Ask Barts-MS – May 2018

If you have any questions unrelated to the posts this is the place for you.

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  • Couple days ago Mouse Doctor 2 wrote that the Barts MS Team is to publish an important study on the relationship between SM and EBV, which is to please all readers of the blog. When will it happen?


      Is this including carers etc as there are only about 400,000 americans with MS.

      We have reported on this already and will do again when the paper is published.

  • Two questions:

    1) Given the new drugs and therapies available today, what is our best estimate of how long someone diagnosed with MS today will be able to continue working?

    2) I've been reading a lot about therapeutic fasting as a way to deal with autoimmunity, do you all have any opinions about that line of research?

  • Paper for HSCT to DMT naive aggressive patients presented at AAN

    Autologous Haematopoietic Stem Cell Transplantation in Treatment Naïve Patients with ‘Aggressive’ Multiple Sclerosis

    Joyutpal Das, MBBS; John Snowden; Mark Freedman, MD, FAAN; Sona Mistry; Simon Bell, MB, ChB, MRCP; Azza Ismail, PhD, MBBS, MRCP; Helen Jessop; Marjorie Bowman; Ricardo Sarccardi; Chiara Innocenti; Harold Atkins; Joachim Burman; Basil Sharrack, MD, PhD, FAAN

    Objective: To assess the safety and efficacy of autologous haematopoietic stem cell transplantation (AHSCT) in treatment naïve patients with ‘aggressive’ multiple sclerosis (MS). Background: AHSCT is a very effective treatment in patients with highly active relapsing remitting MS who failed to respond to standard disease modifying therapies (DMTs). International guidelines advocate its use in treatment naïve patients with ‘aggressive’ MS (1). Design/Methods: A total of 19 patients: 7 from Sheffield (UK), 7 from Uppsala (Sweden), 4 from Ottawa (Canada) and 1 from Florence(Italy) with ‘aggressive’ MS received AHSCT between May 2004 and May 2017. None received standard DMTs before AHSCT. BEAM (carmustine, etoposide, cytarabine, melphalan) with antithymocyte globulin (ATG), cyclophosphamide with ATG or combination of cyclophosphamide, ATG and busulphan were used as conditioning regimens. Results: Median age at diagnosis was 33 (21–52) years. Median time between symptom onset and AHSCT was 9 (2–58) months. Median pre-treatment Expanded Disability Status Scale (EDSS) score was 6.5 (1.5–9.5). Median follow up was 30 (6–118) months. Median EDSS score at the last follow up was 2.0 (0–6.5). Median improvement of EDSS scores was 2.0 (0–8) (p<0.05, Wilcoxon signed-rank test). None had any clinical relapse following AHSCT. Three patients had new T2 lesions with or without gadolinium enhancement at the first six month follow up MRI, but no further new or enhancing lesions were observed in any subsequent scans. Routine toxicities were observed with no treatment related mortality. Conclusions: AHSCT was safe and highly effective in inducing rapid and sustain remission in this cohort and was associated with a significant improvement of their level of disability. AHSCT should be considered as first line therapy in patients with ‘aggressive’ MS. 1. Snowden et al. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of European Group for Blood and Marrow Transplantation. Bone Marrow Transplantation 2012Jun;47(6):770-90

  • 1) Why there are lesions specific for MS in MRI, if it is called a "snowflake disease" (every case seems to be different)?

    2) Is NfL test good enough to replace MRI as diagnostic tool for MS? If so, when it is going to happen (I am curious of your opinion)?

    • I doubt NFL will replace MRI as a diagnostic tool as NFL is not going to show lesions in "time" or "space".

  • Why is it that a lot of ms papers and this website focus brain legions and not spinal? You very rarely see anything about spinal legions, is that because they correlate with the brain or is it simply a forgotten part of MS’ers? Is there any research as to prognosis of spinal legions vs brain legions?

    • Most centres and only monitor with brain MRI and not spinal MRI. Spinal MRI cover three regions and hence take 3x as long. Therefore there is more brain MRI data than spinal MRI data.

  • Do dmds reduce your risk of progressing to SPMS. Are there studies on this? It’s impossible (unethical?) to run this study. Are there comparisons to historical controls?
    Are you anectodaly seeing less patients progressing to SPMS with DMDs?

  • Yes I find this disturbing as well. Almost all the studies focus on the brain but MS effects the spinal cord as well should that not be central here. I understand not allMSers gave these lesions but most do .

    • The MRI can image the brain because you can keep your head still, however the spine is more problematical because you breathe and so it is harder to image. However many brain lesions are clinically silent.

      It reminds me of something DrK says….. about a man searching on the ground under a lamp post, which is lit.?

      Someone says. "What are you doing?"

      "Looking for my keys comes the reply".

      "Where did you drop them?"

      "Over there"…and he points away from the light.

      "So why are you looking under the lamp post?"

      The reply is "It's the only place I can see"


    • You may be able to control EBV in some people with treatment, however as to any impact this would have on MS is unknown and needs testing, maybe it will work maybe it won't

  • Back and forth…

    A new study challenges conventional thought on the origins of multiple sclerosis. Researchers say biochemical injury to myelin appears to trigger an immune response that leads to additional damage as a result of inflammation. The new theory challenges the view that MS is primarily at autoimmune disease at origin.

    “We collaborated with researchers at the University of Toronto and found that by targeting a treatment that would protect the myelin to stop the deterioration, the immune attack stopped and the inflammation in the brain never occurred,” says Stys. “This research opens a whole new line of thinking about this disease. Most of the science and treatment for MS has been targeted at the immune system, and while anti-inflammatory medications can be very effective, they have very limited benefit in the later progressive stages of the disease when most disability happens.”

    • Thanks for this. The important words to remember here are "in a mouse model of MS" but looks interesting. Will have a read. Post on this study is likely.

    • Not sure how widespread the exposure to cuprizone or similar compounds is in pwMS. Intersting nontheless.

  • Interesting

    Microglial activation, white matter tract damage, and disability in MS

    Results [11C](R)-PK11195 binding was significantly higher in the normal-appearing white matter (NAWM) of patients with secondary progressive vs relapsing MS and healthy controls, in the thalami of patients with secondary progressive MS vs controls, and in the perilesional area among the progressive compared with relapsing patients. Higher binding in the NAWM was associated with higher clinical disability and reduced white matter (WM) structural integrity, as shown by lower fractional anisotropy, higher mean diffusivity, and increased WM lesion load. Increasing age contributed to higher microglial activation in the NAWM among patients with MS but not in healthy controls.

    Conclusions PET can be used to quantitate microglial activation, which associates with MS progression. This study demonstrates that increased microglial activity in the NAWM correlates closely with impaired WM structural integrity and thus offers one rational pathologic correlate to diffusion tensor imaging (DTI) parameters.

  • Is there any further evidence on the use of Low Dose Naltrexone? I've read the blog post "LDN does not affect MS" (Wednesday, 15 November 2017) but keep meeting people who say its working for them. The overcoming MS book also seems to lend support to this. thanks

    • You can find some papers on the ECTRIMS database about LDN. Hashimoto patients claim that LDN brings their auto-antibodies down. I would stay away from Overcoming MS.
      A patient.

    • Still equivocal –

      Multiple Sclerosis Journal, Feb/Mar 2018 (supplement) [meeting abstract]


      Low Dose Naltrexone in Multiple Sclerosis: Web-Presence Versus Scientific Evidence

      Dr. Ahmed Z Obeidat, M.D., Ph.D., Dr. Michelle Bowman, M.D., Dr. Elizabeth Dragan, M.D., Dr. Lawrence Goldstick, M.D. and Dr. Aram Zabeti, M.D.

      University of Cincinnati, Cincinnati, OH

      Background: Naltrexone is an oral semi-synthetic opiate receptor antagonist, licensed in a 50–100 mg daily dose for the treatment of heroin and alcohol addiction. Preclinical studies identified several mechanisms by which low dose naltrexone (LDN), less than 5 mg daily, can benefit patients living with multiple sclerosis (MS). Those included the ability of LDN to upregulate opioid receptors, increase endogenous opiate production, prevent oxidative damage and glutamate-mediated cytotoxicity to neurons/oligodendrocytes and inhibit T-cell/glia replication

      Objectives: To compare readily available web information for patients on the use of LDN in MS to published research on the subject

      Methods: We searched Google for terms such as “low dose naltrexone,” and “multiple sclerosis.” We searched PubMed for: “naltrexone,” “low dose naltrexone,” “naloxone,” “experimental autoimmune encephalomyelitis” and “Multiple Sclerosis.” We navigated relevant websites and reviewed the scientific literature

      Results: We screened a total of 24 articles and included 18 publications (7 clinical investigations, 6 preclinical studies, 1 medical hypothesis, 4 commentaries). We excluded 6 studies irrelevant to MS. We found 3 clinical trials for LDN in MS patients which suffered limitations, and none provided conclusive evidence on the subject. However, all studies agreed on the safety of LDN. Google searches for the term “naltrexone and MS” yielded about 413,000 results and for “low dose naltrexone and multiple sclerosis” yielded about 184,000 results. Numerous patient-oriented websites discussed LDN and MS with phrases used such as “Overcoming Multiple Sclerosis” or “A Wonder Drug that Eases Multiple Sclerosis Side Effects,” among other claims. A limited number of websites, such as the National Multiple Sclerosis Society, provided evidence-based information for patients and caregivers on the subject and acknowledged the limitations of the scientific evidence

      Conclusion: It remains challenging for health care providers to answer various patient queries regarding potential effects of LDN in MS due to the inadequacy of clinical evidence. We identified a gap between readily available information off the internet for MS patients and actual scientific evidence. Preclinical investigations showed promising effects on inflammation and disease modification. Further studies are needed to determine the effect of LDN as an add-on therapy on quality of life measures such as pain, energy, social, cognitive and sexual functions in patients living with MS.

  • Spinal fluid could be used to predict the progression of multiple sclerosis, study finds

    They found that the cells were producing a significantly higher ratio of one type of antibody molecule. These antibodies originated from cells within the nervous system of these patients – yet these cells are not normally found in this part of the body.

    In the blood of MS patients there is a normal ratio of around 2:1 of each type of antibody, but in the spinal fluid of the study's MS patients the researchers found ratios of more than 100:1.

    Joint lead author Dr John Curnow, of the University of Birmingham's Institute of Inflammation and Ageing, added: "What was interesting about our findings was that this unusual extreme ratio bias mostly occurred in patients in the early stages of the disease, while there was far less bias in those patients who later developed greater disability.

    "Our research suggests that this early bias in this type of antibody could be related to a trigger of MS.

    "For patients who later develop more severe disease we find that this attack by the immune system, even when analysed at the time of diagnosis, has already developed beyond the initial trigger of the disease, resulting in greater damage to the nervous system in subsequent years.

    "The unusual pattern of antibody suggests a very distinct immune response early in the disease. We are hoping to identify the target of this immune response.

    He added: "If our findings are confirmed, then we would have a relatively simple test that could be used at diagnosis to help identify patients with a poor prognosis.

    "This will enable clinicians to justify the use of highly effective therapies, which could potentially improve the long-term outcomes for these patients."

  • MD2?

    Denali Therapeutics is taking a swing at neuroinflammation with a first-in-man trial of a RIPK1 inhibitor, while the company and others search for ways to target microglial biology more precisely.

    Repeated failures with amyloid-modulating drugs in Alzheimer disease (AD) have forced industry to start at last to dig into other possible mechanisms of intervention. With Denali Therapeutics' recent decision to push its RIPK1 inhibitor DNL747 into phase I trials, drugs that act on microglia — the immune cells of the brain — are re-entering the clinical limelight.

    For Ryan Watts, CEO of Denali, these microglia-targeted drugs promise to revolutionize neuroscience in the same way that immune-acting agents have transformed cancer drug development. “The ability to modulate the immune system could be a very powerful path forward,” he says. Beyond AD, they might also open up new treatment options in Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis and other hard-to-treat central nervous system (CNS) diseases. Neuroinflammation also appears to play a key role in psychiatric indications such as depression.
    If this is the case, drug developers must figure out how to shift microglia away from the harmful phenotypes and towards the beneficial ones. Denali's RIPK1 inhibitor is a first test case of this approach. “Our hypothesis is that when you inhibit RIPK1, you inhibit the inflammation and promote normal function of these innate immune cells, which includes phagocytosis,” says Watts.
    RIPK1 acts downstream of the canonical inflammatory TNFR1 pathway, and as such is also of interest to GlaxoSmithKline, which is testing a RIPK1 inhibitor in phase II trials in psoriasis and rheumatoid arthritis. The kinase is robustly activated in Denali's models of neurodegeneration, and modulates the production of pro-inflammatory tissue-damaging cytokines in the brain, says Watts. Other teams also reported last year that RIPK1 mediates a disease-associated microglial response in AD, and that it induces programmed necrotic cell death of neurons in AD brains.

  • TOX, a DNA-binding factor that may play a role in triggering multiple sclerosis – the team reports that TOX allows cells to cause autoimmune damage to brain cells.

    They used two different pathogens – one viral and one bacterial – that are known to elicit a response from the immune system. The research was performed using healthy rat models. According to co-author Nicolas Page, a researcher in the Department of Pathology and Immunology at UNIGE, both pathogens elicited an "identical quantitative immune response" from a certain type of white blood cells: CD8 + T lymphocytes.

    Was this the reason for the causal link between EBV and MS?

    • Yes – this is another remarkable impact of Trump(etism) that was also picked up by the BBC, and is entirely predictable from a financially obsessed president supporting companies and private investors to feather their own nests. Further disappointment for humanity coming out of Trumpet-land.

    • This is a very serious issue and will no doubt be raised post-Brexit when the British want a trade deal with the USA. We may need to close NICE and agree to pay a lot more for drugs to get the USA to agree a trade agreement.

  • Microglia eat every neuron 🙁

    What´s death and and what not so death

    When cells at the stroke core die, they release damaging toxins into the surrounding brain tissue," explains Ali Alawieh, an M.D./Ph.D. candidate in the Department Microbiology & Immunology and first author on the article. "Neurons in these nearby areas respond by temporarily shutting down. An immune recognition system consisting of natural antibodies sees stressed, non-functioning cells and assumes they're about to die and release their own damaging toxins, so it activates the complement system to start clearing out the damaged cells. It's all part of the body's normal homeostatic processes but, in stroke, complement becomes pathological and inappropriately labels live neurons for elimination."

    Novel therapy inhibits complement to preserve neurons and reduce inflammation after stroke


  • was wondering if more posts could be done relating to diet and exercise.

    questions such as, does stopping diary or meat really help? Just to name a few…
    There is a lot of literature and people advocating certain lifestyle and diet choices.
    while to me, its quite easy to see the benefits of certain suggestions. such as eating a plant based diet, with fish for example..
    does gluten impact MS?
    is the swank diet or overcoming MS diet suggestions positive?

    Is exercise really a potential DMT? Are certain types of exercise best?

    are there any studies that look at the impact of diet on MS? for example, looking at people with MS, from certain regions, and seeing the progression rates, comparing to local diets?

    What about, studies that look at those who exercised consistently after diagnosis, versus patients that lived a more sedentary lifestyle, due to whatever cause.

    for someone with MS, trying their best to read through the BS… its not that easy.. some help from you guys, is really welcomed.

  • Was I the only one to watch this weeks episode of 24 hours in A&E and be totally appalled and angered. One patient admitted with sepsis had MS. Her husband describes how the neurologists told them that if she got to 40years and had minimum problems she'd be fine and basically go away and lead a normal life.

    Although the programme did finish with confirmation that the lady had sadly died, at the age of 52years, it was barely mentioned that she was already bedridden with her MS and had no use of any of her limbs.

    When it is going to be made abundantly clear to the wider world that this is not a benign chronic disease?!?

    When is it going to stop being understood solely in terms of being in a wheelchair or not?!?

    No one, but no one knows it affects so much of the body, and definitely not that it damages the brain.

    When will people learn that it is the second most common cause of disability in young adults, after traumatic injury?!?

    Nor was any reference made in the programme to the fact that sepsis isn't untypical in PwMS, particularly when the MS is advanced.

    How in the world do we get the full truth out there and heard?!?

    • "Now she’s 42 and although she still wears a wig after the chemo, takes hormone replacement therapy for the chemo-induced menopause and is on antiviral drugs after several bouts of shingles"

      If you go from bedbound to able-bodied it's worth it..but my god those are some bad after effects.

    • The overall figures are quite as rosy as this. It may not be as effective as alemtuzumab, natalizumab or ocrelizumab. What we need are head-2-head studies.

    • Authors’ reply

      "We have
      followed our patients for up to 16 years
      and have yet to see progression return
      in any whose disabilities had stabilised
      or improved. None of our patients had
      mild disease—rather they all had highly
      active inflammatory disease with
      progression to be eligible for the study.
      This makes our results that much
      more striking because such patients
      would be expected to progress in the
      timeframe of follow-up in our report.
      Although the transplant conditioning
      regimen and donor source used by
      the correspondents are not stated, we
      believe early intervention in patients
      with highly inflammatory multiple
      sclerosis before significant damage
      occurs to the CNS is an effective
      means for long-term prevention of
      progression. This early intervention
      uses a high intensity immunedepleting
      conditioning regimen to
      eliminate autoreactive immunity,
      followed by aHSCT with a graft
      depleted of immune cells to prevent
      reintroduction of autoreactive cells
      and allow lymphopoiesis to generate a
      naïve immune system.
      Existing treatments for multiple
      sclerosis are increasingly effective
      but extremely expensive and
      more complicated. A single aHSCT
      procedure resulting in decades long
      disease remission without the need
      for ongoing treatment would be a
      very acceptable alternative for most
      patients—especially those that have
      already shown a high level of disease
      with resistance to most therapies

  • In patients with relapsing remitting multiple sclerosis, the development of gray matter damage is linked to a higher incidence of early relapses and a higher risk of rapid disability accumulation,

    The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis

    Conclusions Extensive cortical damage at onset is associated with florid inflammatory clinical activity and predisposes to a rapid occurrence of the progressive phase. Age at onset, the number of early attacks, and the extent of baseline focal cortical damage can identify groups at high risk of progression who may benefit from more active therapy.

  • If I have understood things correctly, the oligoclonal bands detected by electrophoresis of cerebrospinal fluid are made up of antibodies (IgG?). These are probably secreted by plasma cells (derived from B-lymphocytes) that are lodged somewhere within the central nervous system

    Do these antibodies play an important role in the pathophysiology of MS?

    How long-lived are the plasma cells that produce the bands?

    If plasma cells die, does the corresponding oligoclonal band eventually disappear when the antibodies they have secreted are broken down?

    If a patient is treated with a B-cell depleting monoclonal antibody such as rituximab, ocrelizumab or ofatumumab, do the oligoclonal bands eventually disappear altogether?

    • Plasma cells in culture die pretty quickly but they or their progeny are long lived and are their to give you life long protection.

      Do antibodies play role in MS (a) Yes as plasma exchange is beneficial in some people and we know that some antiboides cause problems, for example if we inject them into health mice.

      Plasma cells are long lived

      If plasma cells die the antibody they produce should go to

      B cell depleting agents do not target Plasam cells as plasma cells do not express CD20 and so OCB persist.

  • Remyelination using glia progenitor stem cells

    Rats with human brains??? 🙂 🙂 🙂

    Starts at 2:17 min




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