Unrelated Blogger Comments November


Sometimes you want to say something that is unrelated to the current threads. This is the place for you

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  • I had a bout of cholecystitis recently, which saw me as a hospital inpatient for 7 days and 7 nights.
    They were very thorough, bloods chest X-ray's MRI Scans, CAT scan , physiotherapy, rehabilitation, 7 days intra venous antibiotics, the works. All of which I'm am extreemy grateful for, and now much recovered

    The reason why I mention this , in contrast to my treatment for MS it enraged me. It served to highlight just how lacking in therapeutic treatments neurology has to offer.

    Where is the urgency to treat, make better, discover the cause ,reduce the appalling disability and associated personal calamities that come with the diagnosis? Let's have the urgency to make better , and provide extremely effective treatments as we do for a gall bladder full of stones and pus.

    What were the medics thinking when I reported weak legs, weak bladder, loss of balance and cognitive abilities and therefore loss of employment.relationships, opportunities, income, energy, just to mention a few. Did they feel disappointed and distressed at their lack of knowledge and the tried and tested treatments of MS . Did they feel impotent and depressed as they shrugged their shoulders and said "not in your life time."

    "Nothing can be done" still rings in my ears and I'm angry, very angry.

    The tide is beginning to turn though, with new drugs , and new treatment paradigms' almost a renewed interest and that it's possible to change the course of the disease and therefore peoples lives.

    The social media has been a real boon, not only in providing caring and sharing through groups such as these, but also infomation sharing from the clinical experts that are immersed in the world of neurology. The people that do want to look at the problem differently, have got a mountain of bureaucracy to climb .

    In this age of technology we have the chance to explode stereotypes and suspicious conspiracies, and to base our treatments on good evidence, humane decisions and open communication.

    • I think one of the big problems with MS is that patients often get disabled over the course of a neurologist's career and therefore at times of slow incremental progression it's easier for the 'treating' doctor to rationalise that the disease isn't all that bad.

      A lot of money has been poured into stroke treatment in recent years, but unfortunately the urgent treatments for acute stroke aren't a panacea as yet. But the services for 24hour urgent treatment for stroke have nonetheless been put in place at great expense.

      I'm not saying that this shouldn't be the case as stroke is a devastating disease and can take someone of any age, but more typically those from 65 upwards, and render them disabled or dead.

      What is frustrating is that a 70 year old with MS will often be a very disabled person, just like a 70 year old who's had a moderate to severe stroke. Because the person with a stroke's disability occurred rapidly that is seen as a very bad thing. The person with MS who had slowly and painfully gaining disability over decades just doesn't a look in by comparison, despite having the best years of their lives absolutely blighted by the disease.

      In summary:

      Very rapid accumulation of disability = considered a very bad thing (despite many non disabled decades before)

      Slow tortuous accumulation of disability (with many potentially miserable years before) = less noticeable

      I'm not sure if this is too cynical, but I think MS has been a bit of a Cinderella disease in comparison with many others, despite the misery it inflicts on people and their families

    • A full under standing of progressive physical diseases is needed before people will truly understand the severity of these diseases. This is done through education. Only now is the full impact of MS and other similar diseases been understood. I think that is because drugs are being developed

      I've had MS since 1979, medically retired 2012. Very few people know or appreciate the impact this has had on my life and how my family have coped.

      education, Education, EDUCATION.

  • I share your anger. The neuro who diagnosed me offered little hope apart from saying that some with MS 'don't get it that bad'. I was then sent away and told that i'd need a second relapse before allowed to start an interferon. 3 months later my dad got a kidney condition and was rushed to hospital. Eventually a couple of Profs from a central London hospital came to see him. Over a few days they tried different things and within a week he was out and back to full health. I'm envious of his situation and the contrast with neurology where you are sent away with a disease that will eventually destroy everything and you good heath has gone forever. I am grateful to Team G for looking at different approaches – hit hard and early, the Charcot project. There's also the neuroprotective trials. Hopefully some of these will come good. However, repair is what i need – i'd be happy to get back 50per cent of what i've lost.

  • In regards to the notion that MS is not for certain an autoimmune disease, I think the fact that the recent discovery that the Kir4.1 potassium channel is an autoantigen in 50% of msers raises extreme doubt on this line of thought.

    Furthermore, studies in mice who were bred without this channel way back in 2001 seems to characterize what ms is:


    "Indeed, Kir4.1 is one of the few genes that encode neither a myelin protein, a protein of myelin synthesis/degrada-tion, nor a protein involved in the immune response to myelin, yet still lead to CNS demyelination or dysmyelination when ablated."

    "it is a novel observation that CNS axonal degeneration occurs secondary to genetic ablation of an ion channel rather than of a protein directly involved in the structure or metabolism of myelin."

    "However, we do not believe that this additional damage to neuronal cell bodies implies that the neurons them-selves express Kir4.1; instead, the damage may arise secondary to inadequate K ϩ siphoning or other metabolic support by the poorly functioning Kir4.1Ϫ/Ϫ oligodendrocytes, the cell bodies of which neighbor the large neuronal cell bodies in the gray matter."

    Hopefully with this knowledge we can truly start working on a cure.

  • One problem…i have already seen an abstract that does not repeat the founding observation with less rhan ten percent activity. So lets see this reproduce As to genetic ablatiom so molecules are needed for function block them there is not function but that does not need to mean it is causal.

    • Even if it's 10%, that would be significant for that subset of MSers? There would be a potential treatment here for that subset.

    • I think one thing that should be considered is that in MS, antibodies seem to be developed within the CNS which leads to ogliclonal banding. To me, it would make more sense to try to identify if these CNS antibody are indeed Kir4.1 instead of looking in the blood.

      For NMO on the other hand, only 30% have ogliclonal banding and in many they disappear. So looking for antibodies in the serum makes more sense.

      I would think the scientists who first discovered KIR4.1 antibodies in the blood would be most interested in determing if there is a high prevelance of KIR4.1 anit-bodies in the CSF. This would seem to be a more robust marker for MS in my opinion.

  • I have a question for the medical professionals about PML. I am hopefully going to be started on natalizumab very soon and am very keen to be on the drug regardless of the risks (life is full of risks, no?)! I do like to have all the information, however, and whilst I have read a lot of information about the risk brackets and symptoms of PML, I am not actually able to understand HOW PML might actually kill me. My loved-ones have the same opinion as me that natalizumab is worth the risk and I will be writing a living will, in case the worst happens, but we do want to understand what PML might do to my brain to cause death so that everyone can be best prepared for all eventualities.

    • The JC virus invades and kills oligodendrocytes and therefore myelin is lost from the nerves, therefore nerves stop signalling properly and without that your body does not work properly. It is like a very, very rapid form of very aggressive MS

    • Thanks for your response. I wondered if it attacked the parts of the brain that deal with automatic functions, such as breathing and heart-beating as the list of PML symptoms, such as problems processing language, visual problems and body weakness did not seem to indicate a fatal outcome, no matter how bad they got.

  • Not really, beside being interested in the MS area and having a small investment in Active Biotech. No affiliations or financial interests in TEVA. ;D

    • We feel the same but at the moment they are the best game in town for the foreseeable future.. We've done quite a bit on antigen-specific immunotherapy in our mice over the years but suspect that translating this to the clinic is a long way off, if ever. Good to see that neuroprotectants for MSare finally making an appearance though.

    • This is a bit scary MD 2. You feel negative about the long term risks of alemtuzumab et al? Please explain- do you mean it may not 'cure' MS for the majority of MSers or that it has possible dangerous long term side effects (not thyroid)?

    • Not negative but cautious if you remove large parts of your immune system for large periods have potential problems with infections etc, With an antigen-specific approach this problem is avoided. We have seen how powerful this approach can be.

    • It's the numerous studies that are repeating correlation / association I find interesting.
      Zamboni's first paper highlighted a difference in the sub types of MS just has this one which was published this November. The questions are still there for me, if it was merely a case of vascular problems a result of chronic illnes that could be attributed to other illnesses then why are we see studies duplicating patterns ?
      Or if you like, placement of lesions result in expected MS symptoms and it seems to me studies are starting to show correlation of venous issues to leasion placement. Lots more studying I feel.

      Regards as always.

    • Actually, the correct way to measure for CCSVI is by standing on your head with one arm tied behind your back. If they would measure it correctly they could reproduce Zambonis original results [!]

  • Dear Prof G/MouseDoc,

    I am one of the adherents to your 'early, aggressive' strategy and I am looking to receive Alemtuzumab as soon as it is available (paying privately, as can't wait for NICE). I am very interested in your induced self-tolerance theory (if that's the right phrase for it) and wonder if I should be looking at following up the Lemtrada with GA for that purpose? If so, do I need to commence immediately after the Lemtrada (i.e. before the immune system 'reboots')? Is there some other combination that would work better/equally well? I'm not sure my neuro knows much about this and so wonder how I might get some advice about it? In a post some months ago you (Mousedoc) mention a trial that you are recruiting for along these lines – do you have details of that and how it fits in with the above?

    • The approach does not work effectively if there are no white blood cells to switch off.

      Next question is GA the right antigen?

    • With lemtrada deletion the cells go for a long time so the time interval is less clear cut.

      See below with regards the trial,this has been difficult to recruit and may need to be closed down or the protocol changed.

  • Sorry MouseDoc – I don't understand the "The approach does not work effectively if there are no white blood cells to switch off" sentence? My (no doubt over-simplified and probably wrong!) understanding of the approach is (a) suppress immune system (eg Alemtuzumab) (b) expose the 'new' immune system as it grows back to something like myelin (possibly GA, possibly not).

    Can you point me in the direction of the trial you mentioned a couple of months ago and the inclusion criteria as I may be interested…

    • To induce the tolerance you deplete and give antigen when the cells are regenerating, but if you give the tolerance regime at the same time the depletion it does not work effectively. Therefore you need cells to be present so you can switch them off,

      Does this work with Glaterimer acetate I don't know. The tolerance is antigen-specific and GA is not myelin. In the past treatment with mitoxantrone was followed with maintainence GA.

      Our trial was to turn off immune responses to beta interferon using mitoxantrone as a depleting agent, not using myelin because if it went wrong it would only affect beta interferon whereas if you used myelin it could drive relapses. However the Miller/Marting group have used myelin peptides. Although some people relapsed within 2 weeks of getting the peptides

    • The article above sites a paper that suggests that GA provides non-specific antigen tolerance through type II monocytes. At least this is the case in the mouse:


      So, regardless if the autoantigen is myelin or Kir4.1 or something else, GA may induce tolerance.

      I'm staying with GA unless it fails to work, shots or no shots.

    • So – leaving aside the 'is GA the right antigen' issue; if you were trying to mimic this approach with Alemtuzumab – when would you start GA? When does an Alem treated patient start to regenerate his cells? If you were taking Alem, would you take GA like this in an 'best you can do without being on a specific trial' effort to approximate induced tolerance?

    • I would have to have a look at the data with regard to presence of antibody and deletion but it has to be said there is no evidence to suggest that GA after Alem has any benefit above Alem alone and injecting GA is not without consequences. Maybe Teva or Mylan would like to do theses studies.

  • Mouse,

    Final warning. I've asked you before to refrain from your gobbledygook, dungeons and dragons, white knight / red queen / black swan posts. And what do I see today? A good news for white knights posts. What is the good news. What please do you take in all this cludo / Agatha Christies nonsense? If there's good news tell us. We suffer from anxiety so don't make it worse! Iv'e e-mailed Prof G and if the silly posts continue, the pony tail will have to go, you'll be required to wear a tie, and Prof G will mark you down in your annual appraisal + you'll only be allowed to murder 200 mice per week (50% reduction). Please share news – no more Lord of the Rings nonsense.

    • Yes but there is nothing we can report on because it is simple words and claims on a website and no publication that we can comment on. When published we can comment on it

      However the approach and publications from this Canadian group(s) have been reported previously.

      This is the most extreme form of immunosuppression as you ablate the immune system and replace it with a Bone Marrow Transplant using stem cells harvested before the ablation of the immune response. It is very effect but carries a mortality risk.

      The question is what happens in progression, whilst we have yet to see the full demographics of the people there are studies that indicate that this approach does not stop progressive MS

      As expected it irradiates relapsing MS

  • Mousedoctor,

    The links to Unrelated Comments at the top of the page haven't been working for quite a while on the mobile version, and also on the full version when I tried it. Just thought I should point it out.

  • Can someone please explain these puzzling results?

    Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort.
    Ramien C, Pachnio A, Sisay S, Begum J, Leese A, Disanto G, Kuhle J, Giovannoni G, Rickinson A, Ramagopalan SV, Moss P, Meier UC.
    Mult Scler. 2013 Nov 5. [Epub ahead of print]

    • Ute (Meier UC) has made a post on this. I have forgotten to post this, but hopefully I can remind Ute how to post so we can do it next week

  • Profs,

    What is your opinion regarding if it's appropriate to grant RDP to Tecfidera or not?

    Since Tecfidera is a generic drug ( Fumaderm ) and there is no evidence saying Tecfidera is "safer" than Fumaderm, what would be the reason from a regulatory point of view to grant RDP?

    If the EMA gives in to such arguments from Biogen that they will not launch Tecfidera if you don't give us what we want. Then the regulatory landscape will be non-predictable going forward.

    Appreciate your comments on this.. since I guess if this ends up with a RDP.. it will not be the end of the story.

    • It all depends if Biogen-Idec can substantiate their claim that BG-12 (DMF) and Fumaderm (see below) are different drugs with different mechanisms of action. I know that Biogen-Idec have data from animal and in vitro work showing that the two formulations may have different mechanisms of action. If their case is strong enough then the EMA will have to grant them regulatory data protection (RDP). I am sure some lawyers are making some serious money fighting the case for Biogen-Idec and the EMA; another example how Pharma supports the wider economy. Some of the Big Pharma companies employ thousands of lawyers. A very sad state of affairs. At the end of the day their primary responsibility is to make money for their shareholders; lawyers help them achieve their objectives.

      Fumaderm's main constituents: Calcium Monoethyl Fumarate, Dimethyl Fumarate, Magnesium Monoethyl Fumarate, Zinc Monoethyl Fumarate

    • Well the Jury is in and the EMA have sided in favour of Biogen…….Perhaps not surprising as I have been told the EMA is about 85% funded by Pharma, The figures for the MHRA are even higher. Not surprising that the regulators sets the bar so high that none other than Pharma can afford to develop drugs

      P.S. I have not attempted to verify these figures so hopefully I am not being misled by my source

  • Does Fumaderm really contain Dimethyl Fumarate (rather than Diethyl Fumarate)? It's easy to see how mono-ethyl fumarate derivatives will co-exist with diethyl fumarate in synthetic drug; to have dimethyl fumarate present in the mix, one has to add it on purpose.

    • I have noticed this, but I am not sure how we remedy this one. I have not changed anything in the system and so it may be a Google brain fart as they power the search engine. Maybe ProfG has some thoughts but if you have any ideas it may be helpful

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