Ask Barts-Feb

A

Sometimes you have a question that is unrelated to the posts and this is the place for you.

Will the MHRA follow the FDA or the EMA guidelines in future?

Today is another day but it shows us the importance of having sufficient information to make an informed choice.

The Brexit Beard has been shaved (The Last Leg@TheLastLeg) and is being auctioned for the Australian Bush fire appeal, so please give generously

Adam Hills and the “Brexit Beard

ProfG and NDG have done a runner this week, to avoid their Blog responsibilities, to risk life and limb to get abit of vitamin D. They have left yours truly to “mouse the fort“.

So we all know whilst the Cat is away, the mice will play.

As the New year came in, you (well, it could have been just Mr. Angry having a rant) said “what have you lot been up to?

So this week I will give you a taster.

Adam Hills and the Gang started to do the Last leg to cover 2012 paralympic games in London as a late night TV show. The British Public really engaged with the paralympic games, and the stadia were full, and the competitiors tuned into and were guests on the show. I think it was the US wheelchair rugby team, who gingerly asked a question, that would not be deemed “polictially correct” if asked by an able-bodied person, about disability and they stated the question with #IsisOK.

So you can tweet the question to the Last leg, which is now simply a topical late night show seem in the UK and sometimes I think in Australia too, to get an answer, starting with #Is it OK which now it has a life of its own.

For example

Don’t get it…read here

This week we should tweet @lastleg #ItisOK that disabled people are asked to take physical risks to do drug trials for the data (not in the company’s interest) never to be published?

About the author

MouseDoctor

76 comments

  • Dear MouseDoctor and gang
    I have SPMS. Over the last few months, on average once a day, I seem to ‘forget to breathe’. I might be watching tv with my feet up, or reading, or have just gone to bed (but not asleep) when suddenly I am aware of getting palpitations and feeling dizzy and light-headed, and then I take a big gasp of breath and things gradually settle down.
    Might this be due to MS? Or is it more likely to be something else?
    Thanks in advance,
    Laurie

    • Dear Laurie
      Thanks for your question but the neuros are on hols and we can’t give personal advice on the blog anyway, especially as we do not have access to your notes etc.

      I am not a neuro

      Sleep apnea (not breathing during sleep) is a common issue in MS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425840/
      and apnea whilst being awake can happen https://en.wikipedia.org/wiki/Apnea

      One of the most common sleep problems experienced by everyone – those with MS and without – is a disorder known as obstructive sleep apnea (OSA). Obstructive sleep apnea occurs when the upper airway partially or totally collapses during sleep, leading to a diminished or complete blockage of airflow, despite an effort to breathe. As the body struggles to restore airflow through the blockage, you partially awaken and sleep is interrupted. Another, less known, form of sleep apnea is known as central sleep apnea (CSA). Unlike OSA, CSA arises because of a lack of effort to breathe during sleep. Both conditions can lead to poor sleep quality and decreased blood oxygen levels throughout the night. The brainstem (bottom of the brain) controls muscles that keep the airway open when we sleep, as well as our drive to breathe when we are not awake. In MS, demyelinating lesions can form in the brainstem, disrupting the pathways that control upper airway muscles and respiratory drive.

      Speak to your MS nurse and neurologists about, and they can look at your scans to determine if the can see anything and can do the necessary clinical investigations.

  • Hello Mouse Doctor,

    I recently completed ocrelizumab 1a and 1b. After each infusion I experienced tender swollen lymph nodes in my neck and under the jaw. The swollen lymph nodes started around 48 hours post infusion. I had no infection and other than feeling fatigued post treatment felt okay.
    I was wondering whether the swollen lymph’s were a result of my body trying to regroup post infusion, or were they a result of my lymphatic system cleaning up the detritus resulting from infusion?
    I realise it is both unethical and impossible for you to comment medically, but a wee bit of information would be great.

    • Ocrelizumab is a depleting monoclonal antibody and after an infusion the ocrelizumab will get distributed round the body and it will aim to kill B cells in the blood, spleen and lymph nodes, ec. Once killed the dead B cells will get cleared up by other bits of the immune system. What survives will attempt to regrown. I am guess this may be the reason why you lymph glands feel abit odd.

  • My MRI scan came in and it shows ‘excessive demyelination’.

    Is this serious?

    I have PPMS and have had since my mid-20s. I’m 42 this year and EDSS around 6.5. Walking needs aids, though, still get about and go to the gym too.

    • Not sure what ‘excessive demyelination’ means. Standard MRI sequences can’t tell you this. I suspect it means a high lesion load.

    • The scans (probably T2) show areaas of lesions (T2), whether this is demyelination or not is hard to tell, but if you are EDSS 6.5 you will have accumulated lesions over the years and this can be seen in the scans

  • Would an MRI done to see if things have got worse done in December, after a one in May, not yet reported on/looked at by anyone be a normal time procedure?
    A possible turn around time of at least 6-8 weeks, is this normal?

  • what is the opinion of the thoughts of Alfred Miller,M.D. and his fascination of Neuroborreliosis.?

    I came across some of his tweets in response to Prof GGs account and it strikes me as something to be dismissed, but wonder what the truth is?

    • I have read his Twitter posts of the last few weeks, and imho he is making exactly the same mistakes that MS researchers are making.

      He thinks MS has a single cause. I question this after years of studying past and present MS research.

      Instead, it appears that MS can be caused by various infections. MS should be understood as a symptom rather than a disease. EBV, HHV-6 or VZV and other (herpes) viruses can cause MS, and Borrelia can be involved in the development of MS the same way as C. pneumoniae. The causes and triggers are not the same in all people.

      And I would not be surprised if there are even regional differences in the cause, i.e. in Brazil MS is mostly triggered differently than in Scotland or Canada.

      Perhaps there is even a time component, i.e. there may be different pathogens that influence the course of the disease in different ways. It could start with C. pneumoniae as the trigger for a relapse, which is eventually cleared by the EBV-compromised immune system and some weeks, months or years later another infection triggers another relapse, the intensity of which again depends on the pathogen.

      This is the best explanatory approach I have come across so far: https://www.ncbi.nlm.nih.gov/pubmed/28755684

      It is no coincidence that there are many pathogens that are repeatedly associated with MS.
      David Wheldon, Charles Stratton, Alan McDonalds and all the others who are repeatedly pointing out (bacterial and even fungal) infections as a cause for MS must not be dismissed so easily.

      What is needed here is a combined study that looks at all these pathogens (and not just one) that have already been linked to MS and another study using antiobiotics, antifungals and antivirals as a treatment regiment, maybe even combined with current DMDs to quickly remove EBV from the system.

    • I don’t know…marketing perhaps.If they work the same way why would one be better than the other? One difference is ocrelizumab is continuous treatment and so should stop break through. Ther has not been a head to head

  • Is Aubagio good for later stage MS? Does it help with brain atrophy, and has it been associated with Steven Johnson Syndrome?
    Thanks!

    • Is teriflunomide good for later stage MS, I dont know I would like to see data. In terms of atrophy I think it is better than the effect on relapse would suggest. There have been reports of SJS on teriflunomide

  • ********What does Copaxone do that ocrelizumab doesn’t do?
    Or in this day and age, should that be the other way round?

    ********If the odds of progression from RRMS to the next stage are roughly 80%, do these “hard hitters” possibly delay how quick that will go?

    • Question 1….Do you really want me to answer this question.

      Question 2….Hard hitters I think the answer is yes if you start quickly enough

    • I like it T-time I’ll have a look but first thought is , it suggest IL-17 doesnt have to get into the brain, but the question is what happened to IL-17 blockade in MS….last I heard it wasn’t been developed further cose it isn’t good enough

  • Suicide

    Neurological disorders are linked to elevated suicide rates

    A newly published study in JAMA shows that people with neurological disorders have a 75% higher suicide rate than people with no neurological disorders. Still, suicide deaths are rare events. While the suicide rate for the general population is around 20 per 100,000, the rate for people with neurological disorders is around 40 per 100,000 person-years

    The study shows that people who have been diagnosed with amyotrophic lateral sclerosis (ALS) or Huntington’s disease have particularly high risk, as the suicide rate associated with these disorders is four to five times higher than in the general population

    Furthermore, people who have been exposed to traumatic brain injury, multiple sclerosis or epilepsy have a suicide rate double the level of the that among those with no such disorders.

    https://medicalxpress.com/news/2020-02-neurological-disorders-linked-elevated-suicide.html

  • In your clinical practice, do you do/advise DMT’s switch in the absence of evidence disease activity? (for example to go proactively for one of the big guns ?)

      • Yep i remember…Now ….. 🙂

        Anyway how do you mwrry this:

        I now look at the Charcot programme and ask where are the memory B cell talks? A couple of years ago, we suggested that all drugs that work in relapsing MS target this sub-population of B cells.

        Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. EBioMedicine. 2017 Feb;16:41-50.

        The drugs that work the best, target this subpopulation the best. If you deplete memory B cells you inhibit MS, if you don’t, you don’t ,and natalizumab traps them in the blood so they can’t get in the brain. There it is, MS treatments are so easy to explain and you can make it T cell dependent or independent, depending on how mischevious you want to be. The choices for you and your neuro become in my opinion…. very simples.

        With this

        So in conclusion, don’t let anyone try and convince you that MS is only a B-cell disease. It is a T-cell and B-cell disease and we are really lulling ourselves into a false sense of security by thinking anti-B-cell monotherapy is sufficient to treat MS

        Obrigado

        • Charcot talks….there weren’t really any. We were snubbed?
          There was an EAE talk which can largely be discreditted although they probably said the right things for the wrong reasons and one person did some kind of comment on them. It therefore says some thing about the thought process of the meeting. The first talks were all about T cells

        • I can change my mind as data emerges however,

          Yep the mememory B cell effect has been consistently supported and whilst I can made an extreem view about T independent B cell activity, this is not the likely biology as T cells have evolved to help B cells….However, it is clear that you can get big effects without having to deplete T cells by if you inhibit the memory B cells you can be inhibiting memory T cells that get anigen presenting cell function from T cells

          • Yep so much so for the 10000 antibodies a second producing factories (plasma cells)

            Response to theraphy largely independent of any indirect effect on plasma cell-produced antibody levels

  • How do you think BTK inhbitors work and will they be good enough?

    Investment bankers say “Based on the scientific literature, we believe the reason BTK inhibitors fail in autoimmune disease is because their main effect is to prevent the development and proliferation of new B cell lines – while leaving existing B-cell populations largely unscathed. But the problem in autoimmunity lies precisely in the established subsets of misbehaving cells; new cell lines are irrelevant. Thus we believe Principia’s approach is doomed to fail. Indeed, it may even be dangerous: by halting the birth of new B cells, BTK inhibitors narrow the range of novel pathogens that patients can effectively combat, leaving them open to opportunistic infections”

    • Good question and relevant given the new data surfacing of the CNS-penetrant BTK inhibitor, but you would think there is merit given the stories that 4 phase III are planned, if true.

      However, first things first, is the investment firm making the quote trying to manipulate the share price?

      We have to see the data but the MRI data with evobrutinib did not appear to be in the same leauge when compared to B cell depleters but that is in part based on the comparitors and looking at the effect on relapse rate at 0.1 it is up there with the best. There is no mention of the CNS penetrant effect and can it scrub the CNS clean and I guess it affects all B cells as it blocks proliferation and there is cycling of all B cells not just the new ones and importantly there is no mention of macrophages. It influences EAE when CD20-depletion has no effect…yep peoples EAE is T cell mediated.

      However could this stop alemtuzumab ADA and autoimmunity probably yes.

      I guess we wait to see the data…it is probably too late for AAN but bet its in the late breaking at ECTRIMS, but if they are announcing data they have the data now so why would it be in the regular session with dealine in April.

  • so the constant battle of contrasting advice hits again

    https://www.bbc.co.uk/food/articles/vitamin_d

    in this story the below extract suggests a negative aspect of taking Vitamin D… I was advised by Prof G to take 4000 a day… what is the truth here? is there risk of taking vitamin D and are the benefits of taking high doses outweighing these risks? Are there actually any proven benefits of high dosing or is it all still just a hypothesis? So tiring to continuously fight for a consistent answer
    The below states anything over 800iu as high… fml

    Professor of Genetic Epidemiology, King’s College London, Tim Spector, explains: “Patients with very high vitamin D blood levels (over 100nmol) are becoming routine in my clinic and elsewhere, and toxic overdoses are increasingly being reported. Several randomised trials have shown that patients with high blood levels or taking large doses of vitamin D (above 800IU/20 micrograms) had an unexpected increased risk of falls and fractures.”

    • I also stumbled on some research on vitamine d-mediated hypercalcemia. Would be interested in some thoughts of the doctors here…

        • yes, thank you, quit taking supplements when I read the research. Is there also information on the ‘safe’ amount of vitamin d supplements one can take? Or on how to best spread intake (e.g. daily doses of 4000 versus weekly 25.000)?

    • Probably only if you are a C57BL/6 mouse. They prefer alcohol to water…abit like the British:-)
      Surely this study could be done in humans. if I was a mouse with EAE I would take ant–Cd4 T cell therapy

  • Physical stress (exercise) lead to adaptacion

    Fasting (stress) leads to adaptacion

    Learning a new language (cognitive stress) lead to adaptacion

    Long-distance skiers may have ‘motor reserve’ that can delay onset of Parkinson’s disease

    Investigators found that the skiers were almost 30% less likely to develop PD than non-skiers. However, this dissipates with time and increasing age and results in diagnoses of PD among skiers matching the general population

    “If a person is physically active, it may be possible to maintain mobility for longer, despite the pathological changes in the brain,” added Dr. Olsson.

    No excuse for us not to exercise

    🙂

    https://medicalxpress.com/news/2020-02-long-distance-skiers-motor-reserve-onset.html

  • What is the status on T cell therapy? Is anyone other than Atara Bio looking into it? Realistically how far are we away from seeing it as a monotherapy if it is efficacious?

    • Devils in the detail…If we look in EAE give that anti-CD20 depletion before you induce EAE and EAE gets worse. Given cyclophozphamide before inducing disease and animals get worse. When I was a wee snip of a mouse my boss put this down to regulatory B cells, when every one was going on about regulatory T cells. Maybe we will see B regulatory cells make a return a 40 year round trip This study depletes B cells before stroke and they get worse too. There are regulatory B cells and pro-inflammatory B cells and the outcome is a balance of the competing effects. Do people with MS get worse MS after ocrelizumab….generally I would say no…do mice with disease get worse after depletion I would say the answer is no too. Do I accept regulatory B cells can be beneficial…absolutely

      • Impossible to give anti cd 20 in human before disease starts

        Unless you give them cuprizone 🙁

        You know that are patients who relapse after anti cd 20 theraphy with zero b cells in the blood

        • Yes I know that it is well documented and perhaps tells us that the blood is not the important place to look, however we ust ask if this is true that there are no B cells in the blood as the odd one is perhaps all that you need. Stand on a bridge over a motorway at noon and you see lots of cars going past and you don’t see the problem which is a single red fiat. Do the same at 4.00 AM and you see no cars on the motorway and then at 4.13 a single red fiat car goes by, but you sy you haven’t seen any cars when you look. If you dont have a few thousand cells you can’t really do flow cytometry so the odd few are seen.

          • But those patienta that do respond to theraphy

            Have also 0 b cells in the blood and your reason cant be aplied to them

            Like you say manny time you cant eat the cake and have the cake afterwards

            🙂

          • Yes it can you could have no B cells in the blood and it works…as you sit on the bridge at 4 in the morning and you dont see a red fiat or you need to see ten but you see nine

      • Its not only il-10

        Interestingly, treatment
        of mixed cortical cultures with IL-10–deficient B cells was not
        neuroprotective for total neuronal counts, but a 1:1 ratio of IL-
        10–deficient B cells to mixed cortical cells still protected arborization.
        This suggests that IL-10 is not the only neuroprotective
        effector produced by B cells following oxygen-glucose deprivation
        that should be addressed in future studies.

  • hi Mousedoctor,

    any chance to take the ask barts decade post as the tagged post and replace it with this? I doubt you guys intend to keep the decade post for the next 10 years? and will save a lot of time scrolling.. ta very much

    my question is

    are there any new promising DMTS in the pipeline, which will compete with the existing big guns?

    I am going from TY to CLAD very shortly, but curious whether anything is coming to the streets soon?

    • I don’t know how to change that bit. That’s prof GS job, they don’t tell me how to work it, in case I go rogue.

      Personally I hate the tagged post it was so much better when the tagged post was on the side.

      Google blogger was easier to deal with, the search engine of this site is equally bad.

    • According to the researchers, when the antibodies are able to enter the brain to act on NMDA receptors, people suffer less depression and anxiety. These autoantibodies are clearly acting as the body’s own antidepressants…..I guess I will wait to see what Oxford think their neurologists have plenty of experienece with NMDA antibodies Why bother with rodents when you can talk to humans to get an answer.

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