June: Unrelated Blogger Comments


Unrelated BLOGGER Comments

Sometimes you what to say something that is unrelated to the threads. This is a spot for You. 

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Not a comment but an important question, foremost to the research team
in relation to the article posted on

is VERY likely that I am one of those people with thrice as high Vit B
12 levels than normal (blood tests for over 3 years). Nobody can explain
why. From my own research I strongly suspect pernicious anemia because
I’ve got 2 disorders linked to that (I also have iron deficiency which
coincided with the onset of RRMS).

So my question is: which
tests should I suggest to my GP next time I see him in order to know
what’s going on for sure? Since I’ve got more than one autoimmune
disorder it is imperative to tackle a faulty Vit B metabolism, methinks.

Your thoughts on this would be GREATLY appreciated – I’ve hit a brick wall so far with my doctors.

Gavin Giovannoni

Re: “So my question is: which tests should I suggest to my GP next time I
see him in order to know what’s going on for sure? Since I’ve got more
than one autoimmune disorder it is imperative to tackle a faulty Vit B
metabolism, methinks.”

I suggest you make your GP aware of the
article in the NEJM and he/she should screen you for auto-antibodies
associated with pernicious anaemia and/or do a Schilling’s test. The
latter is a specialised test done by haematologists to assess the
absorption of vB12.

Please note this blog is not the forum for personal medical advice. So I can’t give you anything more specific.


Dear Prof

thanks a lot, that’s exactly what I needed to know –
helps a lot. I apologize for this very me-centred question but I had no
choice in this specific case.

Tony Fonda

Dear Gavin, Mouse,

I have a quick question that has been puzzling me lately.

I am trying to understand Pharma’s marketing material.

When Company X says that its DMD Y cuts down on relapses by 50% per annum:

Does it mean that:

if 2 people with MS are taking this drug (1 relapse per person per year), one will relapse as usual and the other will not.


same 2 people (1 relapse per person per year), will have 0.5 relapse
per year after taking the drug (i.e. a relapse every 2 years)?

In other words, I am wondering if the 50% relapse reduction rate is an average (or median) or a sum or positive/negative obs ?



Dear Tony

You personally can not have half a relapse (0.5) so in this case it would be one relapse every two years as you say

terms of the 50% reduction in relapse rate, this means that you have
half as many relapses as would occur if you were not having the drug.

if the Annual relapse rate on drug was 0.25 compared to 0.5 on placebo.
It means that on average people on placebo have one relapse every two
years and the person on the drug had on average on relapse every 4
years. As you say this is an average so the middle mark and within any
trial some people to better than the average and some people to worse.

Tony Fonda

Thanks Mouse.

But I must say that this does not really address my question.(probably because I didn’t phrase it properly).

If you have 4 balls in a box, and you take 2 balls: you are left with 50% of the balls.

If you cut each of the 4 balls in half, you are left with 50% as well?

what does 70% reduction on Tysabry mean? NO RELAPSE for some and full
relapse for the rest, or reduction for all on an equal basis?

logged a formal question to Biogen Idec (both USA and UK) this
afternoon. Awaiting their replies (ought to come from the statisticians
who analysed the data of the clinical trials…)


so what does 70% reduction on Tysabry mean? NO RELAPSE for some and full
relapse for the rest, or reduction for all on an equal basis?

no relapse of full relapse there is nothing in between in this context.
You have a relpse or you do not. There is nothing about a mild or
severe relapse in this context

If you have a 70% reduction of
relapse it means you are 70 percent less likely to have a relapse that
would occur if you took nothing=placebo

So if 100 people were taking tysabri only 30 would relapse compared to a 100 taking placebo.

The beneficial effect is statisitical and not impirical and not on an equal basis

if you relapsed does this means the drugs failed… well not
necessarily as you may have been destined to have two or more relapese
as the drug got rid of one or two etc. of them. Likewise it could be
less severe than it would have been

Tony Fonda

Thanks again Mouse you’re the best.

Let’s wrap-up: I did not mean
that you could have a partial (or light) relapse as it is an
indivisible event. Either it happens or not.

But as you know, MS is a long term experiment.
You are answering me as if our horizon is 1-2 years. but how about 5-6 years? then no need to talk about decimals any more .

you have a 70% reduction of relapse it means you are 70 percent less
likely to have a relapse that would occur if you took nothing=placebo

So if 100 people were taking tysabri only 30 would relapse compared to a 100 taking placebo.”

Over a time frame of 5 years, does the above means that:

I) all tysabri takers will have a total reduction in relapses over 5 years of 70% – on an equal basis.


some people will have a reduction of 100% and the others will relapse
as frequently as needed to get to a population average of 70%?

second scenario clearly excludes NABs, SPMS, drug holidays… as those
extreme observations will render the average irrelevant.

again, I appreciate the technicalities of this question and will post if I ever hear back from the manufacturer.


The information comes from clinical trials these last no more than 3 years so there is no real answer for 5 years.

Tony Fonda

Can I conclude that 70% were relapse free during the 3 year time frame?

Any post-marketing study on these guys with a longer horizon?


i’ve always understood the relapse reduction to be an aggregate for all patients:

When there is a 70% relapse reduction with a drug
-some patients may have 0 relapses
-some may have fewer relapses
-a few may stay the same
-and a few may even get worse

70% is for the group as a whole. We need to know many were in each of
the above categories. Perhaps half the patients fell in the 0 relapses
category and 5% of the patients got worse

Tony Fonda


Neither you nor me are averages.

An average may work for a regulator, a manager or an investor.

But as we know, I am an individual and not an average.

“look through” data analysis should be published if it has not
already…. I wonder if there are statistical tables out there?

Tony Fonda

Biogen-Idec return to me after 48 hours with this answer:

“We investigated this situation for you and can tell you that Tysabri has cut ARR by 68%”.

Then I called to understand more and was outraged by their reply:
“We can not and will not disclose any more information”

calmly explained to them that this information is needed in my decision
making as it is a matter of life or death – and asked them to provide
me the info within the next 10 days or I will file a claim in the UK

And I will. I am not playing poker games.

To be continued….


Good! We should have complete information clearly laid out and I think
treating neurologists need to have it. An average is not enough


You can read the actual figures in phase III trial the paper by Polman et al. As you will read it was based on a two year study.


one year of treatment, natalizumab reduced the annualized rate of
relapse to 0.26 relapse per year, as compared with 0.81 relapse per year
in the placebo group (P<0.001) (Table 2). The 68 percent relative
reduction in the annualized rate of relapse produced by natalizumab was
maintained at two years (P<0.001)”.

“The proportion of
relapse-free patients was significantly higher in the natalizumab group
than in the placebo group at one year (77 percent vs. 56 percent,
P<0.001) and at two years (67 percent vs. 41 percent, P<0.001)”.

If you are considering Tysabri please read the posts on PML.


The problem with post-marketing data is that there is no placebo arm and generally no natural history data.

if you are thinking about Tysabri you need to know your JC virus status
so taht you can asses the risks of taking the drug, which increase alot
if you go past the 24 month period.

If you look at the Polman paper you can see the neurological landscape changing over time.


That NEJM paper has all the figures
So the Biogen person who said ‘we cannot and will not disclose …’ was very uninformed

Tony Fonda

Dear Mouse,

I have done good progress on this.

Caroline Wilding (head of the medical information distribution dept) reached out and agreed to share the post marketing data.

I am potentially looking at 6 years of history for up to 80,000 users.

That should allow us to cluster in subgroups to understand more how Tysabri affects different patient-types.

One hick: I am not a medical professional and not allowed to received the data directly.
Can you kindly reach out to Caroline requesting the tape? She agreed to provide it : caroline.wilding@biogenidec.com

I will happily run the stats in Matlab once I get the tape.

Thanks for your help.



Well done Tony!

We are the 99 percent!!!


Dear Tony
I suspect that I am not considered a medical professional either.

Write to Prof G
with details of the conversation that you have had with Caroline
including what she said she would supply and the details of what you
have requested and a contact email.

I don’t understand what you
mean by tape and in terms of looking at subtypes. Tysabri is licenced
for treatement of RRMS there is a study in progressive MS ongoing.

About the author



  • I have a question about what we know about the effects of inflammation in the brain and how we feel.

    There are two common symptoms for which I have made up theories. My theories are obviously just guesses, but I'm very curious.

    1) When I get a Tysabri infusion, I often have very mild headaches for a few days after. My theory is that Tysabri fairly quickly reduces inflammation in the brain and the change in pressure is something I can feel, therefore the mild headaches. The re-rise in pressure during the weeks after that before the next infusion happens so slowly I don't feel it and get no headaches.

    2) Heat sensitivity. I am very heat sensitive, much less since Tysabri. But when I am, I'm heat sensitive on my head, really "in" my head is what it feels like. My legs aren't heat sensitive, my chest isn't heat sensitive, but I will pour sweat from my head if I don't take action to cool down early. Sitting with my legs in the sun is fine (within reason of course), sitting with my head in the sun is dangerous and to avoided at all costs. Is this related to inflammation? I remember writing a blog post once about the five signs of inflammation and one is heat and it made me think.

    I know these are questions you probably can't fully answer, but if you have any related facts, insights, or opinions, I'd love to hear them.

  • MouseDoc, another day – another new breakthrough in repairing nerve damage in the spinal cord.

    The British media, especially Sky News has been reporting today on Rubia van den Brand and colleagues in Switzerland repairing the neuronal damage to a severed rat spinal cord and making the animal fully functional again. The hope is that within 2 years there will be human trials to see if the methodology utilised works in peopole.

    Now I realise the road is long but I love news stories like this. It gives me hope and makes me want to fight on in the ambition that the future for diableled MSers may actually hold promise. Surely such advance medical progress will eventually give great aid to some of us for whom current medicine offers very little.


  • Dear Matt

    "When I get a Tysabri infusion, I often have very mild headaches for a few days after."

    This is likely to be due to the effect of Tysabri on the peripheral immune system; activation release mediators that can trigger a headache. It is common with other infusions as well. I assume you have been tested for anti-Tysabri antibodies? The latter are positive in ~5% of MSers on Tysabri; headaches and infusion reactions are commoner if you have antibodies.

    "Heat sensitivity. I am very heat sensitive, much less since Tysabri. But when I am, I'm heat sensitive on my head …"

    These observations are very difficult to explain. Your body temperature tends to controlled centrally, therefore any increase in the head will be mirrored by an increase in the periphery.

    Apologies, these answers don't address your questions.

  • "Apologies, these answers don't address your questions."

    Not at all. There are two common things that happen with MS: patients have misunderstandings of how things work and come up with wacky ideas; and doctor's do not have the answers we seek.

    If you're willing to be patient with my wacky questions and theories then the least I can do is be patient with the fact that we don't always know exactly what's going on. There will be times when you really can answer definitively and it will really help people out.

    I do think the heat issue is fascinating though, someday we will know why that happens and I'm sure the answer will be very interesting.

  • I know that you've recently commented on rogue anti bodies and lipids, but knowing how fond you are of all things micey,there has been an article inScience Translational Medicine June 6 about injecting mice with lipids that affected their MS like disease

  • Rogue Lipids: I have seen the story and am reading the article and am working on a post..tub of lard here we come:-)?

  • 5 years into RRMS: a particular symptom started over two years ago and slowly got worse. There have been periods of improvement too, the last of which ended with a relapse 5 months ago. It is now very severe

    Is any chance it could improve again?

  • Re: "s any chance it could improve again?"

    It depends on the symptom; i.e. were is been generated in the nervous system. In general symptoms can continue to improve for up to 2 years after and attack. Most improvements in the first 6 months are considered to be due to recovery of function and those after 6 months due to plasticity or adaptation.

  • This is maybe out of scope (if so, my apologies and don't answer), but it's nagging me. This didn't bother me when I was diagnosed, but as I have come to understand more about MS, it seems that most symptoms, such as paresthesias and spasticity, are caused by focal lesions that have an effect on a specific part of the body. So the areas of the body start out and worsen asymmetrically as different areas are hit. Only as the lesions proliferate do they come to affect more and more of the body and people start to have parallel symptoms on both sides.

    Is it even possible for it to be MS if my symptoms have largely appeared and worsened bilaterally? For example, I started having paresthesias in both feet at the same time (although I was also having weird intermittent tingling at that time behind one knee) and my feet, legs and hands have largely worsened in parallel. Even my facial paresthesias are usually the same on both sides. Both of my legs seem more or less equally stiff (although it is the right that usually spasms). So it's not absolutely the same on both sides, but a lot more so than it sounds like is usual for MS.

    If it's not possible for this to be MS, is there someplace with a comprehensive list of alternate possibilities that also cause spinal cord lesions and o bands? I've often wished for some kind of checklist or chart of differential diagnoses that made it really clear what symptoms, tests and test results go with what possible explanation.

    And yes, I should ask my neuro about this, but I have tried with the last two (MS neuro and my current general neuro) and gotten nowhere.

  • Re: "This is maybe out of scope …."

    It is difficult to comment on your symptoms without examining you. But the lesions causing bilateral symptoms are usually in the spinal cord; even the paraesthesias in the face. Some of the nerves that transmit sensation from the face dive down into the spinal cord before crossing over and turning back to travel to the brain. The symptoms of MS are highly variable due to the fact that lesions can occur throughout the brain and spinal cord.

    AS I have said before neurologists are usually very good at making a diagnosis of MS with an error rate of between 1 in 20 and 1 in 50. The latter drops with time as disease that mimic MS usually declare themselves quite quickly.

  • Re symptom recovery – are there any studies or observations on what typically improves and what doesmt?

  • "AS I have said before neurologists are usually very good at making a diagnosis of MS"

    Thank you so much for your reply. It's very reassuring. I had more stuff ruled out than most of the people with MS I know because I was atypical in other ways, but I don't think they were paying attentional to the bilateral part and I didn't realize that it was unusual at the time. My lesions are generally described as being in the central cord (for example, 25 mm superior-inferior, 5 mm anterior-posterior central cord T2 hyperintensity) so maybe that explains the symmetry?

  • I would be really interested in your opinion on the Tysabri/SPMS trial currently recruiting. As I work f/t it would be quite a burden to undertake the monthly infusions which have a 50% chance of being placebo…hmm I'm wondering what aspects to consider/weigh up – have you got any advice? Sorry I know this is a tricky question and everyone is different.

  • Re: "I would be really interested in your opinion on the Tysabri/SPMS trial currently recruiting."

    We don't have a treatment that works in SPMS. Natalizumab works by blocking the influx of lymphocytes. we know that in SPMS there is ongoing inflammation so natalizumab may work. The only way to test this hypothesis is to do placebo-controlled trial. I suggest you put yourself forward for screening so that you can get all the information in hand before making a decision. I would give the trial a 30% chance of being positive; i.e. slowing progression in SPMS, not stopping or reversing progressive disability. I am not sure if this answer helps.

  • Thanks, your answer does help. I have put myself forward, will meet w/ MS nurse soon to find out more. I'm not sure if I can face additional travel to a London hospital… especially in the winter months. All these things to weight up, Can you say more about 'blocking the influx of lymphocytes' and what that actually means/the effects of that, or refer me to another post? Thanks, really appreciate you taking the time to do this.

  • Re: "Can you say more about 'blocking the influx of lymphocytes' and what that actually means/the effects of that, or refer me to another post?"

    By blocking lymphocyte migration into the CNS you prevent the cells getting in that are mean to cause the focal areas of inflammation and the clinical attacks. In addition, you stop normal lymphocytes from doing their job, i.e. fighting infections. This is why MSers on Natalizumab are at increased risk of getting PML; a viral infection of the brain. If you want to read more on the blog about this just do a search on natalizumab and/or PML.

  • What is this drug MIS416? They've been testing it on progrssive MSer's, and say it may have relevance to oncology and against infectious diseases. Is it a wonder drug, or is it smoke and mirrors?

  • Innate Immunotherapeutics from New Zealand announced data from their phase 1/2 trial in progressive MS.

    In short this is a fund raising exercise. The company announces positive results so they can get more financial backing for the next phase II/III study.

    It seeems that this was based on 8 MSers over 12 weeks of study. There were improvements in EDSS.

    Therefore is this some wonderdrug or it is regression to mean that is people on trials tend to get better with time as people start when disease is more active. A study of 8 people is meaningless so do not get your hope up until they do trials of 600 of more.

    This an agent that targets Toll-like receptor 9 and inhibtis the innate immune response.

    It seems it wss injected intravenously

  • "Do you not think he's leading us astray?"

    If he is talking stem cells… in a word…. yes….it is still science fiction

    If you have the cure in your hand today……it is going to take 4-5 years to do the phase III trials plus time to get it registered, if you don't then you have to do the phase II trials first which is another 3 years, if you haven't started then you need the phase I so another 1-2 years.

    So once you know there is a cure in the offing it will take time to get to all MSers

    However, who knows? Someone may have the cure in hand and is doing the trials as we speak. The Charcot project maybe…

    We need to know the long-term effects of some of the effective DMT. Maybe start early enough and no more disease. This could be known within 10 years.

    Can we cure animals from their MS-like disease I would say…yes

  • Dear Alvaro
    I would avoid…

    There are no published papers in pubmed on Protomyxzoa as far as I can see. Google it and it goes to Dr Fry in Scottsdale…… the potential recipient of your cash?

    The claims are so wide Lymnes disease MS, ALS Lupus I am very dubious and the article you link to is a ramlble with loads of technical words thrown in biofilms, vegeation CCSVI parasite, blah, blah blah.

  • Furthermore Search Fry SE on pubmed you get 8 references and they are on cancer..so differnt person.

    No published information suggest it is dubious to say the least.

    Find the company and you pay up-front for tests. Lucky for people in New York they don't accept your samples so they can't take your money.

  • Anonymous said…

    MD – what would you think of a drug with the following components that someone praised as a 'cure' for MS? This is not an ad but I am curious what this stuff is:

    First one contains: OPN, TNFa, IFNy, MyD88, TWEAK, CD40, CD80, RANTES, CXCL13, CXCR5, IL17-23, GSKS

    Second one: BNDF, IGF1, NT3, PDGF, CNTF, CD47, CD200, EPO, OLig1, VIP,
    PACAP, LIF, IL-10, TGFb
    Sunday, June 24, 2012 4:39:00 PM
    MouseDoctor said…

    "This is not an ad but I am curious what this stuff is":

    In short: Science fanstasy
    Sounds like the Larry Steinman's Top Ten and the rest

    First one is a group of immune modulators-a cocktail of eighteen agents, none of them licenced for MS as a single entity. Some of the things you may want inhibitors of IL-17, IL-18, IL-19, IL-21, IL-22, IL-23 not the cytokines. Some of the above cytokines make things worse based on their mechanisms of action. TNFa maybe good in one context bad in others anti-TNF makes MS worse. Finally IFNy is reported to make MS worse….Therefore DOOMED

    Second one. This is the repair cocktail. Group of 14 none licenced individually for MS. EPO may be neuroprotective in MS, but blood dopes. However TGFb causes kidney fibrosis in humans…it is a no no in its active form.

    This is a potential problem with using cytokines as treatments they are found in a balance (so raise in one and others change could be in a good or bad way) they act in a sequenced fashion (agent at the wrong time may have unknown effects) and they are pleiotrophic, which means that they have more than one effect and so can do good things say to glial cells but bad things to B cells.

    So at least one in each cocktail raises a known saftey problem so whilst elements may target desirable pathways as a drug cocktail it would be a nightmare for the regulators..

    Importantly where is the evidence?

    I could find a few animal studies to support these individually but some are doing the same thing do you need that many in a cocktail?

    This needs testing to make sure it it is safe and the changes of that are minimal with such a large cocktail.

    This cocktail is not going to happen and for a fact by the time you get your testing done, it would have to go on top of exisiting anti-inflammatories that show some or better level of activity.

  • Monday, June 25, 2012 8:52:00 AM
    Anonymous said…

    Thank you Mouse, good to have such experts on this blog!

    It's probably sugar drops with a fancy label on it – will throw the thing into the bin. Unbelieveably, it was given to me by a GP turned 'natural healer' who urged me to abandon INF beta instead & made by some strange pharmacy in Belgium – very suspicious.
    Monday, June 25, 2012 1:32:00 PM
    MouseDoctor said…

    If a pill contained all of the above it would cost hundreds of thousands of Euros. Just think of the cost of beta interferon and then times it by 18.

    So it is probably a herb, or mix of herbs that have reported to do some thing to some of the cytokines (named above). We can make stories around any bit of half-baked data, but tangible evidence is what is needed.

    If you want to send any more details we can have a look.
    This could be a case for Doing a scully 2

    The physician mantra should be "Do no harm"….with unproven medicine it could be worse than a just a sugar pill……..the bin is a good place.
    Monday, June 25, 2012 2:12:00 PM
    Anonymous said…

    Well, Mouse, the whole story is more than hair rising – doing a scully would be an excellent idea to warn others – I have FOUR culprits all of them more than suspect. I had taken some of them because I couldn't find any reliable info (before finding your blog) & God knows how much harm did I do to myself.

    I think I'm going to drop you an email with the names of the drugs.
    Monday, June 25, 2012 6:23:00 PM
    MouseDoctor said…

    OK our emails are listed under Team
    Best wishes

    Tuesday, June 26, 2012 8:16:00 AM
    MouseDoctor said…

    God knows how much harm did I do to myself.

    You never know, but many of these nutriceutical/herbal remedies have so little of the action that they are claimed to have that they do nothing good or bad except lighten your pocket.
    Tuesday, June 26, 2012 8:22:00 AM

  • I wonder if you are also looking at the issue of Syncytin-1?

    As far as I can establish, retroviral envelopes are pathogenic glycoproteins which – in MS – cause neuroinflammation, neurodegeneration, and endoplasmic reticulum stress responses.

    We know that the human endogenous retrovirus (HERV-W) envelope protein, Syncytin-1, is highly expressed in CNS glia of individuals with multiple sclerosis (MS). And we know that this can result in an increased in Nitric Oxide expression.

    See: “antioxidants ameliorate syncytin-1's neuropathogenic effects raising the possibility of using these agents as therapeutics for neuroinflammatory diseases.”


    In light of this, this quote is interesting:

    "Syncytin expression in astrocytes induced the release of redox reactants, which were cytotoxic to oligodendrocytes. Syncytin-mediated neuroinflammation and death of oligodendrocytes, with the ensuing neurobehavioral deficits, were prevented by the antioxidant ferulic acid in a mouse model of multiple sclerosis. Thus, syncytin's proinflammatory properties in the nervous system demonstrate a novel role for an endogenous retrovirus protein, which may be a target for therapeutic intervention".


    Ferulic acid is similar to curcumin in chemical structure. Ferulic acid is a ubiquitous plant constituent found in plant cell walls, leaves and seeds (which might explain the eat-more-leaves-theory of MS).

    It has been shown to have strong ant-oxidant potential and it has a possibility of inhibiting lipid peroxidation http://www.ncbi.nlm.nih.gov/pubmed/1398220

    So – are you going to be looking at how to downregulate Syncuytin-1? And will anti-oxidants be one way of so doing this? Or NO antagonists?

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