treat malformed valves and abnormal and misplaced membranes within the veins might also explain the failure of CCSVI treatment to significantly benefit many of those who have undergone treatment. This of course assumes that the MS-CCSVI link exists, which despite a growing body of anecdotal evidence, still needs to be confirmed by scientifically robust studies.

Did I over-quote? There's more where that came from.
Even before the CCSVI investigators knew they were treating the valves, they were treating the area of the valves, since that is where the narrowing was. This was true of Dr. Zamboni and Dr. Sclafani, certainly.

That these types of abnormalities would be difficult to spot with the imaging methods (doppler ultrasound, MRV, and sometimes even phlebography fails when not coupled with IVUS) is a significant point, after all the disparity seen in imaging studies.

I would definitely like to see larger future studies of this nature.
Consider this a plug too for Wheelchair Kamikaze's blog. Well worth the read.
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Re: ECTRIMS Cleveland Autopsy Study-jugular VMs in pwMS

Postby cheerleader » Mon Dec 05, 2011 10:20 am

Thanks, Cecel. WK does an excellent job, once again, of summarizing the research--his blog is a must-read.
Here's the Georgetown University explanation of what Case Western and the Cleveland CLinic found in the autopsied veins from pwMS....inverted valves, septums, webs, truncular venous malformations.

The Geogetown team says that these findings are the KEY to understanding CCSVI in MS. Their word in the title of the paper, not mine.
http://www.avidsymposium.com/pdf/vei/4772.pdf
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: ECTRIMS Cleveland Autopsy Study-jugular VMs in pwMS

Postby Cece » Sun Sep 16, 2012 9:13 pm

http://www.ingentaconnect.com/content/m ... 8/art00010
A technical approach to dissecting and assessing cadaveric veins pertinent to chronic cerebrospinal venous insufficiency in multiple sclerosis

Authors: Diaconu, Claudiu I1; Staugaitis, Susan M2; Fox, Robert J3; Rae-Grant, Alexander3; Schwanger, Cynthia3; McBride, Jennifer M1

Source: Neurological Research, Volume 34, Number 8, October 2012 , pp. 810-818(9)

Abstract:
Objective: To establish a detailed technical procedure for studying the anatomical correlates of chronic cerebrospinal venous insufficiency in cadavers of multiple sclerosis and control subjects, and to present our findings of the normal anatomic venous structures, with reference to previous descriptions from the literature.

Methods: This study examined the internal jugular veins (IJVs), the brachiocephalic veins, and the azygos vein from 20 cadavers (10 control and 10 multiple sclerosis). These veins were exposed, isolated by clamps from the rest of the venous system, flushed with water, and then injected with fluid silicone from the superior ends of both IJVs. After the silicone cured to its solid state, the venous tree was removed en bloc and dissected longitudinally to expose the luminal surface. All vein segments were analyzed for anatomic variation. Anatomical analysis for this manuscript focused on normal vein architecture and its variants.

Results: Thirty-seven of 40 IJVs contained valves: 29 bicuspid, 6 tricuspid, and 2 unicuspid. The average circumferences of the right and left IJVs were 2·2 and 1·8 cm, respectively. Thirteen of 20 azygos veins contained a valve, located on average 3·6 cm away from the superior vena cava junction. Nine of the 13 azygos valves were bicuspid; four were tricuspid. Only one of the 40 brachiocephalic veins contained a valve.

Discussion: We detailed a technical approach for harvesting cadaveric neck and thoracic veins with relevance to chronic cerebrospinal venous insufficiency. The anatomy of the venous system has significant variability, including differing number of valves in different regions and variable characteristics of the valves. Average vein circumference was less than that typically reported in imaging studies of live patients.

Technical details of how the autopsy specimens were prepared. There was a concern raised previously that the use of the silicone to harden these veins might hide the abnormal fixedness of the valves. But I don't know how else the specimens could be prepared.
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Re: ECTRIMS Cleveland Autopsy Study-jugular VMs in pwMS

Postby Cece » Mon Mar 04, 2013 7:28 pm

Elsewhere on the internet, I had the opportunity to pose questions to Dr. Fox about his autopsy study. Here are the questions I came up with:
Ok here are my best questions.

Since the jugular veins were prepared for the study in a fixing material, how does that affect the ability of the researchers to see if the venous valve leaflets are stiff and unable to move? Could the silicon used to fix them hide the abnormality? Is there any other way to prepare them?

Will your autopsy research continue beyond the ten MS patients and ten healthy controls currently studied? Are you interested in looking at any differences in intraluminal abnormalities between different subtypes of MS or different durations of MS?

Your abstract conclusion stated that, "Although vein wall stenosis occurred at similar frequency in MS and non-MS controls, the frequency of intraluminal abnormalities with possible hemodynamic consequences was higher in MS patients compared to healthy controls." Can these intraluminal abnormalities be reliably identified noninvasively using Doppler ultrasound? Should there be imaging studies done that ignore vein wall narrowing and look only for these intraluminal abnormalities?

Dr. Fox has finished his responses to the questions but we won't get them until after the AAN conference later this month, which makes me think that he may include information about his AAN abstract: http://www.neurology.org/cgi/content/me ... 007246a612
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Re: ECTRIMS Cleveland Autopsy Study-jugular VMs in pwMS

Postby cheerleader » Tue Mar 05, 2013 8:36 am

Cece---

From the abstract you linked above....The liquid silicone was poured inside the veins, to make a model of the inside of the veins.

After the silicone cured to its solid state, the venous tree was removed en bloc and dissected longitudinally to expose the luminal surface. All vein segments were analyzed for anatomic variation. Anatomical analysis for this manuscript focused on normal vein architecture and its variants.

http://www.ncbi.nlm.nih.gov/pubmed/22971470

So what the silicone did was give a negative, or relief, model of the vein and valve, and then it was removed in a whole piece, after the vein was bissected, renedering the valve useless to study any further. And as you well know, the impact of these valves and whether or not they were fixed or malfunctioning can only be seen in a living person, with actual blood flow.

I am very concerned that we have not heard any more from Claudiu Diaconu, the Case Western medical student who first proposed this study and method, since his presentation at ECTRIMS in 2011. No more publications, nothing more on his work at Case Western. This seems very odd for such a talented medical student. When he made his research proposal, it was picked up by the MS Society, and Dr. Fox was put on as the head of the study.

Claudiu Diaconu first presented his research proposal to study CCSVI in November 2010 at the Lepow Day at Case Western. This is a yearly event, where medical students present their research projects. Diaconu's was called: An Assessment of Chronic Cerebrospinal Venous Insufficiency -Tissue Analysis of the Cerebrospinal Veins. His study was later funded with a grant from the NMSS.

In his proposal, Diaconu set out how he would harvest the autopsied veins and inject them with a silicone gel in the lab, so that the interior of the vein could be studied. This was one part of his study, which also included doppler ultrasound and MRV assessment of CCSVI.

https://www.facebook.com/note.php?note_ ... 5965972211

I hope you get some answers from Dr. Fox!
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Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: ECTRIMS Cleveland Autopsy Study-jugular VMs in pwMS

Postby Cece » Tue Mar 05, 2013 12:33 pm

In the autopsy study abstract, the authors mention that the next step is histological tissue analysis of the veins. That's been done in Italy and it turned up abnormalities in collagen in the MS veins, so I am hoping that Claudiu Diaconu et al. replicate these findings.

I feel like an idiot trying to understand just what was done with these autopsied veins and the silicon. Your explanation helps, thank you.
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