Wednesday, 17 July 2013

Article of interest: inflammation the brain shredder

How do you feel about having a shredder in your brain? #MSBlog #MSResearch

"A lot of readers don't like me using the analogy of a paper shredder when referring to the effects of inflammation on the brain of someone with MS. The classic paper of Bruce Trapp and colleagues explains using beautiful pictures and hard data how damaging focal inflammation is in the brain of someone with MS. In each cubic millimeter of an actively inflammed MS lesions over 11,000 axons were transected or shredded compared to less than 1 axon in a control subject. 11,000 to 1 that is the ratio you need to keep in your head. This is why it is so important to suppress inflammation in the brains of MSers to stop the inflammation from shredding your axons. The problem is that once these axons are shredded they very little chance of recovering. Now you need to scale  this damage up several orders of magnitude as most MS lesions are larger than 1 cubic millimeter, i.e. in the order of 1 cubic centimeter or 1000 cubic millimeters, to get a sense of the magnitude of the shredding that is occurring in MSers with active disease. This is why I am such an active proponent of anti-inflammatories in MS, this includes RRMS and progressive MS; and is why in the PROXIMUS trial we are adding neuroprotective drugs on top of existing anti-inflammatories. I would go as far as stating that I doubt an a pure neuroprotective drug will work in MS unless it has anti-inflammatory properties or is added on top of an existing anti-inflammatory drug. Don't let anyone fool you into believing that progressive MS is non-inflammatory; the brains of progressive MSers, both SPMS and PPMS, are stuffed full of inflammatory cells."

Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338(5):278-85.

BACKGROUND: MS is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most MSers have progressive neurologic deterioration that may reflect axonal loss. Bruce Trapp and colleagues conducted pathological studies of brain tissues to define the changes in axons in MSers.

METHODS: Brain tissue was obtained at autopsy from 11 MSers and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions.

RESULTS: Transected axons were a consistent feature of the lesions of MS, and their frequency was related to the degree of inflammation within the lesion. The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions, 3138 at the hypocellular edges of chronic active lesions, 875 in the hypocellular centers of chronic active lesions, and less than 1 in normal-appearing white matter from the control brains.

CONCLUSIONS: Transected axons are common in the lesions of MS, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.

This picture is embedded from http://www.nejm.org/doi/pdf/10.1056/NEJM199801293380502
A picture tells a thousand words: 
  1. The axonal structure is green in this image and represents neurofilaments the scaffolding that supports axons. 
  2. In panels B & C red indicates myelin. 
  3. When green and red are overlaid you get yellow and this indicates myelinated axons. 
  4. In panels D and E red stains macrophages or microglia the cells that clear up the myelin debris; the so called garbage collectors. 
  5. Panels A and D show the centers of active lesions. 
  6. Panels B, C, and E show the edges of active lesions. 
  7. Panel A shows green bulbs or terminal axonal ovoids with single axonal connections (arrows), an axonal ovoid with dual axonal connections (arrowhead), and many normal-appearing axons. 
  8. Panel B shows three large, green (neurofilament–positive) axons undergoing active demyelination (arrowheads). One axon ends in a large terminal ovoid (arrow). 
  9. Panel C shows some axons (green) terminating at the ends of normal-appearing myelin internodes (arrow), and many axons that express neurofilaments surrounded by normal-appearing myelin (arrowheads). 
  10. In Panels D and E, macrophages (red in Panel D) and microglia (red in Panel E) surround and engulf terminal axonal swellings (large arrows) but have no consistent association with normal-appearing axons (arrowheads) or swellings in nontransected axons (Panel E, small arrow).

"Can I suggest we have a vote on the shredding analogy to describe the effects of inflammation on the brains of MSers? I want to reiterate  that I did not coin the term it came from the script of The West Wing, the popular TV series." 

Abbey Bartlet: We had a deal!

President Josiah "Jed" Bartlet: Yes, we had a deal.

Abbey Bartlet: Yes, Jed. Look at me! Do you get that you have M.S.?

President Josiah "Jed" Bartlet: Abbey...

Abbey Bartlet: Do you get that your own immune system is shredding your brain? And I can't tell you why. Do you have any idea how good a doctor I am and that I can't tell you why?

President Josiah "Jed" Bartlet: I've had one episode in two years.

Abbey Bartlet: Yes, but relapsing-remitting M.S. can turn into secondary-progressive M.S. oftentimes ten years after the initial diagnosis which is exactly where we'll be in two years! Do you know what that's going to look like if it happens?

Abbey Bartlet: Memory lapses, loss of cognitive function, failure to reason, failure to think clearly. And I can't tell you if it's going to happen. I don't know if it's going to get better, I don't know if it's going to get worse. But we had a deal. And that deal is how you justified keeping it a secret from the world. It's how you justified it to God... It's how you justified it to me.

26 comments:

  1. Figure B is the Brooklyn bridge of MS.

    I have noticed that every film/TV show made in New York tends to have a few pictures of Brooklyn bridge.

    So any talk about MS pathology always tends to use picture B

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  2. It's a very painful analogy but I hope it catches on.

    Nobody allows cancer free rein in their bodies on the grounds that I'm doing fine so far & don't need unsafe aggressive treatment yet.
    No oncologist would dare to say something like that to a patient.

    But many MS patients still say they will save the aggressive treatment for when it is really needed. And neurologists still say Your's may be benign, let's put safety first, etc

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    1. The shredder analogy also forces a realisation of how urgent it is to get onto treatment as soon as possible. It will change everybody's attitudes, including that of the NHS/NICE etc

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  3. Prof G this is the most profound post this blog has done. Although the shredder analogy may not be original it gets to the heart of MS and makes the point that we need to be treated ASAP. My guess in that not many people are going to like this post, but as you said you can't live with your head in the sand when MS is doing this to your brain. Bring on the big guns I am ready for any poison you think I need.

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    1. Absolutely agree. It has to recognised that MSdoes shred brains and therefore disability takes over. Goodbye occupation, goodbye some relationships , and so and and so forth.

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    2. Which is why Prof. G is promoting early aggressive treatment. Hopefully this will prevent the devastating consequences of untreated MS.

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  4. Good. Now everyone seems to agree that the brain is shredded by MS (unpalatable as that is), we now need to mobilise to make sure that MSers get access to highly effective DMTs to slow this down and also add to the impetus generated in getting neuroprotective therapies for MSers established.

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  5. This is just pure semantics and won't change a thing. Why don't we just call it the plague or something like dementia sclerentia? That would be cooler and perhaps get more media attention.

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    1. Another MSer with their head in the sand. We need to take this seriously. MS is a serious and debilitating disease we can't ignore it and if we have treatments that can prevent or delay the consequences we need access to them.

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  6. Love this. What antiinflammatories should I be on w SPMS?

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    1. I can think of a few...but evidence based is the mantra so can't give my thoughts.

      Anti-inflammatories not T cell immunosuppressives

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    2. or B cell immunosuppressives.

      Rituzimab has been tried in progressive MS with some success, but it seems to be the relapsing, Gd-enhancing subset that responsed

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  7. Love this. What antiinflammatories should I be on w SPMS?

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  8. A very scary message. I wish I knew about this earlier I would have been more proactive about treatments.

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  9. MSer's he is not going to give up unless we stop giving the "wrong" answers to his questions... but I think it's just semantics and am disappointed by the continual reverential reference point of an American fictional tv show. The use of "Shredding" reduces a serious, progressive condition to wild-eyed, juvenile analogies.

    What's happening is on-going brain damage (why aren't we allowed to call it this) and the fact that :
    a) there is masses of evidence about the damage in the early stages of CIS / MS and
    b) imaging now allows greater visualisation of the damage seems to have past most neurologists by - it is those people that need to be convinced of the need to monitor better and prescribe DMT's earlier and appropriately. NICE is not preventing them doing this.

    Sure there also needs to be pressure put on NICE and the wider NHS, but is hysterical language really going to help influence those people ??

    Is it seeking to use the same techniques as the CCSVI brigade who re-named the angioplasty procedure "Liberation" ?

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    1. Not sure if the CCSVI analogy is fair; too many people think MS is a benign or relatively benign disease. Using terms such as dementia and shredding focuses the mind. As a term damage does not have much impact; the difference between the message being ignored and being notice is not trivial. The fact that we are debating it means it is having some effect. Let's focus on the issue at hand; inflammation is bad and we need to access effect treatments to suppress it.

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    2. Liberation therapy? If only. What planet are you on? NICE won't allow us to access effective therapies because they are too expensive or too dangerous. If it means changing the name of a disease process to make it more emotional so be it; shredding sounds so much more urgent than damage. The good news is that it appears some of the treatments may work at switching off the shredder. Is this not good news?

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    3. Anon 4:43 I haven't personally come across anyone who seems to believe MS is a relatively benign disease - whenever I tell anyone what's wrong with me (apart from a stick I have few visible symptoms) I get a shocked face and an expression of sorrow for me, much akin to the reaction people get from sharing the news they have cancer.

      Brain damage does not in any way sound trivial.

      Anon 5:47 I am not advocating CCSVI. I have been on Tysabri (and am JC+ so am all too aware about dangerous treatments). The key word in your last sentence is "MAY".

      I want my brain damage to stop, and ideally want something to re-myelinate those areas already damaged. But I also need to keep my job for as long as possible as I have a family to support. I have already had to overcome prejudice about what MS means for my employability and think juvenile words like "shredder" are going to fan the flames of prejudice much quicker than encouraging NICE to change it's policies.

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  10. Sadly, semantics is important. It goes hand in hand with effective marketing and advertising, no matter how much we like to think it doesn't. Just about everyone knows what the pink ribbon stands for, hands up who hasn't heard of Prozac, and on and on and on. (And why do you think so much of big Pharma's budget is spent on marketing programmes?)

    People can do a double-take when you say you have brain damage, I know, because I have used this to try and shock others into paying attention when I have tried to get them to understand that I know need time to write information down. (I might also have used it on occasion to explain away when I have said something inappropriate or offensive, albeit funny, though with less success.)

    And just to throw something else into the pot - if one of the strands behind this re-branding is to emphasise that aggressive treatment can help keep people economically active, and should therefore be part of the bottom-line (money talks, it just does), then perhaps something that has been holding us back is that MS is more prevalent among women, aside from the common misconception that it is something that only women get. Putting it very crudely, and to deliberately upset people, MS doesn't interfere with baby production (get pregnant, and repeat, to hold off those nasty symptoms), which is a 'good' thing. And women do have less economic earning power, so the loss of women, during their child-bearing years, from the market place, isn't perhaps taken quite as seriously.

    ........and discuss....... but please be kind, after all, I have got brain damage you know! ;)!

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  11. Good point mossy.

    Sorry to hijack, but back to a question raised earlier inthe post, what anti inflammatories are there for SPMS? Are there any?

    Thanks

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    1. As far as I know there is not much evidence that anti-inflammatories are much use in SPMS. However Novartis are doing a trial on siponimod, which is a fingolimod derivative in SPMS at the moment.

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    2. MD has different opinion, see comment above

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    3. But with the proviso that it's in a subset of patients that are still having relapses as measured by gadolinium enhancement MRI not in those who no longer had relapses.

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    4. I see I am causing confusion and this is the problem about talking about inflammation

      MD2 was taking the tack of immunosuppressives which block white blood cell function are of course anti-inflammatory and these have not been shown to work in progressive MS unless it is relapsing/gadoinium progressive.

      However some drugs that may be neuroprotective and useful for progression may block glial cell function by say blocking mediators and are therefore also anti-inflmmatory, but work on a different part of inflammation to the immunosuppressives.

      I will not give examples

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  12. Interferon-beta-1b is licensed in Europe for MSers with SPMS and ongoing relapses. Siponimod (Fingolimod me too) and Natalizumab are being tested in SPMS. We need to wait and see what happens. Unfortunately, by the time MS has entered the SPMS stage so much damage has been done that there is no reserve capacity left in affected pathways therefore any further damage causes worsening of symptoms. This is why we need to treat early, before this phase, to maximize the effectiveness of treatments.

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