Thursday, 8 June 2017

#ThinkSpeak: to find a cure we have to define what we mean by the term 'cure'

What will an MS cure look like? #ThinkSpeak 

Since the recent press article on curing MS I thought it would be useful to re-post some of my thoughts on this topic. There is nothing like some open thinking to generate discussion.

How will we know if we have cured MS?

The current thinking is that MS is an autoimmune disease of the central nervous system that is driven by focal inflammatory lesions. We think the MS lesion, or focal inflammation, is responsible for both acute (now) and delayed (in the future) neuronal loss. Permanent loss of neurological function (impairment or disability) is due to neuronal loss, which can be measured clinically (neurological and neuropsychological examinations), electrically (evoked potentials), on MRI (brain atrophy or loss of brain volume) and/or biochemically (spinal fluid neurofilament levels).

Acute Neuronal Loss (the Shredder or Scissors): Inflammation transects neuronal processes, or axons, acutely that results in loss of function. If the lesion is an eloquent site it causes a relapse. Loss of function is then restored by the surviving axons taking over the function of the lost axons, or other areas of the brain taking on new functions, we call this axonal and cortical plasticity, respectively. Recovery can only occur if there is sufficient reserve capacity. The accumulation of damage and ageing reduces reserve capacity, which explains why recovery from relapses tends to fail with more advanced disease and with age. This is why it is important to treat MS early so as to protect reserve capacity.

Delayed Neuronal Loss (Slow Burn): Neuronal processes (axons) that survive being transected are compromised and never recover fully. They may remain demyelinated, or if they are remyelinated the myelin sheath never gets back to what it was in health. In addition, the so called microenvironment within the chronic MS lesion is stressful to the axon. All this programmes the previously damaged axons to die off over time. This is why anti-inflammatory therapies that switch off the development of new focal inflammatory lesions may not prevent the delayed neuronal loss that characterises progressive MS. Even if we were able to cure MS as an autoimmune disease we may not be able to stop, or prevent, progressive disease from occurring in the future as it may already be programmed to occur from previous damage that has accumulated in the past. In other words progressive MS is like a ticking ‘time bomb’.

Premature ageing: We seem to forget that as we get older we lose brain this is what we call age-related cognitive, or neuronal, decline. From the age of 35 our brains start to shrink and our neuronal systems start to fail. The manifestations of this are not that subtle; how often do you battle to find the right word, or remember an important fact, only to find that your memory has failed you. Similarly, your balance is just not as good as it once was; you realise that you can’t put on your trousers standing-up unsupported and you have to resort to sitting down, or holding onto to a piece of furniture, for balance. If we all lived long enough we would all dement from natural ageing. Evolution never designed our brains to live as long as we are living today. What protects us from the ageing process is brain reserve; the more brain reserve we have the later we will present with our dementia. As MS reduces brain reserve we hypothesise that people with MS (pwMS) will notice age-related cognitive decline earlier than the general population. So even if we cure you of your MS you may still get a drop off in neuronal function earlier than expected that is simply due to ageing. However, this drop-off in neuronal function will interpreted as MS-, and not age-, related decline.

The insights above highlight some of the reasons why we started the ‘Brain Health: Time is Brain’ campaign and why it is going to be so hard to prove that we have cured MS. However, if we don’t define what a cure looks like we won’t find it. I am very aware that a lot of people in the field disagree with me on this.

Defining a cure in MS: Based on what I have said above you may be cured of our MS, but still have progressive disease. The difference between progressive disease that is due to previous damage and that which is due to premature ageing is that the former should burn-out, i.e. after a period of time your worsening disability should stop. In comparison, premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier would be easier. Importantly, a cure can only really occur in relation to PIRTs (pulsed immune reconstitution therapies), i.e. treatments given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity returns.

Let’s say we have treated a group of pwMS early in the course of their disease with a PIRT and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 15, 20 or 25 years? In the past I have proposed defining a cure as NEDA at 15 years post treatment as a starting point. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that should be accepted by the wider community; this may be wishful thinking many in the field are saying that we can’t cure MS therefore we should not be having this discussion. In addition, the average time to the onset of secondary progressive MS is ~14-15 years, so one would expect to see a significant proportion of people manifesting with SPMS in this timeframe if we had got the autoimmune hypothesis wrong; I estimate at least a third should have SPMS if our hypothesis is wrong. The problem with 15 years is that it is too long to wait; some pwMS want to know 'now' if a PIRT offers a cure, therefore we need data to convince the naysayers and laggards to support the ‘cure hypothesis’. Hopefully convincing data will change their minds and get them to at least offer PIRTs to their patients.

Deep phenotyping: We are therefore proposing to do a deep phenotyping project to look at pwMS who are NEDA-2 post-PIRT to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. We propose interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term to interrogate brain and spinal cord integrity in a lot of anatomical and functional detail to see if a PIRT has stopped ongoing damage and protected reserve function. At the same time we look for evidence of ongoing inflammation in the periphery and spinal fluid. 


One of the problems I am finding with pwMS who have had a PIRT and are now in long-term remission is that they forget that they have MS and get on with their lives. They disengage from the MS community; they stop reading MS blogs and stop coming to MS research meetings. In short these people act as if their MS has gone away; they act differently and start to believe they have been cured of MS. Therefore, I see the biggest problem of doing this study will be difficult recruiting subjects; who will want to take a day off work and come into a research unit to be interrogated in detail? Deep phenotyping will include quantitative neurological examinations, multiple questionnaires (PROMS), multidimensional MRI scans, a full set of sensory evoked potentials and central motor conduction times, detailed neuropsychological testing, a large number of blood tests and a lumbar puncture. The latter is to make sure spinal neurofilament levels are normal and to see if the oligoclonal bands (antibodies) have disappeared. I am hoping they will have disappeared. If we can show that the majority of the subjects in a PIRT cohort has stabilised with no evidence of progressive disease compared to the maintenance DMT group we may convince the field of the value of PIRTs. What do you think? Will you be convinced?  


CoI: multiple

29 comments:

  1. It makes sense that a partially or wholly demyelinated axon will degrade slowly over time. However, two studies on people with MS who have undergone HSCT show continued inflammation and demyelination. That is, it's not simply that axons that have already been damaged are degrading, it's that they're still actively being damaged and demyelinated. These were people who died after HSCT, sometimes a few months after, as much as a couple of years afterwards, of varying causes - sometimes related to HSCT, sometimes not. In all, continued demyelination and neuroinflammation was present. No demyelination was found in control groups (neurologically normal people who had undergone HSCT and died a time afterwards), although increased inflammation was found.

    If MS is an autoimmune disease, and PPMS is simply MS with a CNS ineffective at repairing itself, HSCT should halt PPMS taken early. There is no evidence of this. HSCT appears to halt disease in people with early RRMS, but perhaps it just masks the disease enough, or downregulates part of the disease enough that the RRMSers natural repair mechanisms are mostly enough to halt brain atrophy even if demyelination is still occurring albeit at a slower rate.

    ReplyDelete
  2. Also, I don't think the term NEDA-2 makes sense. Brain atrophy is evidence of disease activity. If you don't measure one of the ways the disease manifests itself, you can't really say anything about the disease activity. You can say that you looked at a small subset of the ways the disease manifests itself and didn't find anything, but you can't throw around terms like no evidence of disease activity; there may be plenty.

    ReplyDelete
    Replies
    1. NEDA-4 = brain atrophy, EDSS, Relapse, MRI lesion

      Delete
    2. Yep, I know, and that's the important measure. What I'm saying is that there should really only be "NEDA". NEDA-2 does not include brain atrophy, which is the most important measure of the disease. So it seems dishonest to be to talk of "no evidence of disease activity" at all when there may well be evidence of disease activity, you're just not measuring it.

      We shouldn't put numbers on the end of NEDA. NEDA is NEDA. If you look merely at relapses, for example, even Interferon beta-1a could probably give "NEDA-1" status to a considerable proportion of people over a relatively long time frame. People with SPSMS and PPMS would also ironically mostly be NEDA-1. But the concept of "NEDA-1" is, to me, a little bit silly, as is NEDA-2. NEDA, or EDA. There shouldn't be an in between.



      Delete
    3. NEDA is only as good on how hard you look...

      Delete
  3. Excellent post. I am 10 years post first Alemtuzumab infusion and have had no relapses, no sign of disease activity, and stable EDSS score. I think I would be happy to participate in your study. My only concern is a worry that you if you dig deep you will see some evidence of ongoing activity / damage. This would burst my bubble / current state of contentment.

    ReplyDelete
    Replies
    1. It could give you a chance to correct it though, for example with a neuroprotective and/or more immune therapy.

      Delete
  4. Trying to run before learning to walk?Thursday, June 08, 2017 11:46:00 am

    But this is all a bit theoretical still. We don't know that progression is not the core of the disease, not only the result of inflammatory damage.

    ReplyDelete
  5. There is no mention of effective monitoring of B & T cells which are targeted by PIRT. A cure would have to show that patients' lymphocytes no longer activate after stimulation with CNS antigens. Yes, neurodegeneration occurs after demyelination but this is secondary to the initiating and underlying pathology of lymphocyte dysregulation. If there is not a clear understanding of what defines MS then a cure may be moot.

    ReplyDelete
    Replies
    1. Inside outside inside outside inside outside...Thursday, June 08, 2017 4:40:00 pm

      but this is secondary to the initiating and underlying pathology of lymphocyte dysregulation

      It may not be though? Inside outside inside outside...

      Delete
  6. Prof G,
    How long after Alemtuzumab (the standard 2 courses one year apart) would you expect OCBs to disappear, if they were to at all?

    ReplyDelete
    Replies
    1. I think they persist. alemtuzumab does not get in the brain properly and siiiito deplete the plasma cells

      Delete
  7. In September 2003 a young woman fell ill. It began with a facial palsy, soon
    followed by weakness in a leg, pronounced fatigue and loss of vision. A
    diagnosis of multiple sclerosis was made. Although these symptoms got
    better, others more ominous took their place. She became paralyzed from the
    waist down and her bladder stopped working. She got treatment and again
    she got better for a while. However, this was just a short respite and by
    spring she was completely paralyzed.
    She was transferred to the University Hospital. At the darkest hour, she
    was offered a novel treatment. Hematopoietic stem cell transplantation. With
    little to lose and everything to gain, she accepted. None could have guessed
    at the outcome.
    A few days into procedure, she was able move her toes again, for the first
    time in two months. Rapid improvement followed. Some weeks after
    discharge, she could walk with a stroller. After three months she could walk
    unaided. After one year she was working part-time.
    Ten years later, she is living a normal life. She works full-time. She is the
    mother of two healthy children. She has no treatment. She has not had any
    relapses.
    Is she cured from multiple sclerosis?

    https://uu.diva-portal.org/smash/get/diva2:714003/FULLTEXT01.pdf

    ReplyDelete
  8. Table 3.3 Comparisons of natalizumab, alemtuzumab and HSCT.
    Natalizumab Alemtuzumab HSCT
    Follow-up time
    (months) 24 24 47
    AAR baseline 1.44 1.7 4.1
    AAR on study 0.34 0.26 0.03
    Freedom from
    relapses 54 % 65 % 87 %
    Freedom from
    disease no data 32 % 68 %
    Mortality 0 % 0.59 %
    (pooled data)
    0 %
    (pooled data 0.76 %)
    PML 0.2 % per annum
    (post-marketing data) n/a n/a
    This table compares data from the SENTINEL125 and CareMS-2126 trials with data
    from the Swedish experiences of HSCT for MSI. Pooled alemtuzumab data are from
    the CAMMS223,128 CareMS-1129 and CareMS-2126 studies, whereas pooled HSCT
    data are derived from the studies in table 3.1 and 3.2.

    ReplyDelete
  9. Multiple sclerosis is a gruesome disease. On average it takes ten years of
    life. Even today, the most severely afflicted will die in their middle age. Not
    only will life be significantly shorter, the final years will be spent in agony.
    As a neurologist, I have seen too many wither away in the heart of life.
    I sincerely believe that MS can be cured, and that we have the means to
    do it. Every year, some one thousand Swedes are diagnosed with MS.
    Currently, less than 1 % of them will be treated with hematopoietic stem cell
    transplantation. Why are so few patients treated?
    The difficulty of making an accurate prognosis is one serious obstacle.
    Even though we know that more than half of patients will end up with
    secondary progressive MS and severe disability, we cannot with any
    certainty identify who they are at diagnosis. Neither do we know what an
    adequate treatment response to conventional treatment isThe perceived peril of the procedure is another impediment. We are today
    very far from the close to 10 % treatment related mortality that was reported
    in early years. In fact, we saw no mortality or life threatening adverse effects
    among the Swedish patients. We have come to a point when adverse events
    occur so rarely, that they are hard to measure accurately.
    A third hindrance is that patients and neurologists adopt a wait-and-see
    approach to MS. It usually takes several years before MS start to manifest
    itself with permanent disability, and many patients and doctors do not take
    MS seriously until then. In fact, most of the requests for transplantation are
    self-referrals from patients with progressive disease and EDSS ≥ 6.
    These hurdles are not insurmountable. Newly diagnosed patients should
    be continuously and carefully monitored to evaluate disease activity and
    tissue damage. Non-trivial disease should be hit hard and hit early. Patients
    and doctors need to be educated, in order to disperse prejudices against the
    treatment. Data from a phase III trial would be helpful to convince the
    skeptics and to establish the therapy as a second line treatment. We are
    currently participating in one (ClinicalTrials.gov Identifier: NCT00273364).
    Meanwhile, every wheelchair is a failure and every premature death is a
    tragedy.

    ReplyDelete
  10. - Do you still have MS, I asked.
    - I want to say no, she said, but I dare not. Some of my friends who have
    gone through the procedure say that they had MS, but when I’m asked, I
    usually say that I still have it, but that it is inactive.
    - Do you still think a lot about your disease? I continued.
    - Not that much. In the beginning I thought about my disease all the time, but
    now many days can pass without me thinking about it. Then something
    comes along that reminds me of it, a scent or a tune, and then I am back
    again. Nevertheless, I consider myself lucky. I don’t think I would still be
    around if I hadn’t got the transplant. Ever since I got ill, I have celebrated
    two birthdays, my original birthday in November and my second birthday in
    May. That’s when I got the transplantation and life began anew. This year, at
    the 10th anniversary, I will have a real jamboree, to celebrate life. After that,
    maybe I’ll be able to let go. Then I’ll stop. No more celebrations…
    Ten years have now passed since those dreadful months when she fell ill and
    she has made an astonishing recovery. Even though we have carefully
    searched for signs of MS, we have found none. For all we now, she is cured
    of her multiple sclerosis. With time, perhaps she will be fully healed as well.

    ReplyDelete
  11. Four-year relapse-free survival was 80% and progression-free survival was 87%
    https://www.researchgate.net/publication/271219475_Association_of_Nonmyeloablative_Hematopoietic_Stem_Cell_Transplantation_With_Neurological_Disability_in_Patients_With_Relapsing-Remitting_Multiple_Sclerosis

    ReplyDelete
  12. With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new
    T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy
    controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained
    improvement in their Expanded Disability Status Scale score

    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30169-6/abstract

    ReplyDelete
  13. I believe I speak for many of us when I say that I consider this disease cured as when we remain relapse and progression free while taking medication without risk of serious side effects.

    ReplyDelete
  14. Sadly, I was diagnosed in January 2000 with benign MS but in a few years that became RRPMS and yet I was never treated with any DMTs, just drugs to relieve some of the symptoms. Within ten years I had 2PMS. Why did this happen so fast? Did I go to the wrong NHS hospitals? The best treatment I ever got was hydrotherapy. Now I've moved to the US and the first neurologist I saw was amazed that even at the benign stage nothing was done to slow the progression - they seem to act promptly here in Idaho. Now I face having the one form of MS without a DMT treatment. Where do I stand or rather park my wheelchair? If I was in the UK I'd probably be an interesting study case. Here in the US anything will cost me a lot of money.

    ReplyDelete
  15. I had no PIRT in 1965 when I had an acute episode..not available ...I then had 45 years of complete recovery and no further episodes . Recently my walking has deteriorated ...but that in my opinion poses many more questions which seem to be unanswerable.

    ReplyDelete
    Replies
    1. Tessa do you mind me asking your age when you were diagnosed and have you ever taken a DMT?

      Delete
    2. 16....ACTH gel during the episode which was complete paralysis from waist down for 6months. Total recovery, never saw a healthcare professional,again until three years ago now have the axonal loss and ageing .

      Delete
    3. How was it diagnosed? It could have been transverse myelitis caused by an infection, for example.

      Delete
    4. If I had received any of the current DMTs then I presume they would be posited as the reason for my complete recovery. This is the time dilemma

      Delete
  16. Omg people, when did the concept of a cure become so complicated?

    (Since science doesn't fully understand what causes irreversible disability in MS).

    MS = causes disability (permanent or temporary) that impairs people's ability to function and live their lives.
    Cure = stopping the creation and the accumulation of disability that impairs people's ability to function and makes them feel bad.

    Problem = you don't really know what causes it or how to stop it.

    Your solution = theorise about what a cure looks like?

    The moment you are able to stop disability in people with MS, you'll know what a cure is :)

    All this hype about hsct, lemtrada, ocrelizumab is blah blah blah blah blah. They are effective meds, great. Better with them then wihtout.

    But we'll miss the cure cos we don't know what it looks like?

    Please.

    ReplyDelete
    Replies
    1. This is actually pretty insightful.

      Since science has only a rudimentary knowledge of the enormous complexities of the brain and CNS how a cure is construed could indeed be way wrong.

      Perhaps cure is a wrongful term and clinical and research need consider the term remission. I know... I know... Lets add some confusion due to RRMS as a term.

      "My MS is in remission" sounds more accurate than "I am cured at 15 years."

      Yet, we really dont know what that cure looks like from a point of the biology but instead more one of measurements currently used.

      Another concern is using the term cure which is how this message thread came to be from the "oh no media at it again on another cure statement."

      If at 15 years this/that person is NEDA++ that does not constitute usage of the term "cure" which is a more broadband term that remission.

      A cancer patient may well have no more activity their entire lives but this does not warrant the term cure, instead, remission.

      MS being construed as autoimmune or immune mediated may well all wind up with some dung on the fan if the research connecting the brain to the immune system proves to be true.

      The pathology of MS and in fact neurodegenerative disease/disorders may well be off based on the results of that research. On the other far side of the spectrum is most brain disease researchers are well aware of pathologies, results and science thereof. They tend however not be aware of how complex actual neural network function is in the brain as science is not even close yet.

      I've said this before... We live in a world that likes the term multitasking. Multitasking is a software engineering term. Multitasking is not how the human brain is set up to operate. Not using the machine in the way it harmoniously is meant to operate induces stress. Stress on the machine, stress on the individual the machine operates upon.

      Medications are used to mask forms of stress caused due to multitasking +/- lifestyle. They do NOT solve the stress.

      Point being, neural networks be they simulated by computers or in the real world of living creatures w/ neurons are authored in a way to be harmonious. The moment that goes out of whack correction is in order.

      Current science has only scraped the surface of low-level / high-level (and between) brain function in real-time. As networks fail, just as in simulated software, networks downstream will fail. The result is degradation, a cascade... These cascades require further correction.

      Delete
    2. Thinking might be along the lines of new new inflammation, no difference in atrophy in comparison to populations w/o MS, no CSF biomarkers, no significant increase in disability accrual.

      But that doesnt work.

      Failed neural networks will cascade and presently there is no mechanism science can readily employ to see this in the real world in patients.

      Science describes neuroplasticity in respect to cognitive reserve yet really is not all too aware of process. The how's and why's the brain can be so versatile. When it runs out, "pfffttt..." change.

      Certainly there are finite resources and regenerative medicine or the bodies natural abilities to regenerate provide hope. But is that where it all at?

      Uh uh...

      Understanding how this enormously complex brain works is paramount. At the sametime we have governance that doesnt want that. Hence why "dumbing down" populations on more effective use of the brain is not taught.

      Point all being, what the poster above stated is important.

      The term cure and what it represents needs be looked towards on both sides... Start to bottom, not simply based on a result that spans time .vs. true science, understanding thereof as well as no signs of clinical activity.

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.