Monday, 23 March 2015

ClinicSpeak: not diagnosing multiple sclerosis

Can I have MS with a normal MRI? #ClinicSpeak #MSBlog #MSResearch

"I have recently had an email query from someone with multiple neurological symptoms. Each set of symptoms are compatible with a lesion in the neuraxis (brain and spinal cord), but the MRI has been reported as normal. The question is can you have MS with a normal MRI? The answer is yes, but this is uncommon."

"Please note that to make a clinical diagnosis of MS, like other diseases, there needs to be a clinical features that are matched with a pathological (abnormal) process; the so called clinicopathological correlate. Please note that many psychiatric diagnoses are not based on this principle, which is why there remains such a large divide between psychiatrists and neurologists in the way they diagnose diseases."

"In relation to making a diagnosis of MS, having symptoms of involvement of the nervous system is not enough; the symptoms have to be linked with objective signs and a pathological process compatible with MS. What do I mean by this? According to the McDonald criteria for diagnosing MS an attack has to be objectively documented; in other words the neurological examination needs to be abnormal and show objective signs of involvement of multiple neurological pathways; this is particularly relevant if the MRI is normal. This is why some sensory symptoms, particularly if they are intermittent, frequently don't fulfill the definition of a clinical attack or relapse."

"For a diagnosis of MS there has to be dissemination in time and space; in other words clinical attacks or MRI lesions have to develop at different times. The current criteria imply at least one month apart is sufficient for dissemination in time. The exception to the latter is the finding of old and new (Gd-enhancing) lesions on the same scan; the assumption is that these lesions developed months apart. The latter, however, clearly does not apply to someone with a normal MRI. What about dissemination in space? The MRI is usually very helpful here, but if  the MRI is normal the neurologist has to rely on the clinical examination, and possibly abnormal evoked potentials, to document involvement of the central nervous system in two distinct sites."

"Another essential part of the MS diagnostic criteria is to exclude other diagnoses. This is probably the main reason for doing the MRI scan. We all know that in MS the lesions can be microscopic hence the initial brain MRI can be normal. If the brain MRI is normal scanning the spinal cord may help and show the telltale lesions needed to support the diagnosis. Finally, I would not make a diagnosis of MS in anyone with a normal brain and spinal cord MRI without paraclinical and laboratory support; i.e. I would want to see abnormal evoked potentials, or central motor conduction times, compatible with demyelination in a particular pathway and I would want an abnormal spinal fluid analysis (positive oligoclonal bands or OCBs). In addition to this several other tests may be necessary to exclude other diagnoses or MS mimics."

"Getting the diagnosis of MS right is very important for several reasons. Having MS can be stigmatizing in that it may affect your future prospects; for example getting a job and obtaining insurance cover. As relapsing MS is now a treatable disease we need to be confident about the diagnosis; some of the treatments for relapsing MS can have life-threatening complications and it would be a tragedy to expose someone to these complications who did not have MS. Based on the literature the MS misdiagnosis rate is in the order of 2-5%; in other words 1-in-20 to 1-in-50 people diagnosed as having MS, don't have MS."

"My moto is if in doubt don't diagnose MS. I would prefer to wait and see than get the diagnosis wrong. If you have MS it will almost certainly manifest itself in the future. Professor Tom Bothwell, who was one of the most influential mentors, would frequently say: 'Time is often the best diagnostician'."

"I hope the message is clear, making the diagnosis or MS, or not, is complicated and requires skill. This may explain why it takes approximately 15 years of training to become a neurologist and why we sometimes get it wrong."



"The following slideshow is a presentation I posted last December. The presentation highlights some of the problems with defining a disease, the diagnostic pitfalls that occur when you try and make a diagnosis of MS and the impact biomarkers have on this process."


60 comments:

  1. Prof G this is a very useful post; thanks for taking the effort to try an explain things to us. Can you please tell me what happens if someone you see, who has previously been diagnosed with MS, turns out not to have MS?

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    1. Re: "Can you please tell me what happens if someone you see, who has previously been diagnosed with MS, turns out not to have MS?"

      This can be very hard as it may mean stopping DMTs and unwinding a long list of consequences of misdiagnosis. There is no avoiding doing it, however.

      Delete
    2. I agree - a very useful post. From what I have learnt on this blog and elsewhere it can be difficult sometimes to confirm a diagnosis of MS because of the number of MS mimics and I can understand the consequences and impacts of a misdiagnosis.

      However, I can also see that neuros must sometimes be stuck between a rock and a hard place if they subscribe to a treatment philosophy of "hitting hard and hitting early", especially if the usual diagnostics such as MRI etc are not confirming MS, and they cannot offer treatment that they do believe is required.

      Not much fun for the patient/s either, being stuck in limbo land.

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  2. Twice now I have come across people with MS who have been on a DMT for some years (on a particular forum). One was on Copaxone and the other Rebif. Both had a follow up MRI and no lesions were visible anymore on MRI. The patient on Rebif had the follow up MRI as they told their neurologist they were getting much worse symptoms. Then all the lesions were gone.
    But this may be that the lesions were now not visible on MRI and are too small.

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    1. Re: "But this may be that the lesions were now not visible on MRI and are too small."

      Yes, I agree. This is why we are moving away from just treating what we can see and are now targeting end-organ damage. The latter includes the things you can't see using conventional MRI and will include normalising brain atrophy rates and CSF neurofilament levels.

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    2. When you say "we are moving to", do you mean the NHS in general? Not sure my neuro offers this..!

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  3. Prof G,

    you state that an "attack has to be objectively documented" according to the McDonald criteria.

    When you read the McDonald criteria the document states the following:

    "The Panel considered again what constitutes an attack (relapse, exacerbation) and defined this as patient-reported symptoms or
    objectively observed signs typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection. Although a new attack should be documented by contemporaneous neurological examination,
    in the appropriate context, some historical events with symptoms and evolution characteristic for MS, but for which no objective neurological findings are documented, can provide reasonable evidence of a prior demyelinating event."

    This clearly states that an attack need not be objective, but that that it is preferrable.

    My personal issue is that my first attack 3 years ago was objective (optic neuritis with optic nerve head swelling), was accompanied by four limb paraesthesia, then a host of other issues (urinary, sensory, balance) occurring roughly 1 to 3 monthly thereafter ever since. Horrendous tiredness/fatigue - overall quality of life probably at about 50% of what it was before. The problem is that even residual sensory syptoms can be absolutely horrible and the fatigue is grim. Normal MR and no OCBs, VERS bilaterally at upper limit of normal (there was a second discrete but less obvious episode in the other eye). It all looks like nothing else other than MS, and the McDonald criteria as written suggest that this would be compatible with a diagnosis.

    If these episodes weren't apparent to me and I present with gradually deteriorating leg weakness in 15 years time, some neurologist would tell me that I have PPMS and that there is no treatment, so I feel it is in my interests to get treated now and that any risk of diagnostic doubt is worth it given the long term outlook in even those with what appears to be "benign" disease. I have a job where even one further episode of ON could very well render me unemployable.

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    1. I have simmalar isue like u , clear mri and spine tap still dx optic neuritis, abnormal vep :( fatigue, tinitus, balance issued etc ..

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    2. With a normal MRI you need objective evidence of neurological dysfunction in a neurological pathway. I am not sure if any neurologist would diagnosis MS in a person with a normal neurological examination, a normal MRI and no para-clinical or laboratory support. You need a clinico-pathological correlate to make a diagnosis of MS; please read paper highlighted on slide 66 for further information.

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    3. Please note that the interpretation of the McDonald criteria will vary depending on whether there is an abnormal MRI or not.

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    4. Prof G,

      does optic nerve head swelling not count as an objective finding, particularly in the presence of reported painful eye movement, decreased colour vision, visual dimming, phosphenes, then photopsia (the latter months down the line)? It is my perception that neurologists have a tendency to underplay the effect that optic neuritis has on people. Going from 6/4 vision to anything less than that in the course of a couple of days then it never improving to what it was is difficult. I really feel for those who have multiple episodes of optic neuritis, but can't get a diagnosis and hence possible treatment.

      I know those who present with ON initially are supposed to have a better course of disease (at least early on), but do you think that those with milder disease should equally have access to highly effective treatment if they and their neurologist can live with the level of risk, as they may have most to gain in the longer term? Is there any evidence that the highly effective treatments are only highly effective in those with more aggressive disease?

      thanks as always.

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    5. Prof G - unfortunately Theoretical Medicine and Bioethics is not a journal I have ready access to.

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  4. Re: "As MS is now a treatable disease we need to be confident about the diagnosis..."

    Prof G, are you trying to provoke outrage with such a comment or are you just being glib?

    So are those with PPMS and SPMS being treated with DMTs? Are the medicines trialled and tested and approved? Do you know something the rest of the neurological fraternity do not?

    Such ignorance and arrogances is inexcusable. MS treatments are wildly disproportionate and you know that. Rephrase, please.

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    1. Did you attend the research day? If you didn't then you obviously didn't hear that an announcement on treatment for progression is on its way soon.

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    2. Slide 3 & 4 of the presentation is of a patient who died of PML as a complication of the treatment of her MS. At post-mortem she did not have MS. On reviewing her history she probably had migraine, a well known MS mimic. This is why we need to get the diagnosis right because some of the treatments we use have life-threatening complications.

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    3. Oh. Which is why I asked how soon SPMS treatment announcement will be...

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    4. Before we get carried away for those at the research day it was evident that it is one thing to do a trial and another thing to deliver treatments.

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    5. Who said we are treating SPMS and PPMS? Not me. It is a sad fact that outside of relapsing SPMS we don't have any licensed treatments for non-relapsing progressive MS. In those young PPMSers (<51 years) with active MRI scans (Gd-enhancing lesions) we used to motivate via an IFR (individual funding requests) to treat them with rituximab. Unfortunately, this has has to stop as NHS England have stopped funding rituximab via the IFR route. We have now resorted to using mitoxantrone or cladribine in this situation.

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  5. I have to decide soon whether to go on Tysabri in ASCEND trial. When will the progression treatment be available?

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  6. In 2009 I had a major attack which left me paralyzed from the waist down for 6 months and permanent loss of bladder function. Since that time I have had other less intense attacks (usually double vision and dizziness) but my MRI's are all normal except one which showed a faint lesion in the pons.

    The first attack was suspected to be ADEM. Since ADEM is known to not show any MRI abnormalities I think I might have recurring ADEM. But at this point there does not seemed to be a difference in the diagnosis with MS.

    Why do MRI lesions fail to coincide clinical decline in ADEM?

    http://www.ncbi.nlm.nih.gov/pubmed/11415907

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    1. Could it be your major attack was Transverse Myelitis?, this is often triggered by infection. TM is often quite a severe attack and it sounds like yours was severe. TM can be the first MS attack.
      An attack of ADEM can lead to MS on rare occasions though this is contested and the lesion pattern than can help diagnosis. Yours is an interesting case as your MRI's are normal except lesion in pons which I expect may be connected to your double vision.

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    2. I had the test for the NMO antibody and it was negative. I also had a battery of test to look for a pathogen, twice. Both times negative. My spinal fluid was checked and no ogliclonal bands but a high IgG index and elevated proteins and WBC counts.

      It seems like I have symptoms of MS (Lhermites sign, Babinski reflex, etc.) But the MRI doesn't show permanant lesions. I am dxed with MS as a working diagnosis and am on meds but I think it might be more related to recurrent ADEM which if it keeps reoccurring there is no distinction from MS at this point.

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  7. Page 34 of slides lists trauma as a cause of MRI white matter changes. That is interesting.

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    1. Yes, many of the MSers seem to have had head trauma - I certainly did fall off a high bed as a baby so the link between a damaged brain barrier and white matter changes i.e. MS is quite logical.

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    2. I had head trauma six weeks before my first MS symptom.

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  8. For those who couldn't attend the research day can you elude any further to the treatment for progressive types or when this will be announced? I know you want to stay loyal to those who came but some had no option
    Thanks

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    1. The next set of announcements is at the AAN in april we thing we already know what one of the trials will say...a bust I am sorry to say but as to the other we will need to wait until April. The videos will take a couple of weeks or three and then we will need to edit out the beansz that seemed to flowing freely.

      I am sorry you could not make it, It is also shame that so many people who were no-.shows and did not let us know's there were people that we had to turn away...its such a waste money.

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    2. Mouse, I'm left confused. Good news about a progressive treatment was on its way. Now it looks like bad news about a progressive trial is on its way! And the good news about a progressive trial may be round the corner, but actually it might not make it as a licensed treatment. The white knights posts and this confusion about what was said at the research day (I didn't attend) leaves me frustrated beyond belief. Sounds like you need to keep a tighter leash on MD2. One thing I'd like to see from this blog is clarity and honesty. Too much fog is doing my head in.

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    3. Yes but, no but
      Look at the slides. There is the information....You have to wait for the videos to see what is said and deal with the frustration.

      There there is also what was said at the tables.

      There were 26 tables with one researcher and they were rotated 6 times from table to table So it is impossible to say what was said no one person would have got the same thing repeated.

      Keeping leashes on people and were treated like dogs....then they may bite:-) or pooh on your lawn:-)

      We like to keep it honest what are we being dishonest about?
      It is also clear...clear as mud but clear:-)

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  9. I'm pretty sure we all know one of the trials is a bust but is this relating to the biotin trial being a success and a treatment option?

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    1. Do you know the results of the biotin trial...Novartis released the results of their trial to the shareholders so we know about that

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  10. If this is all to create a buzz then md2 should be banned, you cannot play with people's lives like that!!!!!!!!!!!!!!!!!!!!!!!!!

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    1. Re: "If this is all to create a buzz then md2 should be banned."

      This post was not to create a buzz; it was in response to an email I received about someone with a real problem; symptoms suggestive of MS, but a normal MRI. MD2's simply responded to a comment from someone with made a rather pedantic, and possibly aggressive, comment about the fact that I had not differentiated between relapsing and progressive MS when I mentioned that MS was a treatable condition. This has now been corrected. What MD2 was referring to is some work we at UCLP are doing targeting the processes that underlie progressive MS. Apologies, if we have offended you. All we are doing is trying to have an honest dialogue with MSers and their families about MS-related research. May be it is time for us to consider closing down this blog?

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  11. He's implied that a treatment is near and that is disgusting, he has no idea what effect his flippant remarks have

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  12. I dont think it's time to close it down just to realise that these flippant comments have a great effect on people looking for cures desperately before anything becomes to bad to cure or stop

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    1. Fine. On one one hand we get comments that the blog is full of bad news, then you try to give a hint that there is some good news to come (which we can't announce here before it's made public) and that's no good either. Looks like it's time to shut up.

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    2. MD2

      Please don't take it personally. I think we are all a bit grumpy because we were looking to hear the good news on the research day and now we have to wait again before it's made public and another trial seems to have failed so again we are left in the dark.

      It's so stupid really that you have to keep quiet about good news which will immediately impact the lives of MSers for whatever (probably financial?) reasons. Actually it's sick and disgusting. But I guess it isn't your fault.

      Oh and another thing regarding the no-shows at the MS Research day. Shame on you - you are seriously selfish. I also wasn't able to attend but it took me 1 minute to email and let the team know. Others deserve a chance to hear the good news and you took that away from them. It doesn't matter what state your MS is in - but that is equally sick and disgusting - to not be able to spend 1 min and give another person the chance at happiness.

      As a solution all people who do not attend such events should be banned from going to any future research days. How you like them apples?

      -Kon

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    3. MD2

      come back and don't sulk. i know you mean well and wanted to give us hope. thanks for that.

      I know that you can't say more (probably due to a patent/legal stuff).

      I really like you lots x

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    4. "It's so stupid really that you have to keep quiet about good news which will immediately impact the lives of MSers for whatever (probably financial?) reasons."

      It is not financial just courtesy to the researchers involved. Agree that it's hugely disappointing that people who booked tickets for the research day didn't come and so others who could missed out. We might have to rethink things for the future.

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    5. Banned from future events?

      The question is what form future events occur. Maybe we need a another format where things don't have to be planned and paid for.....yes these things are not free, so it was money down the toilet for the no-shows

      If we had delayed things by a month we could have a different meeting , three months and a different one again.

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    6. People not attending? This is so common. Patients do not turn up for precious hospital appointments, GP appointments, physiotherapy and other therapies without a thought for those of us languishing on waiting lists. I understand the outrage but I don't understand what causes this selfish behaviour.

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    7. My NHS bowel and bladder service appointment letter mentions I will be charged if I don't attend the appointment. It may be a hundred pounds, it's because some people don't bother turning up or letting them know they can't make it. Same with my private dentist, they require at least 24 hours notice for me to cancel appointment or I will be charged something.
      I would be happy to pay £5 for a ticket to the research day. This money could go towards MS research or catering/refreshments on the day.

      Delete
    8. I hope it wasn't anything more sinister. Having said that the room was pretty packed.

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  13. It's not the hint of news it's the target audience and their desperation I guess
    Maybe when it comes to news such as that it's woth being more descriptive and not so suggestive, how long will it take for this good news to make real life impacts?

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  14. I think it would be an overreaction to close the blog. A lot of people rely on this blog for news on research and more. It's almost the only place to get an honest opinion that isn't written as if it is for children.

    Closing down this blog would be a big loss to lots of people. Believe it or not, not all neurologists are equal or interested in new treatments. Reading this blog allows the patient and their family to keep up to date with new treatments and methodologies - that they will not neccessarily (and unfortunately) be told about in the clinic.

    Regarding the tantalising recent posts from MD2, fine, I think most people can wait for the news to be released properly. Equally, it's also natural for people to want good news quickly. They are no different to your team spilling the beans on Saturday - they couldn't contain it. Just human nature really.

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    1. Well said, Anon @ 10.40am - and the reach of this blog is far wider than just the UK, and it benefits so many people. I have found no other site like it.

      I don't like having MS - I hate it and what it has done already and is most likely going to do to me I the future. I would give a lot to not have MS, but I do. It could be worse - I could have terminal cancer or Motor Neurone Disease instead.

      To those Anony-mouses who keep posting nasty sniping remarks - I suggest you go and buy one of those old Yogi Bear inflatable bounce-back punching bag toys and stop using Prof G et al for venting all your frustrations on. Go get a life, even if it's not quite the one you expected because MS has picked on you.

      (Now there's a thought - maybe Team G could use a few of the Yogi Bear toys to give a good smack to when the Anonymous grumpies get a bit overwhelming - hmmmmm...... that could provide a few interesting spectacles........)

      Delete
    2. Swedish Sara gave us the hedgehog
      http://multiple-sclerosis-research.blogspot.com/2013/02/hedgehog.html

      She also gave be a Swedish Troll on saturday...I wonder if MD2 is getting some British ones:-)

      Delete
  15. Now calm down everyone.

    My suggestion is to keep it factual;

    obviously you got some good news to share - that's good.

    MSers get overexcited easily cos we're desperate but it's better to keep it real to spare us the disillusionment.

    So the scale could look like:

    1. just a hint at the lab = okay news
    2. a positive trial = good news
    3. pills coming soon = fabulous news!!!!!!!!!

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    1. Sorry to say even it it were the best news ever...we would still get the grumpies....... funny what a difference a weeks makes....last week butter wouldn't melt in the mouth of MD2 and now he's/she's (did we work this one out at the research day) the devil:-)

      Maybe we should trash any post with the word "disgusting" in it otherwise I might have to tell the joke about the bloke and the custard:-)

      Delete
    2. I remember a 2 Ronnies restaurant sketch where one says "That's disgusting", other Ronnie holding up two hands: "That's a lot of gusting" ;-)

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    3. Hi I hope I didn't insult you with my "disgusting post". I also still like MD2 and she/he is definitely no devil!
      I suggested financial reasons as the reason you couldn't say more because I am still annoyed that the white knights idea didn't work out, but I more than understand respecting other researchers involved. Hope you guys have a great night.

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    4. Has the knights idea not worked out? I saw someone with a red hot poker:-)

      P.S. If you got the beans at the weekend, when they were indeed spilled by some please keep it to yourself for the time being.
      It was 57 varieties time from me:-).

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  16. So what is the actual truth regarding the news on treatment for progressive Ms? I still can't quite work it out after all this? Is there a treatment close?

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    1. We don't know if there is a treatment close..we have to wait and see, just as you have to do.

      The closest we can be to knowing, is a phase III trial on Biotin we have to wait until April for the result to be announced unless it has leaked somewhere. If that is positive then we have to wait until the next trial ends that readout is towards the end of 2015. The next phase III is ASCEND I think that was due to read out at the end of the year. Anything in phase II is wait for phase III trial. We have had positive news with simvastatin in 2010 and we are still waiting for phase III.

      Anything us researchers do, then it is 10-15 years away as we showed on the research day, we may get excited by the results and want to tell you but, I suspect many of you won't be that interested because of the time to translation.

      However, a treatment could be on your doorstep and the only way to get it is to be part of the clinical trial......There is MS SMART and there is PROXIMUS, which will soon die without your involvement. You all talked a good game when asked but few are prepared to walk the talk.

      We tried to switch off the immune response such that it will switch off the immune response without affecting other immune responses, so using this logic you could switch of immune response to the oligodendrocyte or myelin and you could get rid of the JC virus just fine......However not enough interest and so it was stopped and the trial died and know we will never know the answer.

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    2. Did you write the puzzles that were used at the end of the TV series 3-2-1? MS hasn't yet affected my cognitive skills, but you have left me completely muddled. Would you mind if I joined you and Mouse2 for a drink in your local one evening. Seven pints of Guinness and two pickled eggs might each and the 3 of us could sort out the world's problems and you could de-muddle me on all this progressive trials / treatments saga. I think the mice docs have earned themselves a little break. Time for the Big G to take the reins for a bit.

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    3. Always up for a bit of problem solving over a pint.

      Delete
  17. What's involvrd in the MS smart trial?
    From what I've seen the biotin trial looks very good, but what's the science behind it? Not that it matters if it slows or stops progression and is as harmless as proposed, surely that's a win?

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