CCSVI not associated with HLA DRB1*1501 status?

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

Postby Cece » Tue Feb 15, 2011 8:33 pm

I agree with Cheer that the title is at odds with the content of the research.

I find this abstract to be a bit misleading. There was a correlation with HLA frequency in MS and CCSVI ....53% in MS and around 40% in CCSVI. What I find incredibly odd is that the HLA % is HIGHER in controls (32%) than CCSVI is in controls (21%)...yet they have no problem stating the HLA is associated with MS, but CCSVI is not (?)

The title of the abstract is CCSVI is NOT associated with HLA DRB 1501 status
Cece
Family Elder
 
Posts: 8989
Joined: Mon Jan 04, 2010 4:00 pm

Advertisement

Postby smokey » Tue Feb 15, 2011 10:53 pm

Thanks Cheer. I was puzzling over the results. I read the paper and just couldn't make sense of the conclusion. Very strange logic here.
User avatar
smokey
Family Member
 
Posts: 93
Joined: Sun Mar 21, 2010 4:00 pm

Postby ikulo » Wed Feb 16, 2011 2:22 pm

The frequency of CCSVI was higher (OR = 4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group.


I don't see what the debate is.
User avatar
ikulo
Family Elder
 
Posts: 444
Joined: Tue Aug 04, 2009 3:00 pm
Location: colorado

Postby patientx » Wed Feb 16, 2011 3:50 pm

cheerleader wrote:Here's the abstract-


Background
Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients.

Methodology/Principal Findings
This study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR = 4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group. The 51.9% frequency of HLA DRB1*1501 positivity (HLA+) in MS was higher compared (OR = 2.33, p<0.001) to 31.6% to controls. The HLA+ frequency in the non-progressive (51.6%) and progressive MS groups (52.3%) was similar. The frequency of HLA+ CCSVI+ was 40.7% in progressive MS, 27.5% in non-progressive MS and 8.4% in controls. The presence of CCSVI was independent of HLA DRB1*1501 status in MS patients.

Conclusions/Significance
The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS.


I find this abstract to be a bit misleading. There was a correlation with HLA frequency in MS and CCSVI ....53% in MS and around 40% in CCSVI. What I find incredibly odd is that the HLA % is HIGHER in controls (32%) than CCSVI is in controls (21%)...yet they have no problem stating the HLA is associated with MS, but CCSVI is not (?)

The title of the abstract is CCSVI is NOT associated with HLA DRB 1501 status
This is a very conclusive statement, for inconclusive results. And what I fear is that it will be taken as another negative study to add to the neurological pile, when actually, the information and complete paper was more nuanced than the abstract


Actually, the title of the paper is "CCSVI is NOT associated with HLA DRB 1501 status in Multiple Sclerosis Patients.". And that is exactly what the authors showed, so the abstract is not misleading. You can't just go by percentages. Using a Fisher's exact test for CCSVI/DRB1*1501 Positive correlation in the MS group, the probability is calculated to be .085. This is greater than the standard cutoff of .05. So, the authors report there is only a trend toward association. They also showed there was no correlation between CCSVI/DRB1*1501 Positive in the control group; the p-value in this case was .41, well above the .05 threshold.

There was a significant association between CCSVI and HLA DRB1*1501 status when the entire study population was considered, but if there was a correlation between CCSVI and this gene, the significance should have held within each group.
The associations between HLA DRB1*1501 status and CCSVI status were significant when the entire study population was considered (chi-square =10.3, Fisher exact test p= 0.002). However, there was no evidence for associations within the Control (chi-square = 0.88, Fisher exact test p= 0.41) sub-group and only a trend in the MS (chi-square = 3.15, Fisher exact test p= 0.085) sub-group. This suggests that the significant associations in the entire study population are largely the result of the indirect association or confounding of the HLA DRB1*1501 status and MS, which exhibits more CCSVI.
User avatar
patientx
Family Elder
 
Posts: 1066
Joined: Wed Sep 10, 2008 3:00 pm

Misleading

Postby fiddler » Wed Feb 16, 2011 4:04 pm

Hmmm... seems to me that misleading would be if the title says "not associated..." if what they really mean is that there was no certainty of association from a statistical perspective. "No certainty of" is NOT "not". Ergo, the title was misleading.
...Ted
Dx SPMS in 2004.  Liberated 29/04/2010.
My blog: www.my-darn-ms.blogspot.com
User avatar
fiddler
Family Elder
 
Posts: 398
Joined: Wed Dec 02, 2009 4:00 pm
Location: Fredericton, Canada

Postby cheerleader » Wed Feb 16, 2011 4:46 pm

Hi Patient--
I also had a problem with the conclusions section of the abstract:

Conclusions/Significance
The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS


It's actual the word caution that bugs me, it reads as a negative. Let me explain what I'm thinking.

If HLA DRB1 1501 is a susceptability gene, which is known to be related to northern European ancestry, acts as an immune system response gene, and also shown to be related to MS vis a vis a three time higher susceptability risk of contracting MS with this gene...how does the lack of "strong associations with CCSVI and HLA DRB1 1501" lead to caution in associating CCSVI in MS?

The HLA DRB1 1501 allele does not cause MS, it does not mean one with this allele will get MS. Having this allele means that the likelihood is increased. Do you see where I'm going with this.....

What if MS is a vascular condition which might secondarily activate this immune response, and people with the allele have more likelihood of this activation becoming MS? Not everyone with MS has HLA DRB 1501---actually, only 53% tested in this study had it. Isn't that an avenue which should be explored? In fact, the body of the paper goes further into the environmental and external factors related to both CCSVI and this allele....and suggests further studies need to be undertaken.

Other than the report of Ferlini et al. [13], who conducted preliminary analysis of copy number variations associated with CCSVI in a group of 15 MS patients, no information is available on the role of genetic factors in CCSVI. These authors reported that CCSVI was associated of copy number variations in the HLA region for a small group of 15 MS patients [13]. In other diseases with venous pathophysiologies, a role for gender, and environmental and genetic factors is suggested. Female gender, older age, and pregnancy are risk factors for chronic venous diseases [24] and women have greater frequency of variant hepatic veins [25]. Women have also been reported to have a smaller internal jugular vein size than men (1.48 for men vs. 1.27 in women) [26]. Venous malformations may have genetic contributions and a “double-hit” mechanism has been invoked to explain incomplete penetrance and variability [27], [28]. The R849W substitution in the angiopoietin receptor Tie2 [29], an endothelial receptor tyrosine kinase, has been linked to familial venous malformations and results in variable thickness or lack of smooth-muscle cells in the veins of patient lesions. Interestingly Tie2 activates Stat1, which is also critical in interferon signaling. We did not observe, age, gender or disease duration differences in the occurrence of CCSVI (results not shown) in MS. However, a more detailed analysis of candidate gender-dimorphic factors, e.g., vein diameters and autoimmune factors, is warranted as these could strongly interact with changes in cerebral venous outflow.


Why does the abstract take such a negative stance, when the full paper is much more neutral? That's my question. The Buffalo doctors wrote the paper....who wrote the abstract? I don't think it was the same author.
Did the editor write the abstract? Editor: Christoph Kleinschnitz, Julius-Maximilians-Universität Würzburg, Germany

Here's the full paper, see if you think the abstract is a bit more negative, patient. Am interested in your take on this--
http://www.plosone.org/article/info:doi ... ne.0016802

Or, I could be completely over-reacting...(but I don't think so)
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
User avatar
cheerleader
Family Elder
 
Posts: 5015
Joined: Mon Sep 10, 2007 3:00 pm
Location: southern California

Postby dreddk » Wed Feb 16, 2011 8:37 pm

Cheer, I think what they are trying to say (badly)is if the gene is a causal factor and ccsvi is a causal factor for ms, one would expect there to be a statistical association between the two which there is not ie if the gene is present it should be more likely that ccsvi is present as well, but it is independently associated with ms.

This to me again supports the idea that ccsvi is a symptom of ms.
Last edited by dreddk on Wed Feb 16, 2011 9:25 pm, edited 1 time in total.
User avatar
dreddk
Family Elder
 
Posts: 131
Joined: Sat Jan 20, 2007 4:00 pm
Location: South Pacific

Causes

Postby fiddler » Wed Feb 16, 2011 9:06 pm

dreddk, I can see the logic of CCSVI possibly being a cause of many MS symptoms and perhaps a primary cause of the MS "syndrome" itself, but what would be the explanation for MS causing CCSVI? Perhaps I missed some recent discussion about that since I'm not often on here anymore. Early on, just after "experts" stopped insisting that CCSVI didn't exist, some of them began saying "Well, then, maybe MS causes CCSVI", but there was never a logical explanation of how/why that could be. Do you know of something that would explain such a phenomenon?
...Ted
Dx SPMS in 2004.  Liberated 29/04/2010.
My blog: www.my-darn-ms.blogspot.com
User avatar
fiddler
Family Elder
 
Posts: 398
Joined: Wed Dec 02, 2009 4:00 pm
Location: Fredericton, Canada

Postby dreddk » Wed Feb 16, 2011 9:21 pm

Hi Ted

From the beiruit venography study

"In conclusion, we think that EVS is a late manifestation
in MS, and is unlikely to induce a state of CCSVI
since only a minority of patients has a single venous
stenosis early in the disease. It is more likely to be a
secondary phenomenon, possibly present in other neurological
diseases, reflecting chronic brain disease and
atrophy. The exact mechanism of such process is
unclear, since the extracranial venous system, especially
in the spinal cord, has never been adequately investigated
in chronic neurological diseases. We hypothesize
that chronic degenerative brain diseases resulting in significant
brain atrophy and tissue loss might lead to a
decrease in the volume of venous drainage, resulting
ultimately in venous stenosis. In MS specifically,
chronic perivenous inflammation might hypothetically
lead to release of certain inflammatory mediators that
might alter the venous endothelium or lead to venous
valvulitis resulting in venous stenosis."
User avatar
dreddk
Family Elder
 
Posts: 131
Joined: Sat Jan 20, 2007 4:00 pm
Location: South Pacific

Thanks

Postby fiddler » Wed Feb 16, 2011 10:09 pm

Thanks, I hadn't seen that before. Still, it does seem to go against some other results that say that CCSVI is congenital, and a lot of evidence that fixing CCSVI alleviates many MS symptoms. I suppose that could be some kind of vicious circle working.
...Ted
Dx SPMS in 2004.  Liberated 29/04/2010.
My blog: www.my-darn-ms.blogspot.com
User avatar
fiddler
Family Elder
 
Posts: 398
Joined: Wed Dec 02, 2009 4:00 pm
Location: Fredericton, Canada

Postby Rokkit » Thu Feb 17, 2011 8:12 am

We hypothesize
that chronic degenerative brain diseases resulting in significant
brain atrophy and tissue loss might lead to a
decrease in the volume of venous drainage, resulting
ultimately in venous stenosis.

In my case at least, the stenoses were accompanied by a robust network of collateral veins that completely resolved when the stenoses were opened. I don't see any reason to think my venous drainage had decreased.
Rokkit
Family Elder
 
Posts: 669
Joined: Tue May 19, 2009 3:00 pm

Postby cheerleader » Thu Feb 17, 2011 8:52 am

The exact mechanism of such process is
unclear, since the extracranial venous system, especially
in the spinal cord, has never been adequately investigated
in chronic neurological diseases. We hypothesize
that chronic degenerative brain diseases resulting in significant
brain atrophy and tissue loss might lead to a
decrease in the volume of venous drainage, resulting
ultimately in venous stenosis.



....and yet my husband had no brain atrophy (and still doesn't) but two severely mangled jugular veins, which his doctors have proclaimed were congenitally malformed. He lost his peripheral vision as a child, no reason ever found until now. So, in his case, his jugular damage came first. Guess he was the only one. Huh. My work is done.
But don't you think other pwMS deserve to know if their veins are malformed?

Anyway...back to the paper at the start of the thread. Does anyone else find the abstract much different from the paper?
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
User avatar
cheerleader
Family Elder
 
Posts: 5015
Joined: Mon Sep 10, 2007 3:00 pm
Location: southern California

Postby Cece » Thu Feb 17, 2011 10:06 am

cheerleader wrote:
The exact mechanism of such process is
unclear, since the extracranial venous system, especially
in the spinal cord, has never been adequately investigated
in chronic neurological diseases. We hypothesize
that chronic degenerative brain diseases resulting in significant
brain atrophy and tissue loss might lead to a
decrease in the volume of venous drainage, resulting
ultimately in venous stenosis.

This hypothesis might be convincing if you don't understand what CCSVI is.

Makes sense that neurologists do not understand what CCSVI is. It has taken our CCSVI IRs quite some time to understand it as well as they currently do and they do not yet know everything yet.

Phasic venous narrowing as a result of overall reduced blood volume is not what is going on here.
Cece
Family Elder
 
Posts: 8989
Joined: Mon Jan 04, 2010 4:00 pm

Postby patientx » Thu Feb 17, 2011 10:08 pm

cheerleader wrote:Hi Patient--

It's actual the word caution that bugs me, it reads as a negative. Let me explain what I'm thinking.

If HLA DRB1 1501 is a susceptability gene, which is known to be related to northern European ancestry, acts as an immune system response gene, and also shown to be related to MS vis a vis a three time higher susceptability risk of contracting MS with this gene...how does the lack of "strong associations with CCSVI and HLA DRB1 1501" lead to caution in associating CCSVI in MS?

The HLA DRB1 1501 allele does not cause MS, it does not mean one with this allele will get MS. Having this allele means that the likelihood is increased. Do you see where I'm going with this.....

What if MS is a vascular condition which might secondarily activate this immune response, and people with the allele have more likelihood of this activation becoming MS? Not everyone with MS has HLA DRB 1501---actually, only 53% tested in this study had it. Isn't that an avenue which should be explored? In fact, the body of the paper goes further into the environmental and external factors related to both CCSVI and this allele....and suggests further studies need to be undertaken.

No, I'm not sure I see where you are going with this, but my answer would be along the lines of what dreddk wrote - if past studies showed that MS is significantly associated with that particular gene, and CCSVI is associated with MS, then the authors probably hypothesized that CCSVI should be associated with that particular gene. Statistically they didn't find this to be the case. But the abstract didn't mention expressing "caution in associating CCSVI in MS," as you wrote. The conclusion was
...associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS

I take this to mean, they aren't saying there isn't an association between CCSVI and MS (the Buffalo doctors have asserted there is, more than once); I believe they are saying that there's not enough evidence to say that CCSVI causes MS (at least based on this one study). Again, this is along the lines of what dreddk wrote.

Why does the abstract take such a negative stance, when the full paper is much more neutral? That's my question.

That was the conclusion the authors reached; I guess you would have to take that up with them. I don't see it as being overly negative.

The Buffalo doctors wrote the paper....who wrote the abstract? I don't think it was the same author.
Did the editor write the abstract? Editor: Christoph Kleinschnitz, Julius-Maximilians-Universität Würzburg, Germany

I asked a few people who have written articles for technical and scientific journals about the publication process. They all told me that one or more of the authors writes the abstract. One thing is almost undoubtedly true - the editor did not write any part of the abstract or paper. The editor of the journal may suggest changes, outright reject a submitted article, or cut the length - but he will not change the content without the author's knowledge.
User avatar
patientx
Family Elder
 
Posts: 1066
Joined: Wed Sep 10, 2008 3:00 pm

Postby patientx » Thu Feb 17, 2011 10:12 pm

dreddk wrote:Cheer, I think what they are trying to say (badly)is if the gene is a causal factor and ccsvi is a causal factor for ms, one would expect there to be a statistical association between the two which there is not ie if the gene is present it should be more likely that ccsvi is present as well, but it is independently associated with ms.

This to me again supports the idea that ccsvi is a symptom of ms.

Dreddk:

I don't know if you've had a chance to read the full article, but you might find this passage interesting:
Additionally, CCSVI positivity appeared associated with progressive forms of MS but we did not obtain evidence that HLA DRB1*1501 positivity was associated with progressive forms of MS in our sample. The exact reasons for the associations between CCSVI and progressive forms of MS are not known: only prospective longitudinal studies can address whether the associations are the result of CCSVI modifying disease progression or alternatively, because CCSVI is secondary to the underlying inflammatory/degenerative disease processes.
User avatar
patientx
Family Elder
 
Posts: 1066
Joined: Wed Sep 10, 2008 3:00 pm

PreviousNext

Return to Chronic Cerebrospinal Venous Insufficiency (CCSVI)

 


  • Related topics
    Replies
    Views
    Last post

Who is online

Users browsing this forum: No registered users