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Lithium for ALS – Angioplasty for MS

Peter Lipson reported Monday about new research suggesting that Multiple Sclerosis may be caused by venous blockage. He correctly characterized some of the hype surrounding this story as “irrational exuberance.”

This is a phenomenon all too common in the media – taking the preliminary research of an individual or group (always presented as a maverick) and declaring it a “stunning breakthrough,” combined with the ubiquitous personal anecdote of someone “saved” by the new treatment.

The medical community, meanwhile, responds with appropriate caution and healthy skepticism. Looks interesting – let’s see some more research. There is a reason for such a response from experts – experience.

We have been here before – lithium for ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in the death of motor neurons, leading to weakness and ultimately paralysis or death. There is currently only one proven treatment for ALS, a drug called riluzole, and its effects are modest – prolonging tracheostomy-free survival by 2 months on average. So new treatments are welcome, to say the least, and there is ongoing research looking for possible treatments.

In February of 2008 I wrote about a preliminary study by Italian researcher, Fornai, in 44 patients with ALS, showing a dramatic improvement in outcome. This research followed a mouse study that also showed significant improvement.

Press reporting about this “breakthrough” research resulted in patients with ALS and their families contacting me and other neurologists asking how they could get treated.

Meanwhile, the reaction of the ALS research community was cautious but hopeful. It was felt that this preliminary research deserved further study, but was not enough to conclude that lithium was effective or to start treating patients with it.

The North East ALS Consortium (of which I am a member, although I did not participate in this study), based upon Fornai’s research, performed a randomized controlled multi-center trial of lithium in ALS. The results were dead negative – so negative that the trial was stopped early due to futility.

Here we have animal studies and preliminary human trials showing a dramatic improvement, and a follow-up larger and better controlled study showing zero effect. How do we reconcile these results?

Simple – preliminary data is unreliable, by definition. Most new ideas in medicine do not pan out. And as a result (and as John Ioannidis has taught us) most published studies are wrong. What is reliable are later, larger, more definitive trials, and specifically a consensus of results in the peer-reviewed literature after a question has had time to simmer and mature.

Zamboni and CCSVI

It should therefore be no surprise at all that the medical community is once again taking a cautious approach to preliminary research published by a single researcher claiming dramatic results from a revolutionary new idea. As Peter discussed, Dr. Zamboni, a neurosurgeon, believes he has found a cause and a cure for multiple sclerosis (MS) – a neurosurgical one.

Just like with lithium and ALS, his idea is an interesting one, and his preliminary data deserved to be taken seriously – which means replicating his research and doing follow up studies. He claims that patients with MS – 100% of the MS patients he has studied, but none of the controls – have blockages in the veins that drain blood from the brain. These blockages lead to blood backing up in the brain, which causes iron deposits, which results in inflammation and MS.

At this point there are many possibilities. It’s possible Dr. Zamboni is the victim of confirmation bias (I am always suspicious of 100% results) and his new condition – chronic cerebrospinal venous insufficiency or CCSVI is an illusion.

It is possible he has found a real pathological marker for MS but what he is seeing is the result of MS, not the cause of it. Inflammation is known to follow the venous system in MS, but there are explanations for this that have to do with the immune system in the central nervous system. Perhaps chronic inflammation from MS causes sclerosis in the veins and the blockage that Dr. Zamboni is finding.

If this is true then it is possible that the venous sclerosis is playing no or only a minimal role in MS pathology, and fixing them by opening them up with baloon angioplasty is of no benefit. It is also possible that even though the venous changes are cause by auto-immunity in MS, once they form they worsen the clinical syndrome, and treating CCSVI in MS will improve outcome, even if it does not cure the underlying cause driving the disease.

And it is possible that Dr. Zamboni has discovered the or an underlying cause of MS – that CCSVI is actually the primary driver of the disease. Or perhaps it just triggers the auto-immune response, but once triggered it is self-sustaining.

This is a huge range of possibilities, and it is definitely premature to come to the most extreme conclusion among them. We need time for the MS community to pick over Zamboni’s claims and research. While we do not know what ultimately causes MS, we have decades of high quality research characterizing its pathophysiology. How does this research square with Zamboni’s claims? Let’s wait and see.

Zamboni’s basic claims need to be replicated. And if warranted, clinical studies need to fully characterize the risks and benefits of any procedure to address alleged CCSVI. Perhaps it only has benefit is a sub-population of MS. Maybe it makes the disease worse. We won’t know until quality studies are done.

I am not holding my breath, just as I wasn’t with lithium for ALS, but I will certainly follow the research. I would love for Zamboni to be correct – if we can essentially cure MS with a one-time procedure that would be a huge boon to MS patients and save billions.

Help – the media is not being irresponsible!

The most absurd reaction to Zamboni’s research came from the Huffington Post. As Peter reported, Erika Milva wrote a rambling piece suggesting that the cautious responses of American media, MS societies, and the medical community were due to being risk-averse and the omnipresent (in the fantasies of many) Big Pharma conspiracy.

Milva could not understand why the media was not irresponsibly jumping over this story and hyping it, as some of the foreign press has. So I guess she decided to make up for this with maximal hysteria of her own.

But there is no mystery here. Zamboni’s claims are radical, and therefore by definition improbable. But more importantly, they are preliminary. That doesn’t mean they are wrong – it just means we do not yet know. Let’s wait for some quality research.

And that is one of the primary differences between science-based medicine and everything else – basing treatments on evidence, witholding judgment until reliable evidence is in, and not overreacting to every pilot study that pops up.

I will let you know in a couple of years how Zamboni’s claims have turned out.

Posted in: Neuroscience/Mental Health, Science and the Media

Leave a Comment (14) ↓

14 thoughts on “Lithium for ALS – Angioplasty for MS

  1. windriven says:

    Dr. Novella-

    “most published studies are wrong”

    Did you intend to say, most preliminary studies are wrong?

  2. windriven says:

    One can understand the desire of those afflicted with debilitating or deadly diseases – especially those in whom the disease is advanced – to leap at any putative cure. I personally have ethical misgivings about withholding investigational drugs and treatments from the truly hopeless. But as Dr. Novella points out, the track record of these breakthrough modalities is poor. And there is even the potential that an unproven therapy will exacerbate rather than ameliorate the symptoms and course of the disease.

    I would pose the question: when is it appropriate to make investigational – even speculative – therapies available to dying or severely debilitated patients? This of course presumes detailed informed consent, age of majority, etc.

  3. Windriven – no, I meant most published studies. That is what Iaonnidis found. Of course, most published studies are preliminary – not large, multi-center, rigorously designed trials.

    There are already provisions for compassionate use of experimental treatments. The ethics have already been worked out – which is not to say they are not sometime complex and controversial.

    With MS, however, there are already established treatments that are pretty effective, so it is harder to justify experimental treatments outside of a properly designed research protocol.

  4. windriven says:

    Where might I read up on the standards for compassionate use? I have heard a number of horror stories and would like to have the other side of the story.

  5. windriven says:

    An excerpt from Dr. Novella’s 1998, “Interpreting the Medical Literature”

    There are more subtle problems with the medical literature, as discussed by researcher John Ioannidis. In 2005 he published what has become a seminal paper on why most published studies are false. In the summary he writes:

    In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true.

  6. Zoe237 says:

    So how many lesser studies equals one large RCT? What about in cases where RCT is impossible or unethical? IOW, what is your (general) threshold for proof of any claim?

    I thought the HP was more supportive of the viewpoint that the medical profession is too willing to jump on the latest bandwagon and liked to take risks with people. Oh well.

  7. Calli Arcale says:

    I don’t think there’s a straightforward equation, such as, oh, 4 small RCTs = 1 big RCT. This is because the four RCTs are not going to be identical; this will make their data less easily comparable, and in many cases, make it impossible to combine data from multiple RCTs and then look at it as if it were a single RCT.

    Another problem is that RCTs are seldom designed to answer the question of “does drug x work or not?” because a question like that is not sufficiently specific to be meaningful in this context. Instead, they try to answer questions like “does drug x, given at dose y, reduce illness marker z by at least 5 data points, to an adequate degree of confidence?” Or something like that. Different studies aiming for the general question of “does it work” will have different specific questions, and this alone will alter the meaning of the data they collect. On top of that, they will have different methodology, pretty much inevitably, which means the numbers won’t even mean the exactly the same thing from one study to another.

    There are studies which consist of reviewing the literature — these essentially attempt to turn multiple small RCTs into a single large RCT. They have certain weaknesses, and are not strong enough to satisfy the FDA. But that’s the closest thing I know to what you’re talking about, Zoe.

  8. mxh says:

    I don’t fault Zamboni for the work he’s doing (even though I think offering angioplasty for MS is way to premature. It’s the medical reporting by the media that is jumping to conclusions way too early. The problem is that medical reporters are rarely medically trained. They are journalists first, and because of that they would rather have an eye-catching headline and report, rather than the cautious, skeptical reporting that a scientist/medical professional would have.

    I wish more of you guys worked for the main stream media (though you probably wouldn’t wish that for yourselves).

    Nonetheless, I look forward to what comes of Zamboni’s ideas.

  9. Wholly Father says:

    Zoe asks: “So how many lesser studies equals one large RCT?”

    Great question, but the answer is not easy. If the lesser studies are weak to begin with, then you can’t achieve the credibility of a large, well designed, well executed RCT, no matter how many “lesser” studies you have.

    The lesser studies you refer to are often retrospective, poorly controlled studies. There are certain biases inherent in these studies, and trying to somehow sum the results of these studies may only reinforce the bias.

    If there are well done small studies with similar designs, a Meta analysis can pool the data and give the combined data more statistical power than generated by the individual studies, but this is subject to certain biases as well. Meta analysis rarely carries the weight of a Large RCT.

  10. Fredeliot2 says:

    There was a report a year or so ago about the benefit of Prozac as an additional treatment for MS. I was wondering if there have been any further developments in this area.

  11. qetzal says:

    windriven asked:

    Where might I read up on the standards for compassionate use? I have heard a number of horror stories and would like to have the other side of the story.

    In the US, compassionate use of drugs that are not yet approved is regulated by FDA. You can read more here and here for starters.

  12. CureIous says:

    Steven Novella With MS, however, there are already established treatments that are pretty effective. Define “pretty effective”.
    “Already established” doesn’t necessarily equate with efficacious. Disease progression is slowed down, not halted, at a tremendous cost to the patient, and society.

    There’s a reason the %’s of no-relapses in drug trials lean heavily towards the beginning years of RRMS patients. SP and PPMS patients get little to no of that “pretty effective” pie.

    And as an aside, there is actually very little medical reporting on this by the media, just a few online sites and not much more. Hardly a stampede to misrepresent the facts as we know them right now.

    As far as I know, nobody is offering “speculative care” to debilitated and dying patients quite yet. The stenoses are very real, and as such are treated using established procedures well known for their efficacy, to correct an identifiable (and usually corrected) pathology. Whether an etiology is established in the future, of course remains to be seen and proven. In fact Zamboni himself invited openly just that, more studies, more proof.
    That may not establish angioplasty/surgical intervention as the end of MS as we know it, that goes without saying. Zamboni in fact embraces the AI model as it stands.

    While some may characterize the oft pliagarized “irrational exuberance” as the flavor of the day for MS patients, equating one blog on Huffington Post as speaking for all of us patients, is equally irresponsible.

    Internet hype is just that, internet hype, blogs exist mainly to hear themselves think. Find me one reliable US news network that has fed the hype, broadcast, date and time, please.

    I am one of the “Liberated” so take my words with a grain of salt. (full disclosure).
    Thanks.
    CureIous

  13. JohnW says:

    The National MS Society (NMSS) has posted the following to their website regarding a large trial to be conducted by the University of Buffalo’s Buffalo Neuroimaging Analysis Center of the Jacobs Neurological Institute
    ( http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=2510 ).

    I tend to watch the NMSS website since both my sister and my son have been diagnosed with MS.

  14. kuruc says:

    When I saw the W5 program on CTV on Nov 21, 2009, I got my church praying, I resigned my job, and went to search for a doctor willing to test and treat my wife of 34 years. On December 29, 2009 she was operated on in Poland. A blocked left jugular vein was unblocked. Her extreme fatigue quickly disappeared, along with double vision, blurred vision, constant headaches, and overall misery. She is sleeping longer, deeper and wakes up refreshed. I know that I am just a stupid idiot and I should be listening to these overfed overpaid leeches living off the suffering of MS patients but I am glad that I believed the Italian surgeon who loves his wife, went to work and fixed her problem. My wife is living proof of that CCSVI is real and unblocking clogged veins, gets the sewage out of the system and life returns. Placebo effect indeed you self righteous know nothings.

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