Normal CSF ferritin levels suggest against ccsvi cause of ms

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Normal CSF ferritin levels suggest against ccsvi cause of ms

Postby dreddk » Fri Oct 01, 2010 9:30 pm

From Neurology journal.

Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency

Objectives: Chronic cerebrospinal venous insufficiency (CCSVI) has been suggested to be a possible cause of multiple sclerosis (MS). If the presumed mechanism of venous stasis–related parenchymal iron deposition and neurodegeneration were true, then upregulation of intrathecal iron transport proteins may be expected.

Methods: This was a cross-sectional (n = 1,408) and longitudinal (n = 29) study on CSF ferritin levels in patients with MS and a range of neurologic disorders.

Results: Pathologic (>12 ng/mL) CSF ferritin levels were observed in 4% of the control patients (median 4 ng/mL), 91% of patients with superficial siderosis (75 ng/mL), 73% of patients with a subarachnoid hemorrhage (59 ng/mL), 10% of patients with relapsing-remitting MS (5 ng/mL), 11% of patients with primary progressive MS (6 ng/mL), 23% of patients with secondary progressive MS (5 ng/mL), and 23% of patients with meningoencephalitis (5 ng/mL). In MS, there was no significant change of CSF ferritin levels over the 3-year follow-up period.

Conclusion: These data do not support an etiologic role for CCSVI-related parenchymal iron deposition in MS.
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Postby cheerleader » Sat Oct 02, 2010 7:48 am

Interesting, dreddk, thanks for positing
Here is the link to the abstract mentioned above:

link
again, a study undertaken by neurologists, not venous specialists. They are looking at the wrong measure of CHRONIC venous disease. Ferritin is a good marker for a one time vascular insult of the brain, like a stroke--but NOT for ongoing venous disease.

Dr. Zamboni addresses ferritin and its role in chronic venous disease in his paper: The Big Idea: Iron-dependent inflammation in venous disease and proposed parallels in MS-
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/

The ferritin levels in CSF would not be indicative of the process he describes in venous disease. It is about the change of ferritin to hemosiderin. In fact, it was the testing of urine levels of hemosiderin that confirmed this for Dr. Zamboni in 2002, when he noted high levels of hemosiderin in patients with chronic venous disease of the legs, and in pwMS.

The origin of increased leg iron stores is extravasation of red blood cells (erythrocytes) in conditions of significant venous stasis. Erythrocytes are degraded by the interstitial macrophages, with the released iron incorporated into ferritin. Over time, with increasing overload of iron, the structure of ferritin changes to haemosiderin.4-9 In 1988, Ackermann found a twenty-fold higher average concentration of iron in lower limbs affected by venous ulcers as compared to the upper arm of the same subjects.8 The phenomenon of leg haemosiderin deposits seems to be significant for the entire body, since this protein has been demonstrated in the urine of patients affected by CVD.9


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Postby Rokkit » Sat Oct 02, 2010 7:56 am

cheerleader wrote:again, a study undertaken by neurologists, not venous specialists. They are looking at the wrong measure of CHRONIC venous disease. Ferritin is a good marker for a one time vascular insult of the brain, like a stroke--but NOT for ongoing venous disease.

Dr. Zamboni addresses ferritin and its role in chronic venous disease in his paper: The Big Idea: Iron-dependent inflammation in venous disease and proposed parallels in MS-

Great. So how does a paper like this get published? What exactly is this so-called peer review process? Because it's starting to seem more like a kangaroo court.
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Postby cheerleader » Sat Oct 02, 2010 8:02 am

Rokkit wrote:Great. So how does a paper like this get published? What exactly is this so-called peer review process? Because it's starting to seem more like a kangaroo court.


Here's the kicker. Rokkit...it was submitted in April, published in JUNE...these are the fastest turn around times ever noted in medical publishing. And they're looking at the wrong markers for chronic venous disease and getting published. yikes.
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Postby sbr487 » Sat Oct 02, 2010 8:08 am

Rokkit wrote:Great. So how does a paper like this get published? What exactly is this so-called peer review process? Because it's starting to seem more like a kangaroo court.


Rokkit, scientific journals are for people to publish their findings, theories, ideas, so long as there are no basic flaws. Science simply evolves, hopefully leaving behind things that do not work, and refining what works. No peer review can validate a theory in one go.

For example, there is a school of thought that HIV does not cause AIDS. The authors of these paper do make some valid points. Whether one agrees with these points or not, the paper needs to be published.
A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it
- Max Planck
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Postby cheerleader » Sat Oct 02, 2010 9:28 am

sbr487 wrote:Rokkit, scientific journals are for people to publish their findings, theories, ideas, so long as there are no basic flaws. Science simply evolves, hopefully leaving behind things that do not work, and refining what works. No peer review can validate a theory in one go.


Absolutely right...but the problem with many of these papers that have been published very quickly is that they are not studying the correct vascular mechanism and coming to erroneous conclusions--ie: the Doepp German doppler tests (which actually proved CCSVI in MS), which Dr. Zamboni is addressing in a soon to be published response. And then this study, which is looking at a marker for a venous infarction, rather than a chronic venous disorder. The problem is that these negative studies are picked up by other journals and the press as conclusive proof there is no CCSVI, when they are not looking at the right indicators. These studies are not being completed by venous specialists and they are not peer-reviewed by venous specialists.

There are very basic flaws in methodology. If another specialty (neurology) is going to study a very specific vascular disorder, shouldn't they at least know what to look for, and ask venous specialists? Like Dr. Byung B. Lee or any of the other 47 specialists that classified CCSVI lesions as truncular venous malformations?
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Last edited by cheerleader on Sat Oct 02, 2010 9:44 am, edited 1 time in total.
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Postby sbr487 » Sat Oct 02, 2010 9:43 am

cheerleader wrote:Absolutely right...but the problem with many of these papers that have been published very quickly is that they are not studying the correct vascular mechanism and coming to erroneous conclusions--ie: the Doepp German doppler tests (which actually proved CCSVI in MS), which Dr. Zamboni is addressing in a soon to be published response. And then this study, which is looking at a marker for a venous infarction, rather than a chronic venous disorder. The problem is that these negative studies are picked up by other journals and the press as conclusive proof there is no CCSVI, when they are not looking at the right indicators. These studies are not being completed by venous specialists and they are not peer-reviewed by venous specialist. So, these are very basic flaws in methodology.
cheer


I agree with everything you said, Cheer. I was trying to reiterate the role of peer review, though I am am sure Rokkit already knows these pretty well ...

In a way its good that these people who are in a hurry to disprove CCSVI are not filling the holes properly and are leaving trail behind. I hope one day the same papers go on to form legal noose around these egoistic group ... these are the guys we are depending on to find solution for MS ... God help us ...
A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it
- Max Planck
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Postby Rokkit » Sat Oct 02, 2010 10:01 am

cheerleader wrote:Absolutely right...but the problem with many of these papers that have been published very quickly is that they are not studying the correct vascular mechanism and coming to erroneous conclusions

Yes, this is what I'm not understanding. When a paper comes along addressing a straw man instead of Zamboni's actual hypothesis, the peer review process should be catching it, but it's not. I don't really care if it's due to lack of knowledge or conspiracy, it's a broken system.
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Postby Lyon » Sat Oct 02, 2010 10:30 am

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Postby ikulo » Sat Oct 02, 2010 11:23 am

Lyon - I suppose you would have asked for a double-blind placebo study done by Americans to confirm your suspicions that the watch was indeed not a Rolex? :)

Again, the truth is likely much more complicated than just one study. Here are some studies that found higher levels of ferritin in csf of progressive forms of ms, mainly SPMS. I wonder if this could help explain the ineffectiveness of DMDs on progressive forms...?

http://brain.oxfordjournals.org/content/125/7/1462.full

Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations

Disease progression in multiple sclerosis occurs within the interface of glial activation and gliosis. This study aimed to investigate the relationship between biomarkers of different glial cell responses: (i) to disease dynamics and the clinical subtypes of multiple sclerosis; (ii) to disability; and (iii) to cross‐validate these findings in a post‐mortem study. To address the first goal, 51 patients with multiple sclerosis [20 relapsing remitting (RR), 21 secondary progressive (SP) and 10 primary progressive (PP)] and 51 neurological control patients were included. Disability was assessed using the ambulation index (AI), the Expanded Disability Status Scale score (EDSS) and the 9‐hole PEG test (9HPT). Patients underwent lumbar puncture within 7 days of clinical assessment. Post‐mortem brain tissue (12 multiple sclerosis and eight control patients) was classified histologically and adjacent sites were homogenized for protein analysis. S100B, ferritin and glial‐fibrillary acidic protein (GFAP) were quantified in CSF and brain‐tissue homogenate by ELISA (enzyme‐linked immunosorbent assay) techniques developed in‐house. There was a significant trend for increasing S100B levels from PP to SP to RR multiple sclerosis (P < 0.05). S100B was significantly higher in RR multiple sclerosis than in control patients (P < 0.01), whilst ferritin levels were significantly higher in SP multiple sclerosis than in control patients (P < 0.01). The S100B : ferritin ratio discriminated patients with RR multiple sclerosis from SP, PP or control patients (P < 0.05, P < 0.01 and P < 0.01, respectively). Multiple sclerosis patients with poor ambulation (AI ≥7) or severe disability (EDSS >6.5) had significantly higher CSF GFAP levels than less disabled multiple sclerosis or control patients (P < 0.01 and P < 0.001, respectively). There was a correlation between GFAP levels and ambulation in SP multiple sclerosis (r = 0.57, P < 0.01), and between S100B level and the 9HPT in PP multiple sclerosis patients (r = –0.85, P < 0.01). The post‐mortem study showed significantly higher S100B levels in the acute than in the subacute plaques (P < 0.01), whilst ferritin levels were elevated in all multiple sclerosis lesion stages. Both GFAP and S100B levels were significantly higher in the cortex of multiple sclerosis than in control brain homogenate (P < 0.001 and P < 0.05, respectively). We found that S100B is a good marker for the relapsing phase of the disease (confirmed by post‐mortem observation) as opposed to ferritin, which is elevated throughout the entire course. GFAP correlated with disability scales and may therefore be a marker for irreversible damage. The results of this study have broad implications for finding new and sensitive outcome measures for treatment trials that aim to delay the development of disability. They may also be considered in future classifications of multiple sclerosis patients.




Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients.

MS patients with active or stable relapsing-remitting disease had ferritin levels that were comparable to those found in normal individuals. There were no significant differences in transferrin or iron levels in the CSF between MS and normal individuals. Both ferritin and transferrin levels were elevated in patients that had high CSF IgG values but not in patients with a high IgG index. Since ferritin binds iron, the increase of CSF ferritin levels in chronic progressive MS patients could be a defense mechanism to protect against iron induced oxidative injury. Ferritin levels could be a laboratory measure that helps to distinguish between chronic progressive and relapsing-remitting MS.
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Postby Lyon » Sat Oct 02, 2010 12:29 pm

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Postby cah » Sat Oct 02, 2010 1:01 pm

Lyon wrote:...

Therefore my question/point "is it really wise to ask the guy selling the Rolex how to tell a real from a fake?" and who is REALLY to blame for follow up researchers not wanting to consult with the salesman?


Lyon, I think your analogy is not exact. The exact question would be:"Is it wise to ask anyone who can read the clock how to tell real from fake?" That's the case if you ask neurologists about venous conditions. They could have at least asked another watchmaker - another interventional radiologist or vaskular expert.

Having said that, I must say that I'm fine with these publications. If someone disproves a theory and it can be shown that he used the wrong methodology, it in the end contributes to proving the theory. Knowing what CCSVI is not is almost equally important to knowing what CCSVI is, I think.

Edit: Cheerleader is right that it could be a problem what the media makes out of it. But that really shouldn't bother science, should it?
"There is only one good, knowledge, and one evil, ignorance." Socrates
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Postby cheerleader » Sat Oct 02, 2010 1:11 pm

Ikulo--that's a terrific study you found. It had a much larger sample size and also tested autopsy brains, where the highest levels of ferritin were detected in autopsy gray matter of MS brains. And there was lots and lots of ferritin found in lesions and even normal appearing white matter in MS brains as compared to controls. The living patients had CSF tested, and there was a correlation with higher ferritin levels and SPMS.

But Dr. Zamboni's testing method is so much easier---look for hemosiderin in urine in MS patients...how hard is this to replicate? Hand out the paper cups.

Bob, your rolex comment makes no sense. There are no salesmen here, unless you consider Dr. Rohit Bakshi of Harvard the latest salesman (see the thread on his recent visit to Ferrara). Or Dr. Mark Haacke, or Dr. Zivadinov or any of the other neuroimaging specialists who are coming forward saying there is iron deposition in MS brains and it could very well be linked to CCSVI.
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Postby cah » Sat Oct 02, 2010 2:34 pm

Sometimes I really feel sorry for those who do these pathetic attempts to disprove the CCSVI theory, being easily rebutted by laypersons with no other special skill than the ability to use google and read. :D
"There is only one good, knowledge, and one evil, ignorance." Socrates
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Postby ikulo » Sat Oct 02, 2010 2:37 pm

[quote="Lyon]

In situations other than CCSVI, is it normal for researchers trying to replicate the results of a prior researcher to consult with that researcher? I have almost full access to the peer reviews and have spent the last several years reading them and, although I'm sure it does happen, I've never seen mention of a replicating researcher consulting with or taking lessons from the prior researcher.

Admittedly that's because original researchers go to extreme effort in their articles to identify their every step and method so that their work can be replicated.

Whether it's true or not I'm not able to say but with CCSVI it's claimed to be so complicated that you need to be trained by Zamboni and use his machine to replicate the results.[/quote]

Isn't the venogram really the best way to determine if someone has CCSVI? I could be wrong, but is anyone besides the Zamboni team even using his doppler technology to diagnose? (I'm genuinely curious).

There is no avoiding the fact that this is a highly unusual situation and no one can blame researchers attempting to replicate for trying to make due on their own.

Therefore my question/point "is it really wise to ask the guy selling the Rolex how to tell a real from a fake?" and who is REALLY to blame for follow up researchers not wanting to consult with the salesman?


It seems to me that the critical researchers never consulted Zamboni, never fully understood the research, and are now trying to disprove his theory based on peripheral issues such as ferritin levels. If you really want people to take notice of critical research, perhaps it should not be done in such an adversarial way. The point is to FURTHER research, not to hinder it.

And certainly, if anyone in this CCSVI world comes off looking like a cheap salesman it's the authors behind the hitman-like studies that come out blasting CCSVI. It's clear that their hubris outweighs their objectivity. Instead of trying to examine CCSVI as a possible piece of an incomplete and mysterious puzzle, they effectively dismiss the piece with prejudice.

Regarding the rolex... I wouldn't ask the homeless man selling the Rolex how to tell a real from a fake. I also wouldn't ask the other homeless man who doesn't even know what a Rolex is. I would definitely ask the guy who created it.
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