April Q & A 2019

A

Sometimes you have a question or query unrelated to the posts. This is the place for you.

Callanish, Isle of Lewis April 2018

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MouseDoctor2

104 comments

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  • Alemtuzumab is a very potent PIRT, but her long term effect might be lasted when the proinflammatory cells often come back, so the disease return and patients need retreatment. (Cambridge trial 10 years follow up.)
    Could Alemtuzumab be a “cure” (in relation the disease caused inflammation) or not?
    How can we measure the sign of disease related inflammation the best? (When the disease returns half a year means 0.25-0.65 bvl loss)
    Could the neurofilament level of the blood be good?

  • There seems to be confusing messages about the progression to progressive disability from RRMS when patients are put onto high efficacy anti inflammatories, like Tsyabri and Ocrevus and Alemtuzumab. Can you clarify- you go onto anti inflammatories, is there a delay to transitioning to SPMS? A delay to further disability? Not that you never transition- but that you halt the current inflammation. This is in reference to “smoldering MS” which has been stated before in reference to the anti CD20 and anti CD19 therapies and the confusion between thinking of disability scores EDSS and no evidence of disease activity – are there long term results (can you list the publications so those of us with access can get them) in terms of disability progression like 10+ years out for the anti B cell, Tysabri, and alemtuzumab studies? Were some of those studies done if the patients immediately started on the high efficacy vs. transitioning from lower efficacy crab drugs? And those patients never added on on additional neuroprotective therapies like ibudilast or lipoic acid while on the anti inflammatories.

  • Why don’t you create a patients’ forum at the top of the page instead of this Q&A that noone can see after a few days? ProfG?

    • If I understand the question correctly you can see all of the question and answer entries for any given month even the current month under archive

      I agree it would sit better somewhere prominent rather than in the archive

    • It is probably a hang over from the movectro days….the long-term data does not support a major difference between life and drug use, however the chances are there will be cancers in people treated with cladribine, just as there are more cancers in people treated with fingolimod for example. Immunosuppression = cancer risk….it is simple biology.

  • My pet magical unicorn, who was (for the sake of their magic unicornian science, of course) addicted for some reasonable time to opioids. Then he read elsewhere that opioid tolerance and withdrawal aches are highly dependent on activated microglia inside spinal cord, which highly dependent upon mTORc1 signaling activation. Also he read elsewhere that brain-penetrant drug Metformin potently inhibits mTOR signaling. So he quit opioid of his choice “cold-turkey” under therapeutic dose of this Metformin without _any_ signs of withdrawal beyond very minor and transient chills. This is highly atypical, reports my pet magical unicorn, because dosages of his DoC were pretty high and usage was quite protracted.
    So he started to think that Metformin possibly precluded microglial activation in his spinal cord caused by opioid usage and hence ameliorated withdrawal signs to merely no existence.
    So my pet magical unicorn want to know if we do think that microglia could be main driver of MS progression, then may be this drug could be of use in ms also?
    Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation
    https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-016-0754-9
    The effect of metformin on morphine analgesic tolerance and dependence in rats
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040165/

    • The future of MS is innate 🙂

      Marjan Gharagozloo, PhD, and colleagues are working to address the immune and inflammatory aspects of multiple sclerosis, as central nervous system inflammation is a well-known driver of early phases of the disease, in addition to maintaining a presence in the later phases. Although many of the therapies used in the treatment of MS target periphery immune response, the scientist from the University of Sherbrooke’s Department of Immunology expects that the future lies in the targeting of the innate immune response.

      “It’s the future in MS research and something we have to emphasize—innate immune response is also really important. It’s not only the driver of the adaptive immune response, but it’s the only immune response located in the CNS.”

      https://buff.ly/2FzzuIv?fbclid=IwAR0tfFRTXSJyA1UsddoXu300QUvBgMlHnT_JS4DB1d15l4HsaUS-hCZilx4

      (just started few days ago self experimenting on Metformin, lol)

  • Thank you for the blog, and for all your efforts in spreading knowledge, I love the new site.

    I have noted that the European Guidelines recommend annual brain MRI monitoring. Why does this not include spinal MRI monitoring, including for patients who have had previous spinal lesions on initial MRI?

    Would appreciate your thoughts if possible.

  • So, if you don’t have “active SPMS” would Cladibrine still be of benefit? I’m trying to keep all of this straight and wondering how I should advocate for myself.
    Thanks

  • So, if you don’t have “active SPMS” would Cladibrine still be of benefit? I’m trying to keep all of this straight and wondering how I should advocate for myself.
    Thanks

    • Thanks I think this is a product of trial design people with secondary progressive MS are worsening slowly whereas those with PPMS are worsening quicker and so you see an effect. So one suspects that if you were to treat people with more rapidly progressive MS, you would get a treatment effect. This is what happened with THC slow progressive trial…treatment fails….no drug available.but if you had done trial in more rapid progressors EDDS less than 5.5 you get a positive and you would have a treatment

    • Ok I am confused
      I thought there had been a suggestion that spms was the same as rrms both being progressive but a different stages of the progression whereas ppms was potentially thought of as a separate disease

    • If you notice in the title it saysthey disappear in ten years. Therefore highly.possible that there is no direct effect on OCB but it stops disease and so b cell niches are removed. Waiting ten years is too long to wait. Lets see if they go quicker than ten years

      • Yeah, in the abstract it is not clear that OCB disappear on the 10nth year. They say they are not there 10 years after treatment. This is different. The “long lasting” on the title implies that the effect is there before.

      • They did the second LP after 10y, but they don’t know WHEN actually OCBs disappeared. It could be a much quicker than 10y. We don’t know. You can’t deduce that you have to wait all 10y to get rid of OCBs.
        I’m still very curious about what happened to OCBs in 10y to the patients on Alem, Ocre/Rituximab and/or HSCT. You guys all have a lot of data already collected. This are observational studies, so all you need is to get consent and analyze already collected samples. Much quicker and much cheaper than a full trial…

        • We will know this for cladribine as we have repeat lumbar puncture 1 year….DrK has the data I believe. Watch this space.

        • Steroids

          The second case is a 55-year-old female patient with secondary progressive (SP-) MS.
          She was diagnosed with MS in 1996 and transitioned to a SP course approximately in
          2006 (Fig. 2). The clinical symptoms were dominated by a slowly progressing paraparesis.
          Upon the first lumbar puncture performed in our clinic and analyzed in our laboratory in 2007, the CSF analysis revealed an intrathecal production of IgG as evaluated by the
          Reiber diagram. This finding was supported by detection of CSF-specific OCB, again indicative
          of an intrathecal IgG synthesis. At that time, the analysis of the MRZ reaction was
          unfortunately not performed. Due to the progressing spasticity and weakness of the lower
          limbs, the patient was treated by intrathecal application of triamcinolone and at a later
          stage with a three-day course of intravenous methylprednisolone at a dose of one gram
          per day. The next lumbar puncture was done in 2014. At this moment, the patient was mobile
          within the apartment with the help of a wheeled walker. Outdoors the patient used the
          wheelchair. In the new CSF report an intrathecal Ig synthesis could no longer be detected
          in the Reiber diagram and the OCB pattern in the CSF was much weaker. At that time, the
          antibody index for rubella was formally positive, while all other antibody indices were negative
          (<1.5). In the third lumbar puncture done in 2017 and after another three-day course
          of systemic steroids, the CSF findings were completely normal, with an absence of an intrathecal
          Ig synthesis, CSF-specific OCB or antibody production against MRZ. Clinically,
          the patient had also stabilized; with an
          improved mobility in the wheelchair. With the help
          of a wheeled walker, she was now entirely mobile in the home area and could walk short
          distances outside. In the MRI of May 2013 and June 2017 there was no evidence of new
          spinal or intracranial lesions. Similar to case presented above, an elevation in CSF leucocytes
          was never observed at any time

        • Natalizumab
          The third case is a 44-year-old female patient with relapsing-remitting (RR-) MS, diagnosed
          in 2008 (Fig. 3). The initial symptoms were retrobulbar neuritis and a mild left hemiparesis.
          At the time of diagnosis, the MRI showed 23 supratentorial lesions and at least
          one infratentorial lesion located in the left cerebellar peduncle. Following gadolinium administration,
          an enhancement was detectable in two of these lesions. The CSF elaboration
          revealed CSF-specific OCB and a positive MRZ reaction for measles (antibody index 3.9).
          The patient was initially treated with beta-interferon 1b and later on with glatiramer acetate.
          Due to two severe relapses in the following year, the patient was transitioned to natalizumab
          in March 2009. The following years, the patient was completely stable with no further
          relapses, disability progression or MRI detectable disease activity. The EDSS gradually
          improved from 6.0 in 2011 to 4.0 in 2013. Throughout these years, two additional lumbar
          punctures were performed. While in 2011 the measles index was still indicating a weakened
          intrathecal production of antibodies in the absence of detectable CSF-specific OCB,
          in 2013 all CSF findings had completely regressed to non-inflammatory values, apart from
          a formally positive measles antibody index value of 1.6.

          Modification of CSF findings in multiple sclerosis in
          the era of rapidly expanding treatment options

  • Is it the end of ‘statistical significance’? The battle to make science more uncertain

    The scientific world is abuzz following recommendations by two of the most prestigious scholarly journals – The American Statistician and Nature – that the term “statistical significance” be retired.

    In their introduction to the special issue of The American Statistician on the topic, the journal’s editors urge “moving to a world beyond ‘p<0.05,’” the famous 5 percent threshold for determining whether a study’s result is statistically significant. If a study passes this test, it means that the probability of a result being due to chance alone is less than 5 percent. This has often been understood to mean that the study is worth paying attention to.

    https://neurosciencenews.com/statistical-significance-research-11018/?fbclid=IwAR1Lg-DUugWp5DRggsZMR63Adw1_vvNnaYkTT8gWtCXaQADIktgL5rblpXM

  • Has anyone got a view on LifNano? I read that they’ll begin trials in 2020. Is it all a nonsense money making scheme (as some have suggested on the interweb) or something to genuinely keep an eye on?

  • Is there any point posting unrelated questions on this blog under the current month heading as there seems to be no answers offered by neurologists anymore notably prof g?

    • At real risk of sounding corny I’d like to say thanks Anon for posting this link.

      I have no medical or scientific background or knowledge and there is information provided on this Blog that goes clean over my head. But, I have constantly benefitted from taking a look at all the posts and all the links. It’s a silly something, but reading this article meant I stopped prevaricating and got myself down to the gym this morning🙂

      I notice one comment questions whether wheelchair users who exercise benefit neurologically or only those who use their legs, and it would be nice to think that they do. When I have full on fatigue I do the seated exercises provided by Trevor Wicken on his YouTube MS Gym aimed at PwMS in wheelchairs.

      My response to the article, due to your provision of the link, represents one of the unanticipated benefits to the Blog and so yeah thanks, and thanks too to Luis and all the others, mainly Anons, for all the links.

  • NMO closer to a cure? MS?

    Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial

    Application of antigen-specific immune tolerance in autoimmune disease is a long-sought goal. We studied diseases with abundant information on the autoimmune target: in multiple sclerosis (MS), various myelin antigens are known targets of T cells and antibodies, whereas in neuromyelitis optica (NMO), the aquaporin-4 channel is attacked by T cells and antibodies. We tested whether engineered dendritic cells might induce a tolerogenic immune response in these two conditions. In this in-human clinical study, individual regulatory T cells, secreting IL-10, a key tolerogenic cytokine, were detected after treatment. These results might lead to more extensive trials with this approach in autoimmune conditions where the antigenic target has been identified, including MS, NMO, myasthenia gravis, and Graves disease.

    https://www.pnas.org/content/early/2019/04/02/1820039116.long?fbclid=IwAR0siF8KC-jbr3YMlFcbSmpxiGlhWVyKpncZgo_zpYlCsl5f0D8U8_GrZUk

    • “These results might lead to more extensive trials with this approach in autoimmune conditions where the antigenic target has been identified, including MS…..”
      Of course as everyone knows the antigenic target in MS has definitely not been identified.

  • A cohort study of functional electrical stimulation in people with multiple sclerosis demonstrating improvements in quality of life and cost-effectiveness.

    OBJECTIVE: The objective of this study was to determine the impact on health-related quality of life of functional electrical stimulation used to improve walking in people with multiple sclerosis and to explore cost-effectiveness.
    RESULTS:Significant differences ( P < 0.001) were seen in walking speed (baseline 0.670 m/s; with stimulation 0.768 m/s) and maintained over six months (0.772 m/s with stimulation). EQ-5D data significantly improved over six months (baseline 0.486, six months 0.596, P < 0.001) and meaningful mean scores were seen in all aspects of the Psychosocial Impact of Assistive Device Scale. However, there were no correlations between measures. In the cost utility analysis, compared to standard care, functional electrical stimulation was more expensive and more effective with an incremental cost-effectiveness ratio of £6137.

    https://www.ncbi.nlm.nih.gov/pubmed/30971113?utm_source=dlvr.it&utm_medium=facebook

  • If I was to wear tights at a neurology examination could the neurologist accurately measure leg sensations/ numbness through the tights material? With the vibrations and my responses?

    • Why oh why isn’t every country with the capacity to do so, having registers?!?
      Suspect that there’d be international shock and surprise at the true number of PwMS. As Gavin highlights it’s not simply damaged or ruined lives, but economically damaging too. Without accurate figures how realistic is it ever going to be to provide an MS management infrastructure?
      Congrats to Scotland for having a register!

  • Urine test for UTI. I have had months of intermittent UTI. I have UTI symptoms and drink lots of water. This seems to dilute the urine and gives a false negative urine result when I give a sample to the GP.

    Is there a statergy to help. I.e early morning urine sample is concentrated and may show bacteria infection more? Thanks

    • As a fellow UTI sufferer I understand the constant use of antibiotics when culture comes back negative but the symptoms are quite obviously there
      Mine has got worse since going through the menopause brought on early by alemtuzumab

      Luckily my GP treat my symptoms and usually a favoured antibiotic clears it up after a few days although I take longer courses of 14 days to ensure that the infection has completely gone
      Ask your GP for a prophylactic low dose of antibiotic for example nitrofurantoin or trimethoprim although alternate these every 3 months
      Makesure your GP requests a microscopy which will show the white cells which will be high if you have an infection unless of course you’ve had alemtuzumab so the white cells might be lower than expected
      Take a course of those alkalizing cystitis sachets which help alkaline the urine. They should not be taken however with nitrofurantoin
      Take paracetamol
      Use a hot water bottle and your abdomen to help pain and discomfort
      Some people use a natural deterrent called d-mannose although I use something called cranmed

      I’ve avoided a cystoscopy but that may be something a urologist may recommend if you are having constant infection

      One thing I have found is that some of the symptoms can be OB overactive bladder which you can find lots of information on on the internet

      Also prof g did write a very thorough summary of bladder problems some months ago but I cannot find it on this blog but it will be there somewhere

  • In MS, Progression of Disease Activity Is Often ‘Silent,’ 10-Year Study Finds

    Long-term disease progression in patients with relapsing-remitting multiple sclerosis (RRMS) occurs independently of relapse activity and is associated with accelerated brain atrophy, researchers reported. They proposed using the term, silent progression, to describe the accumulating disability in patients with RRMS.

    “I thought that what we’d see was that more severe relapses resulted in long-term disability driven by cumulative injury.

    “But in our dataset, we did not find that link. Instead, many disability events seemed to occur completely independently of relapses… and even if the patient was showing signs of increased disability, they often had no change of disease activity on the MRI.”

    https://journals.lww.com/neurotodayonline/Fulltext/2019/04180/In_MS,_Progression_of_Disease_Activity_Is_Often.2.aspx?fbclid=IwAR0h7p86C9feOkoTMe9YGjdREFCajkgZ2vARCUaKoAh4MinxieEz2Kq7GIk

    • That´s anice one
      How do you reconcile that with this

      “In this regard, not only are relapses a characteristic feature of MS, they have also been
      proven to be associated with the occurrence of long-term disability”

      Relapses in multiple sclerosis: Relationship to
      disability

      https://www.sciencedirect.com/science/article/pii/S2211034815300043

      I kown the “colective cyborg” disagrees with this

      But i thing Prof George Ebers had said that only those that had manny relapses in the first 2 years after diagnose had short time to progressive disease

      https://www.youtube.com/watch?v=OqY-_K1fYJY

      Obrigado

      • The definitions of the older study you posted seem a little blur. In this new study they seem to have a more clear view on those definitions and thus on the goals of this research and can interpret contradictions with more clarity (at least that is what I get).

  • Current therapeutic landscape in multiple sclerosis: an evolving treatment paradigm.

    RECENT FINDINGS: A real-world study from Wales suggests that early initiation of highly effective therapy may provide more benefit that an escalation approach in relapsing MS. A study from the MSBase dataset found evidence that early treatment with highly effective therapies decreased the risk of developing secondary progressive MS.

    https://www.ncbi.nlm.nih.gov/m/pubmed/30985372/?i=29&from=multiple+sclerosis&fbclid=IwAR3JrLyyviSuXMUQEzqe0JxrXDniUslcZ-2XPaqKmoq30cLLQ3pGyjapGg0

  • EBV in cancer (from the “it’s all B-cells” series)

    Cytotoxic T cells targeting the EBV antigen EBNA1 have been identified as key controllers of EBV infection and EBV-associated malignancies. Julia Rühl and colleagues investigated vaccine strategies to improve EBNA1-targeting CD4+ and CD8+ T cell responses. They reveal that relative to adenoviral EBNA1 delivery alone, heterologous prime-boost vaccination with EBNA1-encoding adenovirus and modified vaccinia virus Ankara (MVA) vectors enhanced expansion and maintenance of EBNA1-targeting CD8+ T cells by concomitant CD4+ T cell activation. In mouse models, a heterologous adenoviral/MVA prime-boost regimen protected against EBV-associated lymphomas.

    Heterologous prime-boost vaccination protects against EBV antigen–expressing lymphomas
    https://jci.org/articles/view/125364?fbclid=IwAR06WFfjOvI4HGpYrPZRMURaiXF1jSJndCU1hKQrcHFUotBDKkkY6eIG348

  • The therapeutic landscape of #MultipleSclerosis (MS) has been transformed by the advent of several new #MonoclonalAntibody (MAb) therapies that can potentially lead to full stabilisation of detectable disease activity. Natalizumab, alemtuzumab and ocrelizumab are currently licensed MAbs for the treatment of MS. Daclizumab was licensed for the treatment of MS, although it has been recently withdrawn from the market by the manufacturer. Most patients are initially managed with first-line treatments, and, if disease breakthrough occurs, are escalated to a stronger compound, yet the available evidence indicates an early window of therapeutic opportunity for MAbs to exert most of their efficacy. It is important to balance the superior efficacy of MAbs compared with injectable treatments against more serious side effects, although these are well recognised and can be monitored where indicated and treated. In particular, the risk of progressive multifocal leucoencephalopathy with natalizumab can be managed by screening potential patients for the John Cunningham virus. The MAbs also have the benefit of convenience to patients compared with daily or weekly treatments since they are given via less frequent administration. The cost of these treatments, compared with other therapies, may be an important issue in many countries where healthcare budgets are under pressure. The complex decision of choosing the best treatment for an individual should be made jointly between the doctor and the patient after careful consideration of the many factors to be weighed.

    https://touchneurology.com/monoclonal-antibody-therapy-and-long-term-outcomes-in-multiple-sclerosis-the-challenge-of-treatment-optimisation/

    (“yet the available evidence indicates an early window of therapeutic opportunity for MAbs to exert most of their efficacy” and “best treatment for an individual should be made jointly between the doctor and the patient” but with Alem. 3rd line and no HSCT this doesn’t mean much)

  • Obesity May Affect the Form and Structure of the Brain

    Men watch out for that extra pounds your brain maybe gettin smaller 😦

    Women are a bit more protected

    In men, TBF was negatively associated with all subcortical gray matter volumes (thalamus, cau-
    date nucleus, putamen, globus pallidus, hippocampus, and nucleus accumbens) other than amygdala volume. In women, TBF was
    solely negatively associated with globus pallidus volume.

    https://pubs.rsna.org/doi/pdf/10.1148/radiol.2019181012

    Obrigado

      • Ainda vais a tempo 😉

        Fasting

        And

        Exercise

        Like we say in Portugal

        “Olha para o que digo não olhe para o que eu faço”

        Look at what I say, do not look at what I do.

        🙂

          • Exercise doesn’t have to be boring. Gardening, or walking in a beautiful place. And enjoyment increases when you start to feel the benefits.

            I don’t think fasting would work for me – I’m a light eater anyway, with no weight to lose. I’d worry about running low on essential nutrients, and energy. I focus on fibre, lots of fruit and veg, low fat, low sugar.

          • I agree excersise doesn’t have to be boring…went for a walk to see kingfishers and a day in the garden and off to see the bluebells…but that isn’t going to make me lose weight.

          • No more beer! There’s a lot of calories in alcohol! And it’s not good for you. [Time for a sharp exit I think. 😁]

    • I’m not sure one person a definite truth does make, but it’s working for me. I’ve been on Gabapentin just over a year and have also worked up to being comfortable on 16/8 fasting and my weight is really good. My diet is pretty sound but a small amount of chocolate and a ginger biscuit are daily requirements. I do exercise too.
      If research into IF is anything to go by, it’s a billy-bonus to the health of anyone who does it👍

      • Thanks Fi, I’ve seen many comments regarding Gabapentin and weight gain. I am not sure why that happens though and want to be prepared for it if I can.

  • How can you settle this:

    Much, if not all, of the cortical damage in MS
    can be attributed to the microglial cell – No

    DOI: 10.1177/
    1352458517743094

    “Microglia are in the brain to protect it and they
    do so through several mechanisms”

    With this:

    Retinal microglia initiate neuroinflammation in
    ocular autoimmunity

    https://www.pnas.org/content/early/2019/04/24/1820387116

    We clearly demonstrated that microglial depletion
    blocks the induction of EAU by preventing the infiltration of
    circulating primed inflammatory cells, indicating the primary
    function of microglia is to trigger the infiltration of circulating
    leukocytes early in the development of disease. Although systemic
    exposure to an autoantigen is the trigger of autoimmunity
    in EAU, our results indicate microglia are the critical cell population
    in the retina that allows the entry of autoreactive cells
    required for the initiation of EAU.

    Time to go to the bench

    Obrigado

  • Hopefully prof g will answer this question

    Going through the menopause following alemtuzumab despite being on HRT for 3 years both my fsh and LH are constantly raised while my oestrogen is at an acceptable level

    Does this sound as though it is related in any way to an ms problem as I have read Ms can affect the pituitary gland

    Well I know you cannot give individual advice is there any where you can point me to?

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