The wane in veins draining the brain

July 12, 2009 7:34 PM

A quiet revolution is taking place in the multiple sclerosis community. Long thought of as purely an autoimmune disease, possibly secondary to Epstein-Barr virus infection or even an STI, MS has never been pinned down to a single cause. Now things are changing, in a big and bloody way: MS appears to be related to abnormalities in veins.

In December 2008, Italian researchers reported that the vast majority of 65 MS patients studied, and none of the 235 controls, had significant abnormalities in the veins draining the brain. While it's too early to conclusively identify this as the cause, rather than an effect, of MS, patient forums have been abuzz with talk of this discovery and the ensuing positive experiences of MS patients who have had stents placed to alleviate venous stenoses.

Of course, no new discovery would be complete without word from the non-conventional medical community. The proponents of Inclined Bed Therapy -- raise the head of your bed by six inches, cure all ills! -- are already using this news as justification for their claims.

posted by greatgefilte (48 comments total)

This is pretty remarkable. However, it doesn't appear to explain the geographical distribution - particularly the fact that if you move to an area before you're 15, you then acquire the disease risk associated with that area rather than your native region.
posted by dilettante at 7:42 PM on July 12, 2009 [4 favorites]

Well, couldn't there be an environmental cause that causes the vein change, which causes the MS?

Not saying that's the truth, just that it's conceivable.
posted by Malor at 7:46 PM on July 12, 2009

Fascinating! A friend called me from Wales today asking if I could research MS because a friend has recently been diagnosed with it. I'll pass this info on. Thanks for the interesting post.
posted by nickyskye at 7:50 PM on July 12, 2009

how can this be a cause? Like you're just born with bad veins, it happens in the womb or something?

I mean, this is interesting, but I don't understand how it gives us info on pathogenesis specifically... We already know it's related to myelin in the brain and spinal cord, for instance - that hasn't helped us figure out what causes it...

Still, thanks for the info.
posted by mdn at 7:54 PM on July 12, 2009

mdn, there are lots of possible theories. Blood could be pooling in the cranial veins and noxious stuff could be building up or leaking out, thus causing the auto-immune reaction. The blood flow could be turbulent in areas of blockage, which could damage the walls of the vessels. Have a look at the letters submitted in response to the original article.
posted by greatgefilte at 8:03 PM on July 12, 2009

This is fascinating. My sister in law suffers from MS... I'll have to pass this her way.

Thanks!
posted by fleetmouse at 8:07 PM on July 12, 2009

Like you're just born with bad veins, it happens in the womb or something?

Sure... if you can name it, someone has been born (or at least partially developed without becoming viable) without it.
posted by phrontist at 8:36 PM on July 12, 2009

Time for trepanation!
posted by orthogonality at 8:59 PM on July 12, 2009

The potential importance here is that this deficiency was a near constant across these patients. MS is a wildly unpredictable disease and it tends to affect any two patients in very different ways. There isn't really a typical case that you can speak to as a baseline. If this is indeed a real consistency in MS patients than it has great potential to be a key breakthrough.
posted by cmgonzalez at 9:01 PM on July 12, 2009 [1 favorite]

Also, can someone boil down the medspeak into a plain English summary of the results of the study (with numbers - x of the MS patients showed this abnormality, y did not, etc)?
posted by cmgonzalez at 9:04 PM on July 12, 2009

I feel like I'm missing the news here. This was a journal article published six months ago. I don't see the evidence of breakthrough or excitement in the links posted, and some googling didn't lead me to anything that looked significant, any mainstream news coverage, etc.

I'm actually quite interested in this, as I have (a mild case of) MS, but I seem to be missing something.
posted by alms at 9:13 PM on July 12, 2009

non-conventional medical community

So that's what we're calling quacks now?
posted by deadmessenger at 9:15 PM on July 12, 2009 [8 favorites]

I'll eat my hat if venous insufficiency is the primary cause of multiple sclerosis. It doesn't make any sense whatsoever in terms of the epidemiology. That doesn't mean this can't be important; it's possible that the inflammatory process is worsened or even caused by the venous issues such that addressing those issues could mean great progress in terms of treatment. But I simply can't believe that the venous insufficiency is itself the cause. No no no.
posted by Justinian at 9:21 PM on July 12, 2009

(Needless to say I'm rather skeptical even of that).

My favorite prospective alternative therapy at present? Deliberate infection with hookworm. And it even sort of makes sense!
posted by Justinian at 9:23 PM on July 12, 2009

Where's the link explaining how it's all caused by vaccines?
posted by rokusan at 9:43 PM on July 12, 2009

Justinian, I think it's wise to be skeptical, but just look at what happened when Barry Marshall followed the evidence...
posted by greatgefilte at 9:45 PM on July 12, 2009

I would also like a layman's version of this info.
I have recently been diagnosed with MS (very mild) and am of course very interested in this "quiet revolution" of which this is the first I have heard.
Does anyone have the ability to translate the medical jargon for me/us?
posted by smartypantz at 9:52 PM on July 12, 2009

Conclusion in abstract in BMJ article:

'CDMS is strongly associated with CCSVI, a scenario that has not previously been described, characterised by abnormal venous haemodynamics determined by extracranial multiple venous strictures of unknown origin. The location of venous obstructions plays a key role in determining the clinical course of the disease.'

Multiple sclerosis is associated with cerebrospinal venous insufficiency, which means blood flow is wonky. Extracranial vein problems are relevant, and the location of vein problems has to do with diagnosis and prognosis.

'Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) of unknown pathogenesis.1 2 MR venography3–6 and postmortem studies7 have demonstrated a topographic correspondence between MS plaques and cerebral venous system. The drainage through the extracranial venous outflow routes has not previously been investigated in MS patients.'

Multiple sclerosis degenerates the myelin surrounding your neurons, which fucks up insulation in your neurons while they're transmitting action potentials; MRIs and autopsies say that MS plaques and cerebral veins are correlated spatially and that they've never done this before.

'Posture and the mechanic movement of respiration play a fundamental role in ensuring the correct cerebrospinal venous outflow.8 At the time of expiration, the intrathoracic pressure is approximately –5 cm H2O, and inspiration causes a respiratory muscular action that can generate an even lower intrathoracic pressure, –8 cm H2O. The resulting gradient favours venous return to the right heart, which can be easily assessed with high-resolution echocolour Doppler (ECD) and transcranial colour-coded Doppler sonography (TCCS), which represent an ideal method by which to investigate the haemodynamics of cerebral venous return.9–19 In addition, ECD clarified the postural control of the extracranial outflow pathways, as follows:8–12'

Posture and breathing affect venous outflow in your cerebral cortex, and breathing pattern favors venous return to the right side of your heart, which can be assessed with doppler sonography.

' * the internal jugular vein (IJV) is the predominant pathway in the supine position, confirmed by an increased cross-sectional area of the internal jugular vein (CSA) related to increased blood volume in that posture; and
* redirection of venous flow to the vertebral veins (VVs) occurs in the upright position, with compliant reduction of the CSA of the IJV.

In contrast, MR and selective injection venography are of course limited in evaluating cerebral venous haemodynamics under different postural and respiratory conditions. However, the latter especially provide excellent morphological but static details. '

Depending on how you position yourself, blood returns to your heart in different ways!
posted by kldickson at 11:11 PM on July 12, 2009

Justinian, I think it's wise to be skeptical, but just look at what happened when Barry Marshall followed the evidence...

I'm not saying there shouldn't be some serious investigation done, I'm just saying that we've seen this before.

A couple years ago the big thing was long-term (essentially permanent) treatment with serious antibiotics. You could find studies to support it. You could find some doctors who would swear up and down that it worked. You could find patients who would swear up and down that it "cured" their MS. I'm sure you can find those things today.

Is it a insidious bacterial infection or is it venous malformation? Can you decide based on how enthusiastic the boosters are? No, you can't. And both have extremely enthusiastic boosters. And people who say both are missing the forest for the trees.

We need to see more research. There are constantly BIG NEWS HEADLINES about the latest thing that's going to revolutionize our understanding of the disease and a couple years later they mostly fade away. It's true that one of these days we're going to find one that doesn't fade away and really does prove revolutionary. But it isn't time to pop the champagne cork just yet.
posted by Justinian at 11:19 PM on July 12, 2009 [1 favorite]

There are also associations with severe stress - loss of a child, in particular. How would venous insufficiency arise from that?

I'd really want to see these results duplicated, and that was my first thought on hearing about this study. /Another mefite with a relatively mild case of MS - and I don't think it's autoimmune, either.
posted by dilettante at 3:23 AM on July 13, 2009

There are also associations with severe stress - loss of a child, in particular. How would venous insufficiency arise from that?
—dilettante

I'm not sure, but stress does contract nerves and the hearts start going and whatnot. My impression is that that if your skull-veins are "foldy", you could get some real weird side effects from it all.
posted by krilli at 5:57 AM on July 13, 2009

Oh dear god, that didn't go too well. May I try again? Thanks.

There are also associations with severe stress - loss of a child, in particular. How would venous insufficiency arise from that?
—dilettante

I'm not sure, but stress does contract blood vessels and the heart (singular) starts going and whatnot. My impression is that that if your skull-veins are "foldy", you could get some real weird side effects from it all.
posted by krilli at 5:59 AM on July 13, 2009

This is really interesting; although it is not freely available online, the editors of the journal thought this article was important enough that they wrote an editorial that concluded: "In light of the association between such a previously overlooked vascular picture and MS, a further stimulating research field is opened by this article. This should be addressed in understanding the contribution of venous drainage to the different aspects of inflammation, autoimmunity and neurodegeneration characterising the intriguing puzzle of MS."

The Barry Marshall example is a good one; for those of you who don't know who he is, he is a physician who in the early 1980's hypothesized that most ulcers are caused by infection with a particular bacterium. At the time he was scoffed at as the conventional medical wisdom stated that ulcers were caused by stress, diet, or Zollinger-Ellison syndrome in most cases. Eventually, though, he was shown to be right and now Helicobacter pylori infection is thought to be responsible for 80% of all gastric ulcers. Treatment has drastically changed accordingly, and Marshall was awarded the Nobel Prize in 2005.

I also agree with those who are skeptical; this is only one result and needs to be replicated by others before anything else can be done. Given that genetic and environmental factors are also implicated in MS, it may be that venous insufficiency in combination with other factors influences the development of MS. Or there may be different expressions of MS depending on which causal factors are present. One interesting experiment to look at this association would be to artificially increase venous pressure in a group of patients and see if they have an increased risk of developing MS. Obviously it would be unethical to do this to healthy patients, but it just so happens there are a group of congenital heart disease patients who have required an operation called the Fontan Procedure which results in abnormally high venous pressure (which is responsible for a number of potential complications). If these patients can be shown to have an increased risk for MS, then that would be good evidence in favor of this hypothesis. Even if this is shown to be the case, it will take years, even decades, to fit this in to the rest of the pathological findings in MS and use it to come up with effective treatments. And even though this is interesting to me, I know that most of the sorts of things never pan out. It would be interesting to hear from a neurologist or other neuroscientist about this. I will definitely ask around at work.
posted by TedW at 6:56 AM on July 13, 2009 [4 favorites]

This appears to be the key to understanding the study: "The hypothesis of venous malformations of congenital/developmental origin associated with CDMS seems to be plausible. Nevertheless, additional longitudinal studies are necessary to confirm this hypothesis, as well as to understand the contribution of chronic insufficient venous drainage of the CNS to the process of inflammation and neurodegeneration."

Rephrased, they are saying it is possible that it was inborn anatomical structural problem (which I think it less likely considering epidemiology) or whether the inflammation and/or nerve damage alters venous drainage. The latter seems more likely to me. It may also not be inflammation, but vasoconstrictive substances being produced locally.

Which leads to the next question: does it matter? Is reduced venous outflow a benign effect secondary to inflammation? Will increasing venous outflow relieve MS attacks? When you get these questions answered, you will know if they've found something significant.
posted by dances_with_sneetches at 7:17 AM on July 13, 2009 [1 favorite]

It sounds much more likely to be a symptom than a cause, but having another solid indicator for diagnostic purposes might be good. I know (very distantly) of at least one person who is having stents put in to see if that will help, though.
posted by dilettante at 8:37 AM on July 13, 2009

This is pretty remarkable. However, it doesn't appear to explain the geographical distribution - particularly the fact that if you move to an area before you're 15, you then acquire the disease risk associated with that area rather than your native region.
posted by dilettante at 7:42 PM on July 12

You got a paper for this? Pretty remarkable if true.
posted by wayofthedodo at 8:58 AM on July 13, 2009

I wonder if these wildly different causes for MS (bacterial, veinous, etc.) really means that we have NO CLUE about the fundamental causes underlying MS.
posted by HalfJack at 12:40 PM on July 13, 2009

You got a paper for this? Pretty remarkable if true.

A paper that shows the risk for developing MS depends on where you live before the age of 15-16 rather than after? That's not remarkable, it's long-established fact. Any reputable site will tell you that. If you grow up in New England you have a greater than 1 in 1000 chance of getting MS. If you grow up in south Florida you have very, very little chance of getting MS. If you move from south Florida to New England at the age of 12, you have a MUCH greater chance of getting MS than if you move from south Florida to New England at the age of 19.
posted by Justinian at 1:20 PM on July 13, 2009

and I don't think it's autoimmune, either.

It's absolutely and without doubt autoimmune in some part, although whether or not the autoimmune component is the initiating factor is still open for debate. But the fact that T-cells attack the myelin sheath of your nervous system is no more controversial than the idea that HIV causes AIDS.
posted by Justinian at 1:22 PM on July 13, 2009

But the fact that T-cells attack the myelin sheath of your nervous system is no more controversial than the idea that HIV causes AIDS.

Except for that pesky little study showing the oligodendrocytes are already dead....
posted by dilettante at 2:55 PM on July 13, 2009

Except for that pesky little study showing the oligodendrocytes are already dead....

There has been one study which seemed to indicate that oligodendrocyte apoptosis precedes rather than follows inflammation and destruction of the myelin. So far I'm not aware of followups confirming that finding. But even if we take it as a given I'm not sure how it follows that MS isn't at least in large part an autoimmune disease. Regardless of the order it's incontrovertible fact that your myelin sheath gets attacked by T-cells.

I'm having trouble coming to grips with the idea that there are people who don't accept this; it's like running in to flat earthers. I'm not saying that's the sum total of MS. Clearly it is not. But it happens. We see it happen. Anti-inflammatories relieve symptoms when it happens. Monoclonal antibodies which destroy T-cells mostly prevent it from happening (and sometimes kill you, unfortunately). Campath, natalizumab, etc. I promise you that natalizumab is not working because it increases venous blood flow.
posted by Justinian at 4:01 PM on July 13, 2009

You might start here on the autoimmunity question.
posted by dilettante at 4:08 PM on July 13, 2009 [1 favorite]

Has anyone tried to get their hands on Hookworm larvae? I know it sounds so revolting, but the evidence seems pretty impressive too... I read that one woman with Asthma travelled to Cameroon & walked around barefoot (in latrines no less!) in an attempt to infect herself.

There must be an easier way...right??? In the meantime, since I have a very mild form of MS and couldn't tolerate any of the other meds out there, I've been pretty happy with a drug developed by Genentech that I only need to take once per year, Rituxan.
posted by ohyouknow at 4:13 PM on July 13, 2009

ohyouknow, you can order hookworm and other helminth larvae online, although wikipedia says the importation of the larvae is banned. Can't say I've tried it myself, although I have thought about it.
posted by dilettante at 4:24 PM on July 13, 2009

Thanks, dilettante. You've certainly given me something to ponder...
posted by ohyouknow at 4:36 PM on July 13, 2009

Actually it looks like I misunderstood that link, ohyouknow. That company requires travel to Mexico for larvae. They name another company that does ship larvae into the US, not sure why they call it out by name.
posted by dilettante at 4:50 PM on July 13, 2009

I saw that they operate out of Mexico, but the first link you posted still fascinates me. Their "treatment" is a lot less expensive than travelling to Cameroon (and mucking around barefoot in latrines).

But, pardon the pun, it's hard to stomach paying a few thousand dollars for a parasite. And as far as my squeamishness facor goes, I could barely tolerate getting lasik...
posted by ohyouknow at 5:11 PM on July 13, 2009

dilettante: I've seen that article. It's basically saying "hey lets look at other factors in addition to the autoimmune ones." Which strikes me as sensible, not that different than what I'm saying, and not at all fairly characterized as saying that MS doesn't have a big autoimmune component.

The hookworm thing I mentioned earlier and you're discussing now is a little ironic in context given that the entire basis for its theoretical mechanism of action is, you know, based on suppressing part of your immune system because of MS having a large autoimmune component. Hookworms suppress your immune system in specific ways so that it doesn't kill them. There are anecdotal reports that this suppression helps greatly with MS (to the point that some researchers who have MS have deliberately infected themselves). If the autoimmune thing is a red herring this whole mechanism of treatment is also a red herring.
posted by Justinian at 6:11 PM on July 13, 2009

Oh, be wary of any treatments for serious diseases in Mexico. A lot, lot, lot of them are scams designed to separate the desperate from their money. Not to say that all of them are but you need to be damn sure you're not paying for placebo. This is particularly true of places that advertise "stem cell" therapy.
posted by Justinian at 6:13 PM on July 13, 2009

If the autoimmune thing is a red herring this whole mechanism of treatment is also a red herring.

Not necessarily. That would depend on why the hookworms or whipworms work, if they do. You'll notice I haven't tried it, in any case.

and not at all fairly characterized as saying that MS doesn't have a big autoimmune component.

From a separate article by the same authors: "We have recently proposed that MS is not an autoimmune disease, but a metabolically determined neurodegenerative disorder with a genetic influence." (Follow footnote 2 to get to another full article on this without going through a pay site).

If you want to take the autoimmunity argument far enough, acne, the flu, and the common cold have a big autoimmune component, in that the activity of the immune system does cause many of the most noticeable symptoms. But there are other factors at work that cause the actual disease in those cases, and, I believe, in MS. Whether those are viral or bacterial or metabolic degeneration, I can't really say. I lean to the rather grim idea that it is degenerative, but there are some indications that there could be pathogens involved - perhaps multiple, given the differing disease courses.
posted by dilettante at 6:38 PM on July 13, 2009

dilettante-
This is the first time I have encountered the phrase "metabolically determined neurodegenerative disorder". What does this mean in practical MS related terms? I am familiar with "metabolic" only in the very layman's diet-y metabolism sense (ie my ex had a high "metabolism" and could eat whatever he wanted and stay skinny).

I don't understand how it can NOT have an autoimmune factor as far as my understanding the general process of MS is the T cells attacking the myelin, right? And T cells are part of the immune system, so....

Maybe it's that process in my body (lesions on my brain) that's making understanding all this shit difficult? Can that be the case?
posted by smartypantz at 7:06 PM on July 13, 2009

smartypantz, try reading this article (it doesn't work if I bookmark it, so I'm not sure it will work here, either). If that link doesn't work, it's the article that's at footnote 2 on this article.
posted by dilettante at 7:29 PM on July 13, 2009

dilettante - Hey thanks for those links, although the one of interest has a lot of medical terminology I am not familiar with. Is it basically saying it about the neurons are dying for some reason?
And what are things that are neuroprotective? (Drugs, Foods, Therapies etc)
posted by smartypantz at 8:20 PM on July 13, 2009

Oh, this is interesting...
minocycline appears to be both anti-inflammitory AND neuroprotective
posted by smartypantz at 8:25 PM on July 13, 2009

I don't believe dilettante is denying there is an autoimmune component, she (uh pardon me if you aren't a "she" but I vaguely have that impression) is saying the autoimmune part is secondary to what's really going on. A good example would be the way Spanish Flu acted. Most young healthy people were actually killed by an immune reaction but Spanish Flu is, obviously, not primarily an autoimmune disease; it's a virus.

I understand that argument I just don't think the evidence is there yet. There are still a lot of epidemiological factors that point in the direction of a multi-factor cause but of which a big factor is an autoimmune one.

I would also argue that treating the autoimmune component is important regardless of that fact. If you can prevent the inflammation and destruction of the myelin sheath you're way ahead of the game even if there is another issue which is specifically targeting the oligodendrocytes.
posted by Justinian at 8:51 PM on July 13, 2009

smartypantz: Yeah minocycline appears to be an interesting potential treatment. There are, unfortunately, a bunch of interesting treatments that I don't think are being investigated as well as they might for financial reasons. Nobody is going to make money off minocycline so it's hard to find someone to spend millions of dollars for large placebo controlled double blind trials.

Another potential treatment are statins. Atorvastatin (Lipitor) showed some promise as a potential treatment for not completely understood reasons. Don't know if anyone ever followed up on that or if it turned out not to be the case but like minocycline it's a potential treatment with a pretty well understood and tolerable side effect profile at a decent cost when compared to interferons and monoclonal antibodies and such.

I read about appealing potential treatments a lot but nothing ever seems to come of it. I don't know if that's because they don't pan out or because nobody bothers to investigate the potential of something that won't be a cash cow.
posted by Justinian at 9:00 PM on July 13, 2009

In the meantime, I suggest you test your levels of vitamin D. I'd read enough studies prior to my neuro testing me, so I'd been taking 500mg every day for a few years and I was pretty smug that my test would come back with perfect levels... so I was pretty shocked when he informed me that my level was staggeringly low. And I'd been popping 500mg every day for a while. Now I take 5000mg each day and even though I couldn't for the life of me explain why or how it works, I do notice that I've been feeling better. I found gel capsules online (which I was unable to locate just now, apologies.)

Also, as far as Rituxan goes, Genentech will pay for your treatment if you can prove you were earning less than 100k in the preceding year. Rituxan works by eliminating your B cells (rather than by messing with you T cells, which we all still presumably need to fend off things like the flu).

As far as disease theory goes, I'd found a (somewhat dubious, but nevertheless interesting) article essentially arguing that the most important thing to study is who never gets MS, rather than focusing on each group's chance of diagnosis. The author discussed at length her (?) theory that Gout was essentially the opposite disease. Thought provoking at least.
posted by ohyouknow at 9:22 PM on July 13, 2009 [1 favorite]

Wikipedia provides a few references of interest regarding the under-15 epidemiology question.

Here.
posted by nat at 12:38 AM on July 14, 2009